SEPTEMBER 2016

Vol. 37 No. 9
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Acid-Base Disorders
Hsu, Lakhani, Wilhelm

Evaluation and Initial

Management of Hypopituitarism
Pierce, Madison

Chronic and Recurrent

Abdominal Pain
Hyman

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Spoon Nails and Short, Brittle
Hair in a 3-year-old Boy
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contents

Pediatrics in Review ®
Vol. 37 No. 9 September 2016

Editor-in-Chief: Joseph A. Zenel, Sioux Falls, SD

Deputy Editor: Hugh D. Allen, Houston, TX
Associate Editor, Index of Suspicion: Philip R. Fischer,
ARTICLES Rochester, MN
Associate Editor, Index of Suspicion: Deepak M. Kamat,
361 Acid-Base Disorders Detroit, MI
Associate Editor, Visual Diagnosis: Mark F. Weems,
Benson S. Hsu, Saquib A. Lakhani, Michael Wilhelm Memphis, TN
Associate Editor, In Brief: Henry M. Adam, Bronx, NY
370 Evaluation and Initial Management of Associate Editor, In Brief: Janet Serwint, Baltimore, MD
Hypopituitarism Associate Editor, CME: Rani Gereige, Miami, FL
Editorial Fellow: Aamir Jeewa, Houston, TX
Melinda Pierce, Lisa Madison Early Career Physician: Heather Campbell, Washington, DC
Editor Emeritus: Lawrence F. Nazarian, Rochester, NY
377 Chronic and Recurrent Abdominal Pain Founding Editor: Robert J. Haggerty, Canandaigua, NY
Paul E. Hyman Managing Editor: Luann Zanzola
Publications Editor: Sara Strand
INDEX OF SUSPICION Medical Copyediting: Deborah K. Kuhlman

391 Case 1: Constipation, Irritability, and Poor EDITORIAL BOARD

Robert D. Baker, Buffalo, NY
Feeding in 2-month-old Boy Peter F. Belamarich, Bronx, NY
Nidhi A. Shah, Henry C. Lee Eyal Ben-Isaac, Los Angeles, CA
Theresa Auld Bingemann, Rochester, NY
394 Case 2: Acute Respiratory Distress and Facial Stephen E. Dolgin, New Hyde Park, NY
Lynn Garfunkel, Rochester, NY
Petechiae in a 4-month-old Boy Rani Gereige, Miami, FL
Alpa Patel Shah, Mary Lu Angelilli Nupur Gupta, Boston, MA
Gregory A. Hale, St. Petersburg, FL
397 Case 3: Sore Throat and Fever in a Thomas C. Havranek, Bronx, NY
Jacob Hen, Bridgeport, CT
4-year-old Boy Jeffrey D. Hord, Akron, OH
Katsuaki Kojima, Melissa Rosenberg, B. Keith English Neal S. LeLeiko, Providence, RI
Michael Macknin, Cleveland, OH
399 Case 4: Two Black Eschars in a 6-year-old Girl Susan Massengill, Charlotte, NC
Carrie A. Phillipi, Portland, OR
Zachary Graff, Geronimo Mendoza, Apurv Barche, Curtis Turner Peter Pizzutillo, Philadelphia, PA
Mobeen Rathore, Jacksonville, FL
IN BRIEF Jennifer S. Read, Rockville, MD
402 Pulse Oximetry and the Neonate E. Steve Roach, Columbus, OH
Sarah E. Shea, Halifax, Nova Scotia
Philip Roth Andrew Sirotnak, Denver, CO
Miriam Weinstein, Toronto, ON
405 CME Quiz Corrections
PUBLISHER: American Academy of Pediatrics
ONLINE Mark Grimes, Director, Department of Publishing
Joseph Puskarz, Director, Division of Journal Publishing
e38 Visual Diagnosis: Spoon Nails and Short,
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One

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Not everyone does.

ones
While rare, once meningococcal disease strikes, it can cause death in
10%-15% of patients in as few as 24 hours. Some patients consider
themselves lucky to have survived. However, 20% of survivors suffer
permanent consequences, including lost limbs, hearing loss, kidney
failure, and neurologic damage.1-5

Adolescent patients need 2 vaccines to help protect against the

5 vaccine-preventable serogroups—A, C, W-135, Y, and B. 1

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References: 1. Preteens, teens need meningococcal vaccine. Centers for Disease Control
and Prevention website. http://www.cdc.gov/features/meningococcal/. Updated October 22,
2015. Accessed April 8, 2016. 2. Thompson MJ, Ninis N, Perera R, et al. Clinical recognition
of meningococcal disease in children and adolescents. Lancet. 2006;367(9508):397-403.
3. Meningococcal disease. In: Hamborsky J, Kroger A, Wolfe S, eds. 13th ed. Epidemiology
and Prevention of Vaccine-Preventable Diseases. Washington, DC: Public Health Foundation;
2015. http://www.cdc.gov/vaccines/pubs/pinkbook/mening.html. Accessed March 11, 2016.
4. Slack R, Hawkins KC, Gilhooley L, et al. Long-term outcome of meningococcal sepsis-
associated acute renal failure. Pediatr Crit Care Med. 2005;6(4):477-479. 5. Vyse A, Anonychuk
A, Jäkel A, et al. The burden and impact of severe and long-term sequelae of meningococcal
disease. Expert Rev Anti Infect Ther. 2013;11(6):597-604.

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AUTHOR DISCLOSURE Drs Hsu and Lakhani
have disclosed no financial relationships
relevant to this article. Dr Wilhelm has
disclosed that he holds stock in Inovio
Pharmaceuticals. This commentary does not
contain discussion of an unapproved/
investigative use of a commercial product or
device.
Acid-Base Disorders
Benson S. Hsu, MD, MBA,* Saquib A. Lakhani, MD,† Michael Wilhelm, MD‡
*Pediatric Critical Care, University of South Dakota, Sanford School of Medicine, Sioux Falls, SD.
†
Pediatric Critical Care, Yale School of Medicine, New Haven, CT.
‡
Pediatric Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Education Gap
To treat critically ill children, a physician must have a clear understanding
of acid-base balance.
Objectives After completing this article, readers should be able to:
1. Describe the mechanisms regulating acid-base physiology and identify
blood gas abnormalities associated with an acid-base imbalance.
2. Recognize the differential diagnosis and clinical and laboratory
features associated with metabolic acidosis and metabolic alkalosis as
well as how to manage each appropriately.
3. Calculate an anion gap and formulate a differential diagnosis
associated with various anion gap values.
4. Identify factors contributing to compensatory changes associated with
primary metabolic and respiratory acidoses and alkaloses.
INTRODUCTION
The body’s ability to maintain acid-base homeostasis is based on a complex set of
interactions between the respiratory and metabolic systems. This article reviews
normal acid-base physiology and examines disorders of acid-base imbalances, first
within a primary metabolic cause and then within a primary respiratory cause.
Covering the complex nuances of acid-base control within a limited-scope
review article is impossible. Thus, this article focuses on the traditional model
based on the Henderson-Hasselbalch equation rather than the strong ion (or
Stewart) model, which explores the difference between all the dissociated cations
and anions. Using the traditional model, the authors explore the various meta-
bolic and respiratory disturbances while addressing the implications of the anion
gap on metabolic acidoses.
REGULATION OF ACID-BASE
The Henderson-Hasselbalch Equation
Homeostatic control of acid-base balance is critical for all metabolic and phys-
iologic functions of the human body. The Henderson-Hasselbalch equation
Vol. 37 No. 9 SEPTEMBER 2016 361
 describes the relationship between pH and the bicarbonate ranges and not independently examine any of the variables.
buffering system (the predominant buffering system in For example, a blood gas with a high PCO2 may reflect a normal
plasma) to establish this homeostasis: pH and should be interpreted as nonacidotic (Table 1).

The Anion Gap

CO2 þ H2 O4H2 CO3 4Hþ þ HCO
3
Use of only the Henderson-Hasselbalch equation is insuf-
 
pH ¼ pK þ log HCO =H CO ficient to describe a patient’s metabolic acid-base state com-
3 2 3
pletely. The anion gap further describes the interactions of
the measured positive charges (cations) and negative charges
When accounting for H2CO3, the modified equation
(anions) to the unmeasured charged particles. The anion gap
becomes:
  equation is based on the understanding that the cations in the
pH ¼ pK þ log HCO
3 =½0:03∗Pco2  plasma balance the anions in the plasma at equilibrium.
The “measureable” positive and negative charges in the
Examination of the modified equation reveals the impor- serum refer to those measured with a standard electrolyte
tance of bicarbonate ion (HCO 3 ) and dissolved carbon
panel. To calculate the anion gap, positive charges include
dioxide (PCO2) in the determination of pH. The pK is the sodium (Naþ) and potassium (Kþ) while negative charges
pH at which the bicarbonate ion (HCO include bicarbonate (HCO 
3 ) and chloride (Cl ). In normal
3 ) and carbon
dioxide (CO2) are equal. This value is approximately conditions, the measured cations exceed the measured
6.35. The 0.03 constant is used to describe the PCO2 anions (the normal anion gap), which is predominantly
solubility. When changes occur in the pH due to PCO2 accounted for by the serum proteins. This normal value
changes, the predominant system involved is the respira- for the anion gap ranges from 12 to 20 mEq/L (12–20
tory system. When changes in pH occur due to changes in mmol/L) when the Kþ concentration is included and 8 to
HCO 3 , the predominant system involved is the metabolic
16 mEq/L (8-16 mmol/L) when it is not included.
system. However, the system favors the HCO
   
3 at physiologic 
Anion  Gap ¼ Naþ þ Kþ  HCO
3 þ Cl
pH, therefore, the buffering ability of the metabolic system
is dependent on the body’s ability to eliminate CO2 through
In the setting of low serum protein, such as hypoalbumi-
the respiratory system. Thus, it is evident that two comple-
nemia, the normal unmeasured anions are decreased and
mentary systems, respiratory and metabolic, are used to
the anion gap narrows. Thus, with critical illness when
describe changes to the body’s pH.
protein concentrations are often low, an elevated concen-
Clinically, the acid-base state is normally determined by
tration of unmeasured anions can frequently be masked
a blood gas sample. Although the gold standard remains
by an apparently normal (falsely low) anion gap. Conse-
arterial blood gas measurement, use of the venous or
quently, the combination of the modified Henderson-
capillary blood gas sample is prevalent within the pediatric
Hasselbalch equation and the anion gap calculation begins
population due to the relative ease in obtaining these sam-
to illustrate an individual patient’s acid-base balance.
ples. Although minor differences exist within pH and PCO2
among the different blood gas sample types, these differ-
ences can be accounted for during interpretation by assum-
ing expected slight increases in PCO2 and decreases in pH
TABLE 1. General Reference Ranges for Arterial
for venous samples. As expected due to the location of the
blood draw, venous blood gas samples are unreliable for PO2
and Venous Blood Gases
measurements. Because capillary blood gradually transitions ARTERIAL VENOUS
between arterial and venous states, the PCO2 and pH norma-
pH 7.38 – 7.42 7.36 – 7.38
tive values often are between the arterial and venous norma-
tive values. Of note, a blood gas machine measures the pH PO2 (mm Hg) 80 – 100 30 – 50
and the partial pressure of the gases, but the HCO 3 ion PCO2 (mm Hg) 38 – 42 43 – 48
concentration is a calculated value. HCO 22 – 24 25 – 26
3 (mmol/L)
In examining blood gases, acidosis occurs when the pH
value is lower than normal. In contrast, alkalosis occurs HCO 3 ¼bicarbonate, PCO2¼partial pressure of carbon dioxide, PO2¼ partial
pressure of oxygen. Reference normal values are laboratory-dependent
when the pH value is higher than normal. It is important to and may vary due to differing techniques.
characterize pH in context of PCO2 and HCO 3 reference

362 Pediatrics in Review

 The human body has a natural inclination toward a desired
equilibrium, which accounts for the common finding of
compensatory changes in the opposite direction. Within set-
tings of respiratory derangement leading to changes in the
pH, the compensatory mechanism occurs within the meta-
bolic system. For respiratory acidosis (commonly arising due
to an increase of PCO2), the body compensates by creating
metabolic alkalosis (from a retention of HCO 3 ). In contrast,
for respiratory alkalosis (commonly arising from a decrease
of PCO2), the body compensates by creating metabolic acidosis
(from a loss of HCO 3 ) (Table 2). Metabolic compensation to
respiratory derangements often takes hours to days to estab-
lish. In comparison, compensatory mechanisms within the
respiratory system for primary metabolic derangements gen-
erally occur more rapidly, often over minutes to hours.
ASSESSMENT AND DETERMINATION OF
ACID-BASE STATE
The first step in the assessment of an acid-base imbalance
for a patient is to determine a primary respiratory versus
primary metabolic etiology. A detailed history and compre-
hensive physical examination can offer clues to the present-
ing cause. Such evaluation may reveal a neurologic (head
injury, seizures), respiratory (pneumonia, congenital mal-
formation), cardiovascular (septic shock, myocarditis), gas-
trointestinal (diarrhea, ingestion), or renal cause (chronic
kidney injury, underlying renal disease) of the imbalance.
For example, respiratory compromise from a neurologic
cause such as seizures or traumatic brain injury leading to
reduced consciousness may result in the body’s inability to
ventilate properly. This prompts a primary respiratory aci-
dosis. In comparison, gastrointestinal causes can result in
primary metabolic alkalosis such as through loss of hydro-
chloric acid (HCl) by vomiting.
TABLE 2. Generalized Primary and
Compensatory Relationships Between
HCO3 and PCO2
PCO2 HCO
3 normal saline are delivered to a patient who has metabolic
Respiratory Acidosis [ (primary) [ (compensatory)
Respiratory Alkalosis Y (primary) Y (compensatory)
Metabolic Acidosis Y (compensatory) Y (primary)
Metabolic Alkalosis [ (compensatory) [ (primary)
HCO
3 ¼bicarbonate, PCO2¼partial pressure of carbon dioxide
Extending from this initial assessment, additional clues from
results of blood gas analysis and a basic metabolic panel reflect-
ing the anion gap can help discern a primary metabolic versus
respiratory cause. Determining the acute or chronic nature of the
compensation adds additional diagnostic information.
METABOLIC ACIDOSIS
A combination of the anion gap calculation and knowledge of
the pH state within the body is required to describe metabolic
acidosis. The regulation of the acid-base state, as noted by the
Henderson-Hasselbalch equation, is based on the buffering
effect of HCO 3 . However, from an electroneutrality view-
point, use of the anion gap calculation can further differentiate
causes for the metabolic acidosis. Because reference values in
the calculation of unmeasured anions or anion gap vary
among laboratories, clinicians must be aware of normal values
for the laboratories they use. As noted previously, due to the
importance of homeostasis, normal gap versus increased gap
acidosis indicate vastly different clinical pictures.
Hyperchloremic (Non-anion Gap) Metabolic Acidosis
Chloride (Cl) has an important relationship to HCO 3
because there are few causes of non-anion gap acidosis.
In acidotic states with low HCO 3 values, a non-anion
gap acidosis state (or a normal anion gap) can exist through
the buffering effect of Cl and is termed hyperchloremic non-
anion gap acidosis. In these conditions, the relative ratio of the
anions and the cations remains intact, with the anions bal-
anced by an increase of Cl equal to the decrease in HCO 3 .
Non-anion gap acidosis can result from decreased HCO 3
either through gastrointestinal or renal losses. Both of these
types of losses result in a buffering with Cl ions. Gastro-
intestinal (postpyloric) losses include diarrhea and conditions
such as short gut syndrome. Renal losses include chronic
renal insufficiency and renal tubular acidosis.
A common type of hyperchloremic non-anion gap aci-
dosis occurs in the hospitalized patient who receives infu-
sions of large amounts of normal saline. In these cases, the
relative Cl load from the exogenous fluid results in a
decrease in HCO 3 to maintain plasma electroneutrality.
Often this phenomenon occurs when large amounts of
acidosis attributed to dehydration or starvation (presumed
due to lactic acidosis from hypoperfusion or ketoacidosis
from starvation). These initial metabolic acidosis states
generally are high-anion gap acidoses, with an imbalance
in the plasma electroneutrality state due to the contribution
of lactic acids and ketoacids. Following a large infusion of
normal saline, the anion gap resolves, but there may be a
Vol. 37 No. 9 SEPTEMBER 2016 363
 decrease in HCO 3 values due to the addition of large amounts
of Cl. Thus, clinicians who do not take into account the anion
gap when assessing the acid-base status after fluid resuscita-
tion can be deceived into thinking that the acidosis state has
worsened by examining only the HCO 3 value. Instead, the
presence of a normal anion gap (especially if the patient
previously exhibited gap acidosis) following hydration with
normal saline indicates an improving clinical condition.
Although the evidence is unclear regarding whether hyper-
chloremic non-anion gap acidosis from saline resuscitation
worsens outcome, clinicians who understand the physiology
may avoid this sequela as much as possible to limit possible
adverse effects (eg, increased respiratory work or increased
intracranial pressure).
Elevated Anion Gap Acidosis
The presence of an increased gap acidosis (anion gap higher
than normal) is due to an increase of unmeasured anions.
This can occur following an increase in acid production or an
underexcretion of acid. The classic mnemonic for causes
of gap acidosis is MUDPILES (methanol, uremia, diabetic
ketoacidosis, paraldehyde, isoniazid, lactic acidosis, ethylene
glycol, salicylates). Although most causes on this list repre-
sent exogenous ingestion of acids, physiologically high-anion
gap acidosis due to increased production of endogenous acids
is more common. The 2 primary sources for such endoge-
nous production are lactic acidosis and ketoacidosis.
Lactic acidosis can be due to a hypoxia event or shock
state, among other causes. Cells produce lactic acid when
energy creation shifts from aerobic to anaerobic metabo-
lism. Although this most commonly occurs when tissue
oxygen delivery falls to a critical level, anaerobic metabo-
lism and increased lactic acid production can also occur in
hypermetabolic states. Lactate can be produced from cells
in the brain, skeletal muscle, and gastrointestinal tissue
exposed to hypoxia. The cause of the hypoxic state can be
multifactorial. For example, direct hypoxia such as drown-
ing or respiratory failure may result in lactic acidosis. In
addition, the failure of mitochondrial function, as occurs in
cyanide poisoning, can lead to anaerobic metabolism and
the subsequent creation of lactic acid. Salicylate toxicity
similarly causes failure of oxidative phosphorylation that
creates subsequent lactic acidosis.
Ketoacidosis occurs in diabetic ketoacidosis or after a
prolonged starvation state. In those who have diabetes, the
inability to produce insulin results in a state of cellular
starvation due to the body’s failure to use glucose. Conse-
quently, the body resorts to the breakdown of lipids, produc-
ing ketoacids. True starvation states in which a glucose source
is limited also move the body toward breakdown of lipids
364 Pediatrics in Review
and creation of ketone bodies. Complicating the diabetic ke-
toacidosis state is the presence of hyperglycemia (from an
inability to transport glucose intracellularly), which leads to high
serum osmolality. The resultant osmotic diuresis can progress
to hypovolemic shock and lactic acidosis from anaerobic metab-
olism due to hypoperfusion.
Less commonly, underexcretion of acid leading to gap
acidosis can occur from renal failure or impaired clearance
of acid (lactate) through the liver due to liver failure. Other
causes of gap acidosis include inborn errors of metabolism,
and ingestion of toxins, such as those represented in the
mnemonic MUDPILES, leading to acid formation.
Respiratory Compensation
When exposed to a low pH from metabolic acidosis, the body
responds with an alkalotic respiratory state through hyper-
ventilation. This response can occur over minutes to hours,
depending on an intact neurologic response and the ability of
the body to maintain hyperventilation. Through hyperventi-
lation, the body reduces the PCO2 within the system, thereby
creating respiratory alkalosis. The respiratory alkalosis com-
bined with the primary metabolic acidosis works to return the
body’s pH back to (but never past) normal.
The classic example of a respiratory compensation to
metabolic acidosis is the diabetic ketoacidosis state. Affec-
ted patients often present with deep hyperventilation, called
Kussmaul breathing. The deep and fast breathing pattern
serves to increase the minute ventilation by increasing both
the volume of each breath (tidal volume) and the number of
breaths (rate) in a minute. In these cases, neurologic injury can
limit the compensatory mechanism for the metabolic derange-
ment. Specifically, with severe diabetic ketoacidosis, cerebral
edema is one sequela that may result in an inability to direct
an appropriate respiratory compensation. When neurologic
injury occurs, the patient may have severe acidosis without an
appropriately low PCO2 as the respiratory system attempts to
buffer the metabolic acidosis.
METABOLIC ALKALOSIS
Metabolic alkalosis, as revealed by the Henderson-Hasselbalch
equation, is due to an increase in the HCO 3 content of the
serum, resulting in an increase in pH. The causes include
gastrointestinal or renal losses of Cl. Gastrointestinal losses
can occur through profuse amounts of emesis or Cl-losing
diarrhea. Renal tubular losses can occur through the use of
diuretics. The subsequent compensation to the Cl loss de-
signed to maintain electroneutrality is to increase the amount
of HCO 3 buffer, leading to a higher pH. Similarly, a net gain
of cations can also result in metabolic alkalosis. Causes
include large amounts of lactated Ringer solution and the
milk-alkali syndrome.
A commonly reviewed cause of metabolic alkalosis in the
pediatric setting is hypochloremic alkalosis from pyloric steno-
sis. In normal physiology, HCl is excreted from the gastric
lumen and neutralized by HCO 3 secreted by the pancreas. In
pyloric stenosis, there is a loss of HCl through vomiting and
concurrent decrease in secretion of HCO 3 , resulting in a
decrease in serum Cl and an increase in serum HCO 3 . This
combination results in the classic hypochloremic alkalosis of
pyloric stenosis. Preoperative hydration to correct both the
dehydration and hypochloremic alkalosis is important for pre-
vention of postoperative apnea because the respiratory compen-
sation for metabolic alkalosis is hypoventilation (to raise PCO2).
Another common cause of alkalosis, especially in the
pediatric critical care setting, is the contraction alkalosis
induced by diuretic use. Contraction alkalosis occurs when
there is loss of fluids that contain a proportionately lower
amount of HCO 3 than the serum concentration. With rela-
tively more free fluid lost, the concentration of HCO 3 re-
maining in the serum increases. Furthermore, the interplay of
the renin-angiotensin system, as triggered by the hypovolemic
state sensed by the body, further increases absorption of
HCO 3 through the process of hydrogen ion excretion. Thus,
the combination of these factors created by diuretic use results
in a higher-than-normal HCO 3 value and metabolic alkalosis.
Although increased morbidity and mortality are associ-
ated with the presence of metabolic alkalosis, most of these
events are self-correcting without clinically significant se-
quelae. One key exception to this rule is from pyloric ste-
nosis. Within the critical care setting, metabolic alkalosis
can also be brought on by the use of diuretics before ex-
tubation in an attempt to improve respiratory mechanics
and pulmonary function in a patient who has had previous
fluid overload. In these instances, acetazolamide is often
used to waste HCO 3 through the renal system by inhibiting
the carbonic anhydrase enzyme responsible for proximal
tubule absorption of HCO 3 . The rationale for this approach
is to prevent acute hypercapnic respiratory failure follow-
ing extubation. Because the respiratory compensation for
metabolic alkalosis is to hypoventilate (and raise PCO2), this
acute rise in PCO2 can lead to hypercapnic respiratory failure.
Thus, acetazolamide is commonly used before extubation
if significant contraction alkalosis from diuretics exists.
Respiratory Compensation
Respiratory acidosis through hypoventilation occurs in
response to metabolic alkalosis. In response to a high pH, the
body’s attempt at equilibrium mandates a move toward
an acidotic respiratory state through hypoventilation.
By hypoventilating, the body drives up the PCO2, thereby
creating respiratory acidosis. Combined with the primary
metabolic alkalosis, the respiratory acidosis works to return
the body’s pH back to normal.
RESPIRATORY ACIDOSIS
Respiratory acidosis is the result of an increase in PCO2
leading to a lower pH. This accumulation can be related to
increased production or decreased elimination of CO2
through the respiratory system.
Increased production of CO2 can be due to multiple
causes. The predominant cause within the pediatric pop-
ulation is increasing cellular metabolic activity, which can
be seen in infection or fever. Increased production of CO2
can also be related to the carbohydrate load of the body. This
derangement is often due to iatrogenic causes such as
parenteral nutrition in which an excess of carbohydrate
relative to the body’s need is given. With the body’s ability
to eliminate CO2 and increase minute ventilation to account
for increased production, an overproduction of CO2 by itself
rarely leads to respiratory acidosis unless the body’s com-
pensation is limited (such as in a paralyzed patient). Instead,
respiratory acidosis more often results from an inability to
remove CO2 from the bloodstream.
Decreased elimination of CO2 can have several causes.
Elimination of CO2 is based on 3 components of the body
working in synchrony: the neurologic component (in rec-
ognizing the need to eliminate CO2), the musculoskeletal
component (in physically moving the chest to create appro-
priate minute ventilation), and the alveolar component (in
allowing for diffusion of CO2 out of the bloodstream).
Failure of any of these components can result in respiratory
acidosis. Neurologic causes include injuries (eg, traumatic
or stroke), seizures, narcotics, and other pharmacologic
agents causing neurologic depression. Musculoskeletal fail-
ure can result from acute causes such as flail chest or chest
wall edema or underlying musculoskeletal disorders such as
myasthenia gravis or muscular dystrophy. However, most
commonly, respiratory acidosis occurs from the decreased
ability to eliminate CO2 through the alveoli, such as asso-
ciated with pneumonia, pulmonary edema, and acute respi-
ratory distress syndrome.
Treatment for respiratory acidosis involves enhancing
CO2 elimination and treating the underlying cause. For
causes such as pneumonia, treatment with appropriate
antibiotics in addition to the short-term use of positive
pressure or mechanical ventilation can improve CO2 elim-
ination. However, there are instances when, despite maximal
mechanical ventilation, CO2 elimination cannot balance CO2
Vol. 37 No. 9 SEPTEMBER 2016 365
 production. Although not frequent, these instances may re-
quire permissive hypercapnia (high PCO2 with low pH) to
limit further pulmonary injury from aggressive mechanical
ventilation. Similarly, permissive hypercapnia is a recom-
mended approach to a neonatal and pediatric ventilation
strategy to limit injury from mechanical ventilation. Studies
have shown that permissive hypercapnia is well tolerated,
with limited morbidity and mortality in an otherwise healthy
patient (without underlying neurologic pathology or pulmo-
nary hypertension), as long as hypoxia is avoided and hemo-
dynamics are normal.
Metabolic Compensation
In response to a low pH from primary respiratory acidosis,
the body attempts to achieve equilibrium by moving toward
an alkalotic metabolic state through retention of HCO 3
within the metabolic system. By retaining HCO 3 through
the renal system, the body can drive up the HCO 3 , thereby
creating metabolic alkalosis based on the Henderson-
Hasselbalch equation. The primary respiratory acidosis
combined with the metabolic alkalosis works to return the
body’s pH back to normal.
Of note, compensation of the metabolic system to a
primary respiratory acid-base disorder is much slower than
compensation of the respiratory system to a primary met-
abolic acid-base disorder. Therefore, in acute respiratory
acidosis, the pH is often well below the normal range.
In chronic respiratory disease, such as chronic lung
disease, the clinician may notice a chronically compensated
state. In these cases, the patient maintains a pH within
normal ranges but has a persistently elevated PCO2 due to the
underlying chronic condition. Over time, the body main-
tains homeostasis and the need for a normal pH by chron-
ically retaining HCO 3 . On blood gas examination, such
patients often have a PCO2 in the range of 50 to 60 mm Hg
with HCO 3 in the range of 30 to 40 mEq/L (30–40 mmol/L)
at baseline.
RESPIRATORY ALKALOSIS
Respiratory alkalosis is the result of an excessive elimination
of PCO2 leading to a higher pH (“hyperventilation”). This
inappropriate elimination is much less common than any
other acid-base derangements. Causes for primary respiratory
alkalosis typically involve an increased respiratory drive due to
toxins or primary central nervous system events. Salicylate
intoxication and hyperammonemia can promote hyperventi-
lation. Anxiety and stress can also lead to hyperventilation and
are typical causes related to the distress a blood draw can
induce in a pediatric patient. In addition, some neurologic
366 Pediatrics in Review
injuries (including meningitis or some traumatic brain injury
or tumors) can cause hyperventilation, depending on the
location and severity of the insult. Mild respiratory alkalosis
frequently occurs in disease with increased lung water (eg,
pneumonia, pulmonary edema) due to alveolar stretch recep-
tors enhancing the respiratory drive.
Metabolic Compensation
In response to a high pH from a primary respiratory alkalosis,
the body’s attempt to equilibrate mandates a move toward an
acidotic metabolic state through elimination of HCO 3 . The
primary respiratory alkalosis combined with the metabolic
acidosis works to return the body’s pH to normal. Again, such
metabolic compensation occurs over days compared to the
minutes to hours needed in respiratory compensation.
CONCLUSION
Understanding the acid-base status of a patient is important
both for those who are critically ill and those who have
general metabolic derangements. Although seemingly com-
plex, an understanding of 2 principles, the Henderson-
Hasselbalch equation and the anion gap calculation, can
offer clinicians a view into possible causes of the acid-base
imbalance. Just as important is a firm grasp of the interde-
pendence of the metabolic and respiratory systems.
Summary
• A fundamental understanding of acid-base balance is vital to
caring for pediatric patients with critical illnesses as well as for
managing electrolyte disturbances in those who are not critically
ill. (1)(2)
• On the basis of strong research evidence, expert opinion, and
consensus, acidosis occurs when the pH value is lower than
normal when examining blood gases. In contrast, alkalosis occurs
when the pH value is higher than normal. It is important to
characterize pH as a combination of partial pressure of carbon
dioxide (PCO2) and bicarbonate (HCO3 ). (1)(2)
• On the basis of strong research evidence, expert opinion, and
consensus, the Henderson-Hasselbalch equation by itself is
insufficient to completely describe a patient’s metabolic acid-
base state. The anion gap further describes the interactions of the
measured positive charges (cations) and negative charges
(anions) to the unmeasured charged particles. (1)(2)
• On the basis of expert opinion and consensus, the first step in
the assessment of an acid-base imbalance is to determine a
primary respiratory versus primary metabolic cause. A detailed
history and comprehensive physical examination can offer clues
to suggest the presenting cause. (1)(2)
• On the basis of expert opinion and consensus, understanding of
metabolic acidosis requires the use of the anion gap in addition
to knowing the pH state. (1)(2)
 A common type of hyperchloremic non-anion gap acidosis occurs
in the hospitalized patient with infusion of large amounts of
normal saline. In these cases, the relative chloride load from the
exogenous fluid results in a decrease in HCO
3 to maintain plasma
electroneutrality.
 The presence of an increased gap metabolic acidosis (anion gap
higher than normal) is due to an increase of unmeasured anions.
This can occur following an increase in acid production or
underexcretion of acid. The classic mnemonic for causes of gap
acidosis is MUDPILES (methanol, uremia, diabetic ketoacidosis,
paraldehyde, isoniazid, lactic acidosis, ethylene glycol,
salicylates). Although most causes on this list represent
exogenous ingestion of acids, physiologically high-anion
gap acidosis due to increased production of endogenous acids is
more common. The 2 primary sources of such endogenous
production are lactic acidosis and ketoacidosis.
 In response to a low pH from metabolic acidosis, the body’s attempt
to reach equilibrium mandates a move toward an alkalotic
respiratory state through hyperventilation. This response can occur
over minutes to hours, depending on an intact neurologic response
and the ability of the body to maintain hyperventilation.
• On the basis of strong research evidence, expert opinion, and
consensus, metabolic alkalosis, as revealed by the Henderson-
Hasselbalch equation, points to an increase in the HCO3 content of
the serum, resulting in an increase in pH. Two common causes
include hypochloremic alkalosis from pyloric stenosis and
contraction alkalosis induced by diuretics use. Compensation for the
metabolic alkalosis comes from the respiratory system. In response
to a high pH, the body’s attempt to equilibrate mandates a move
toward an acidotic respiratory state through hypoventilation. (1)(2)
• On the basis of strong research evidence, expert opinion,
and consensus, respiratory acidosis is the result of an increase
in PCO2 leading to a lower pH. This accumulation can be due to
increased production (such as a higher metabolic state) or
decreased elimination of CO2 through the respiratory system.
Compensation for primary respiratory acidosis comes from the
metabolic system. In response to a low pH, the body’s
attempt to reach equilibrium mandates a move toward
an alkalotic metabolic state through retention of HCO 3 .
Compensation of the metabolic system to a
primary respiratory acid-base disorder is much slower
than the compensation of the respiratory system to a
primary metabolic acid-base disorder. Therefore, in acute
respiratory acidosis, the pH is often well below the normal
range. (1)(2)
• On the basis of strong research evidence, expert opinion,
and consensus, respiratory alkalosis is the result of
an excessive elimination of PCO2 leading to a higher pH
(“hyperventilation”). This inappropriate elimination is much
less common but can occur through an increased
respiratory drive due to toxins or primary central nervous
system events. Compensation for a primary respiratory
alkalosis comes from the metabolic system. In response to a
high pH, the body’s attempt to equilibrate mandates a move
toward an acidotic metabolic state through elimination of
HCO 3 . (1)(2)
References for this article are at http://pedsinreview.aappublications.
org/content/37/9/361.
Vol. 37 No. 9 SEPTEMBER 2016 367
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1. A 6-year-old girl is evaluated in the emergency department after 2 days of vomiting and REQUIREMENTS: Learners
diarrhea. She has had low oral intake and scant urine output for the past 16 hours. An can take Pediatrics in
electrolyte panel is ordered. The results are as follows: Review quizzes and claim
Sodium 135 mEq/L (135 mmol/L) credit online only at:
Potassium 4.8 mEq/L (4.8 mmol/L) http://pedsinreview.org.
Chloride 110 mEq/L (110 mmol/L)
Bicarbonate 8 mEq/L (8 mmol/L)
To successfully complete
Blood urea nitrogen 29 mg/dL (10.4 mmol/L)
2016 Pediatrics in Review
Creatinine 1.0 mg/dL (88.4 mmol/L)
articles for AMA PRA
Calcium 8.5 mg/dL (2.1 mmol/L)
Category 1 CreditTM,
Albumin 4.5 g/dL (45 g/L)
learners must
The anion gap in this patient equals:
demonstrate a minimum
A. 21.8 mEq/L (21.8 mmol/L). performance level of 60%
B. 25 mEq/L (25 mmol/L). or higher on this
C. 25.5 mEq/L (25.5 mmol/L). assessment, which
D. 26.3 mEq/L (26.3 mmol/L). measures achievement of
E. 30.3 mEq/L (30.3 mmol/L). the educational purpose
2. A 4-year-old boy is admitted to the pediatric intensive care unit with overwhelming sepsis and/or objectives of this
due to Streptococcus pneumoniae. The anion gap is normal despite a definite metabolic activity. If you score less
acidosis. Your colleague states that this is likely a falsely low anion gap. Which of the than 60% on the
following is the most likely explanation for the low anion gap? assessment, you will be
A. Conservation of bicarbonate due to decreased urine output. given additional
B. Decrease in unmeasured anions due to hypoalbuminemia. opportunities to answer
C. Increase in carbon dioxide due to respiratory depression. questions until an overall
D. Increase in lactate concentration due to decreased perfusion of vital organs. 60% or greater score is
E. Increase in serum protein concentrations due to inflammation. achieved.
3. A previously healthy 3-year-old girl is admitted to the hospital for dehydration. Her initial
bicarbonate measures 9 mEq/L (9 mmol/L) with an anion gap of 24 mEq/L (24 mmol/L). This journal-based CME
After vigorous resuscitation with 2 bolus infusions of 20 mL/kg normal saline, her activity is available
bicarbonate is 7 mEq/L (7 mmol/L) and the anion gap is 16 mEq/L (16 mmol/L). What is the through Dec. 31, 2018,
most likely explanation for her second set of laboratory results? however, credit will be
A. An increase in her circulatory volume has diluted her chemistry values. recorded in the year in
B. An increased lactate concentration has displaced bicarbonate. which the learner
C. She is becoming more acidotic due to deterioration in her overall status. completes the quiz.
D. She is continuing to lose bicarbonate due to persistent diarrhea.
E. The relative chloride load caused a decrease in bicarbonate to maintain
electroneutrality.
4. An 18-month-old male toddler is brought to the emergency department by his
grandparents, who found him in their bathroom after he opened a bottle of “muscle pain
relief” wintergreen oil (containing methyl salicylate) and ingested some of its contents. The
boy is sleepy and irritable when aroused. Laboratory studies reveal a metabolic acidosis
with an elevated anion gap. Keeping in mind the “MUDPILES” mnemonic for causes of an
elevated anion gap acidosis, which of the following causes for this child’s metabolic
condition is most likely?
A. Ethylene glycol.
B. Ketoacidosis.
C. Lactic acidosis.
D. Methanol.
E. Uremia.

368 Pediatrics in Review

5. A 6-week-old male infant presents with vomiting that began insidiously but progressed to
projectile vomiting of all feedings. Ultrasonography confirms the diagnosis of hypertrophic
pyloric stenosis. Which of the following is the expected primary finding in this disorder?
A. Hyperchloremic metabolic acidosis.
B. Hypochloremic metabolic alkalosis.
C. Hypercapneic respiratory acidosis.
D. Hypocapneic respiratory alkalosis.
E. Metabolic contraction alkalosis.

Vol. 37 No. 9 SEPTEMBER 2016 369

 Evaluation and Initial Management of
Hypopituitarism
Melinda Pierce, MD,* Lisa Madison, MD*
*OHSU Department of Pediatrics, Division of Pediatric Endocrinology, Portland, OR.

Education Gap
Signs and symptoms of hypopituitarism, in particular diabetes insipidus
and decreased linear growth velocity, are frequently overlooked in
patients with craniopharyngioma. (1)

Objectives After completing this article, readers should be able to:

1. Describe the various pathophysiologic causes associated with

hypopituitarism, including craniopharyngioma.
2. Recognize the clinical features of pituitary hormone deficiencies.
3. Describe the principles of hormone replacement therapy for
hypopituitarism.

INTRODUCTION

Hypopituitarism affects between 1 in 4,000 and 1 in 10,000 live births, with

increasing incidence with age. (2) The pituitary, sometimes referred to as the
master gland, is positioned in the anterior midline of the brain in the sella turcica.
The pituitary controls endocrine function through the release of multiple hor-
mones that can have a direct growth effect on target tissue (trophic effects) or
stimulate that tissue to release a hormone that has its effects on other tissues
(tropic effects). The anterior pituitary forms as an outpouching of the embryonic
oral cavity (Rathke pouch). It is responsible for the release of growth hormone
(GH), corticotropin, thyrotropin, prolactin, and the gonadotropins luteinizing
hormone (LH) and follicle-stimulating hormone (FSH). The posterior pituitary
is composed of neuronal projections from the hypothalamus and is responsible
for the storage and secretion of oxytocin and antidiuretic hormone (ADH). This
article examines the pathologic causes of pituitary dysfunction, their diagnosis,
and treatment.

CAUSES OF HYPOPITUITARISM
AUTHOR DISCLOSURE Drs Pierce and
Congenital Madison disclosed no financial relationships
relevant to this article. This commentary does
Congenital hypopituitarism most often results from genetic or embryologic
not contain a discussion of an unapproved/
pathologies. Septo-optic dysplasia (SOD) is the most common congenital cause investigative use of a commercial product/
of hypopituitarism, with an incidence as high as 1 in 10,000. SOD results in device.

370 Pediatrics in Review

variable hormonal deficiencies, absence of the septum pellu-
cidum (Figure), and hypoplasia of the optic nerves, often
resulting in blindness. (3) Although SOD can be associated
with genetic mutations (in HESX1, OTX2, and SOX2), it is most
often multifactorial and is associated with abnormal midline
brain development. (4) Other defects in midline formation
(such as midline cleft lip and/or palate, vascular malforma-
tions, absence of the corpus callosum) can also be associated
with an embryologic malformation of the pituitary gland.
In cases of SOD or facial midline defects, further screen-
ing should be undertaken that includes testing for pitui-
tary hormone deficiencies (see the section on “Evaluation”),
ophthalmologic evaluation, and imaging of the central ner-
vous system (CNS) (eg, magnetic resonance imaging [MRI]).
Such screening should occur in the neonatal period to prevent
complications from untreated hormone deficiency and to
assess possible vision deficits that may require accommo-
dation. Rare genetic causes of hypopituitarism include dele-
tions of the “POU domain class 1 transcription factor,” PIT-1
or POU1F1, and the “homeobox protein prophet of PIT-1,”
encoded by the PROP1 gene. (5)(6) GH, prolactin, and
TSH deficiencies characterize PIT-1/POU1F1 deletion,
whereas PROP1 deletions can manifest as any combination
of deficiencies of the anterior pituitary hormones.
Acquired
Later in life, anterior pituitary hormone deficiency can arise
from any cause that damages the pituitary, including mass effect
(from tumor), infection, autoimmune disease, infiltrative dis-
ease, chemotherapy and radiation exposure, and trauma. Any
trauma or damage to the sella, pituitary, pituitary blood supply,
or hypothalamus can result in hypopituitarism. This includes
Figure. Magnetic resonance imaging of an infant at 4 days of age
showing absence of the septum pellucidum.
surgical manipulation as well as motor vehicle collisions, child
abuse, and sports-related injuries. There are cases of idiopathic
pituitary hormone deficiencies, most commonly isolated idio-
pathic GH deficiency, but this is always a diagnosis of exclusion.
Diabetes insipidus (DI) can occur from any injury to the
pituitary stalk that damages neuronal projections respon-
sible for the delivery of ADH to the storage vesicles in the
posterior pituitary. In cases of isolated DI, an identified
cause is found at the time of diagnosis in 50% to 90% of
cases, with the most common causes being anatomic abnor-
malities, central brain tumors, and infiltrative diseases. (7)(8)
Any mass that comes in contact with the hypothalamus
or pituitary can place pressure on the sensitive endocrine
cells, leading to dysfunction. GH-producing cells are the
most sensitive to damage from any cause. Common pediatric
tumors include craniopharyngioma, primary brain tumors
such as germinomas and optic gliomas, functional and non-
functional pituitary macroadenomas, and cerebral metastases
of other primary cancers such as lymphoma. Prolactinomas
deserve special mention because they are often not of a
size to cause problems from mass effect. However, hyperpro-
lactinemia can cause negative feedback and inhibition of the
hypothalamic-pituitary-gonadal axis, resulting in hypogonado-
tropic hypogonadism with delayed or arrested puberty.
Hyperprolactinemia is also associated with galactorrhea.
Craniopharyngioma is the most common tumor asso-
ciated with multiple pituitary deficiencies in children. A
craniopharyngioma arises from the same oral ectoderm as the
anterior pituitary. In a case series of 42 children with cranio-
pharyngioma, only 10% sought medical treatment for symp-
toms, although more than 50% had evidence of growth failure
before identification. (9) GH deficiency is the most common
pituitary deficiency seen in craniopharyngioma, affecting up
to 75% of patients. Other pituitary hormone deficiencies
include gonadotropin deficiency, thyrotropin deficiency, cor-
ticotropin deficiency, and DI, with the incidence of each
increasing from baseline after surgical intervention. (9)
Because surgical excision of the mass can disturb the pituitary
and the stalk, the patient should be completely evaluated for
deficiencies both before and after surgery to identify any
new deficiencies. This is particularly true of GH and ADH.
Even when a brain tumor does not itself damage the
pituitary, tumor treatment may result in hypopituitarism.
Any radiation exposure to the pituitary can cause permanent
pituitary damage, with GH-producing cells again being
most sensitive. Although 100% of children who are exposed
to more than 30 Gy eventually develop GH deficiency, any
brain exposure greater than 22 Gy should prompt evalu-
ation for hormonal deficits. (10) Common chemothera-
peutic drugs are not currently believed to result in central
Vol. 37 No. 9 SEPTEMBER 2016 371
 deficiency, but multiple chemotherapy modalities can dam-
age the target organs. High-dose corticosteroids for induction
chemotherapy in acute lymphoblastic leukemia can suppress
the hypothalamic-pituitary-adrenal axis, but this treatment is
not associated with other pituitary hormone deficiencies.
Certain infiltrative diseases also have a predilection for the
pituitary, particularly Langerhans cell histiocytosis (LCH),
which results from overproliferation of Langerhans cells.
The classic triad of LCH symptoms is also referred to as
multifocal unisystem disease and includes DI, exophthalmos,
and lytic bone lesions. GH deficiency is also common in
LCH. In cases that were evaluated retrospectively after an initial
diagnosis of idiopathic DI, approximately one-third of patients
were subsequently found to have a pathologic etiology, with
approximately 50% of those found to have histiocytosis. (8)
CNS infection, such as meningitis, is classically associated
with the development of DI, but there is a risk of damage to
other hormone-producing cell types as well. Infiltrative infec-
tions such as tuberculosis can lead to pituitary destruction.
Hypophysitis is a rare cause of autoimmune damage to
the pituitary, similar to other autoimmune lymphocytic
processes such as Hashimoto thyroiditis or Addison dis-
ease. In most cases, hypophysitis is a diagnosis of exclusion
when symptoms of hypopituitarism are present with CNS
symptoms such as headache, nausea, or vision problems.
No reliable antibody assays are available to test for hypo-
physitis in peripheral blood and fewer than 400 cases have
been reported in the literature. (11)
SYMPTOMS OF HYPOPITUITARISM
Symptoms of hypopituitarism are related to both hormonal
deficits and the timing of the insult to the pituitary. In older
children, when not associated with a known disorder, hypo-
pituitarism is often identified after evaluation for poor linear
growth. The symptoms most commonly seen in each in-
dividual hormone deficiency are listed in Table 1. Other
symptoms include those from the underlying pathologic
cause of the hypopituitarism, such as visual deficits or head-
aches from a midline mass, fever or sepsis associated with
meningitis, or bony lesions from LCH.
Surgical manipulation of the posterior pituitary creates a
classic triphasic ADH response. The first phase, manifested
as DI, occurs within 24 hours of surgery. Patients have
excessive urine output, often more than 5 to 10 mL/kg per
hour. The urine is dilute (specific gravity <1.010 and urine
osmolality <100 mOsm/kg), with hypernatremia and in-
creased serum osmolality (often >300 mOsm/kg). The sec-
ond phase is associated with release of preformed ADH from
the dying neurons, resulting in a transient syndrome of
372 Pediatrics in Review
inappropriate ADH secretion (SIADH). Urine output may
be normal or decreased in volume but is concentrated (urine
osmolality greater than serum) and often accompanied by
hyponatremia. After the death of the ADH neurons, the third
phase is characterized by permanent DI.
EVALUATION
Hormones
Each individual hormone should be assessed during labo-
ratory testing. Although idiopathic isolated GH deficiency
is seen rather commonly, other isolated pituitary hormone
deficiencies are relatively rare. Accordingly, clinicians should
test for all anterior hormone deficiencies once any single
deficiency, including GH, is identified. It is also critical that
testing for corticotropin, LH, FSH, thyrotropin, and GH
include evaluation of both the pituitary hormone itself and
the target organ hormones. Frankly low concentrations of
pituitary hormones are not necessary to diagnose deficiency;
they may be inappropriately normal in the setting of target
hormone deficiency.
GH has a typically pulsatile release that makes evaluation of
a random value difficult to interpret. Instead, screening for
GH deficiency relies on evaluation of the secondary growth
factors insulin-like growth factor-1 (IGF-1) and insulin-like
growth factor-binding protein-3 (IGFBP-3). Both are produced
by the liver in response to the presence of GH. These growth
factors have longer half-lives than GH and are maintained at a
steady level in response to normal pulsatile GH secretion. If
growth factor values are low, formal testing for GH can be
performed through stimulation of GH secretion. This is
typically achieved by a combination of medications that
either directly promote GH secretion or create stress in
the body (such as hypoglycemia) that results in GH secretion.
Cortisol has circadian release that increases the difficulty of
assessment with a random value, similar to GH. However, the
tropic hormone corticotropin is required by the adrenal glands
to maintain secretory function. If corticotropin is missing,
adrenals atrophy and cortisol release is impaired. Corticotro-
pin deficiency can result in adrenal crisis if profound or
prolonged. Adrenal crisis is characterized by hypotension
and cardiac instability. Laboratory testing is via provocative
testing of the adrenal glands through administration of
exogenous corticotropin. If central deficiency (corticotropin
deficiency) is suspected, a small dose of corticotropin is used
(1 mg), based on the concept that a normally functioning gland
is sensitive but an atrophic gland is not. (12) This is in contrast
to the 250-mg corticotropin stimulation test that is performed
if there is suspicion of primary adrenal insufficiency. With
either dose, the cortisol is measured at 30 minutes, with a
TABLE 1. Common Signs and Symptoms Associated with Hormone Deficiencies
HORMONE MISSING SIGNS AND SYMPTOMS

Growth hormone Linear growth failure, increased adiposity, decreased muscle mass, fatigue
If congenital: neonatal hypoglycemia, micropenis
Corticotropin Nausea, vomiting, weight loss, prolonged duration of common illnesses,
hypotension, fatigue
Thyrotropin Fatigue, dry hair, dry skin, linear growth failure, constipation, weight gain
despite decreased intake, bradycardia
If congenital and untreated: development delays, intellectual disability
Prolactin Inability to lactate after pregnancy
Luteinizing hormone/Follicle-stimulating hormone Delayed or absent pubertal development with lack of pubertal growth spurt,
secondary amenorrhea, decreased libido, osteoporosis
If congenital: micropenis, undescended testicles
Antidiuretic hormone Polyuria, polydipsia, nocturia, dehydration, hypernatremia

passing value of 18 mg/dL (496.6 nmol/L). (13) In addition,
measurement of both baseline corticotropin and cortisol
concentrations can aid in distinguishing between primary
and secondary adrenal insufficiency because corticotropin
will be elevated in the setting of primary disease. Ran-
dom corticotropin values, especially if measured without a
concomitant cortisol value, are rarely helpful diagnostically.
Thyrotropin deficiency is manifested by low circulating
thyroid hormone (free thyroxine [T4]) concentrations in the
setting of a low or normal thyrotropin values. A normal
thyrotropin with a low free T4 is considered inappropriately
normal because intact feedback would result in elevation
of the thyrotropin above the normal range. In general, when
evaluating suspected hypothyroidism, clinicians should
assess both thyrotropin and free T4 to avoid missing central
causes of hypothyroidism.
Testing for gonadotropin deficiency should always be
performed using a highly sensitive assay that can measure
results less than 1 mIU/mL. It should include testing for
both LH and FSH as well as the patient-appropriate sex
steroid (estrogen or testosterone). Similar to thyrotropin
deficiency, normal gonadotropin values in the setting of low
sex steroid values at the normal age of puberty should raise
concern for pituitary insufficiency.
Central DI from ADH deficiency is primarily manifested
by the clinical symptoms of polyuria and polydipsia. Normal
serum sodium concentrations can be maintained unless
the patient is unable to sustain adequate free water intake,
whether due to developmental stage, absent thirst mecha-
nism, profound illness, or iatrogenic causes such as nil per os
status for surgery. In this setting, the excessive loss of free
water causes hypernatremia with resultant increase in plasma
osmolality. Urine is inappropriately dilute for the serum
sodium concentration. The water deprivation test involves
monitoring of a patient during restricted access to free water.
Urine output, serum sodium, and serum and urine osmolality
are frequently assessed to determine if the patient develops
hypernatremia with elevated serum osmolality in the setting
of inappropriately high urine output with low urine osmo-
lality. Because of the risk of developing significant hyper-
natremia, this test should only be performed in the hospital
where frequent monitoring is available.
Identification of Acquired Cause
Because most acquired cases of hypopituitarism are asso-
ciated with a treatable disease, identifying and treating the
cause is as important as hormone replacement. Often the
first step is imaging of the brain via MRI with and without
contrast. This can identify the solid and cystic sellar mass
characteristic of craniopharyngioma (Figure) as well as
smaller areas of hypoenhancement associated with pitui-
tary adenomas. Hypophysitis is extremely rare but can
appear as an enlarged or diffusely hyperenhanced pituitary
gland. Skull fractures and other signs of trauma are often
readily evident on imaging, although they can be missed
when small. Tumor markers for common brain tumors
include human chorionic gonadotropin and a-fetoprotein.
TREATMENT
Treatment for hypopituitarism is, in principle, very sim-
ple: replace the target hormones that are deficient. In practice,
such replacement can be relatively complicated and requires
close patient monitoring and appropriate dose adjustments.

Vol. 37 No. 9 SEPTEMBER 2016 373

 Adrenal Insufficiency
Once the cause has been identified, treatment should be
directed toward that pathology. However, before undertaking
any surgical interventions, it is critical to treat any adrenal
insufficiency and administer the appropriate stress-dose level
of cortisol replacement both during and immediately follow-
ing surgery. If neurosurgical intervention is undertaken, post-
surgical use of high-dose dexamethasone is appropriate for
replacement stress dosing, although hydrocortisone should
be initiated at the end of the corticosteroid weaning period.
Hydrocortisone has a half-life in serum of 6 to 8 hours
and, therefore, ideally should be administered 3 times a day
(morning, mid-afternoon, and evening). The maintenance
replacement hydrocortisone dose is 7 to 9 mg/m2 per day.
If doses cannot be administered in even allotments, the larger
dose frequently is provided in the morning to better mimic
the normal surge in cortisol upon waking. Stress dosing also
is necessary in times of illness. Typically, doses are doubled
for fevers and tripled for any vomiting or diarrhea. Patients
(and parents in particular) must be trained in the use of
emergency hydrocortisone injection (approximately 10 times
maintenance) that can be administered intramuscularly if the
patient has suspected adrenal crisis or is unable to take oral
medications.
Hypothyroidism
Thyroid hormone is replaced with levothyroxine, the right-
handed isomer of T4. Levothyroxine is well absorbed and
can be converted to the active hormone, triiodothyronine, in
target tissues to allow for tissue-specific control of thyroid
signaling. Weight-based higher doses of thyroid hormone are
required in younger children, and appropriate replacement is
critical for normal neurodevelopment in the first 3 years after
birth. The schedule in Table 2 is modified from the protocol
used in cases of congenital hypothyroidism; doses may be less
for patients with some pituitary function, although the mon-
itoring frequency is similar. Patients are monitored through
measurement of free T4 alone, with the goal of maintaining
the values in the upper half of the normal range.
Growth Hormone Deficiency
Recombinant GH is available to treat patients with GH
deficiency. As a peptide hormone, it is currently only
available as a subcutaneous injection that must be admin-
istered daily. Typically, initial replacement doses range
from 0.025 to 0.05 mg/kg per day, with monitoring
of IGF-1 values and growth velocity. Goal IGF-1 values
should be in the upper half of the normal range. Growth
velocity should be age-appropriate, although it may
be higher than normal in the first 6 to 12 months of
374 Pediatrics in Review
replacement. GH should not be administered in the setting
of active malignancy because of theoretical concerns for
increasing cancer proliferation. Patients are typically advised
to wait 1 year after surgical resection of a craniopharyngioma
and at least 2 years after successful treatment of other malig-
nancies before beginning GH replacement therapy. Some of
the most significant adverse effects of GH treatment are
increased risk for glucose intolerance and hyperinsulinism,
slipped capital femoral epiphysis, pseudotumor cerebri, and
pancreatitis. Overall, GH replacement in a deficient child is
generally considered to be safe.
Gonadotropin Deficiency
Gonadotropin deficiency results in low concentrations of
sex-specific sex steroids: testosterone in males and estrogen
in females. This results in absent puberty manifested by
failure to develop breast tissue and menstruation in girls
and failure to increase testicular size in boys. Deficiencies in
testosterone/estrogen increase the risk for osteoporosis
as well as metabolic abnormalities. Replacement is started
around the time of mean entrance into puberty for the pa-
tient’s sex (ie, age 10 years for girls, age 11–12 years for boys).
Estrogen is available as either a transcutaneous patch or
pill. Many experts prefer the transcutaneous method be-
cause it bypasses the “first-pass hepatic metabolism” seen
with oral medication and may result in better replacement
with lower risk. Doses start small and are increased approx-
imately every 6 months in an effort to mimic the natural
progression of secondary sexual characteristics. Once the
uterine lining has received sufficient estrogen stimulation,
there may be breakthrough vaginal bleeding. At this time,
progesterone is typically added to stabilize the uterine lining
and is periodically stopped to allow a regular withdrawal
bleeding or menses.
Testosterone replacement is available for boys in either an
intramuscular or topical preparation. Initial doses are small
(approximately 1/8th–1/4th the normal adult dose of 200 mg
testosterone) and if given intramuscularly, are spaced out
approximately monthly. Doses are increased every 6 months
in an effort to mimic the natural progression of secondary
sexual characteristics and to allow for continued linear growth
before the closure of the growth plates.
Diabetes Insipidus
Central DI is treated with synthetic ADH, most commonly
in the form of oral desmopressin (DDAVP). For patients
with an intact thirst mechanism, the goal of therapy is to
provide sufficient relief from polyuria and polydipsia to al-
low the individual to sleep through the night without
nocturia and to participate in normal daily activities without

TABLE 2. Levothyroxine Dose Recommendations
DAILY WEIGHT- FREQUENCY OF
AGE BASED DOSE MONITORING
0-12 months 10-15 mg/kg Every 1-3 months
1-5 years 4-6 mg/kg Every 3-6 months
6-12 years 3-5 mg/kg Every 6-12 months
>12 years 2-3 mg/kg Every 6-12 months
excessive disruption. Breakthrough polyuria and polydipsia
must be allowed at least once during a 24-hour period
because it is during this time that the patient self-regulates
to maintain a normal serum sodium concentration. The
starting dose of DDAVP is 0.05 to 0.2 mg once daily, and
doses are titrated to effect, often requiring twice-daily and
sometimes three times-daily dosing to achieve adequate
control of urine output.
For patients with impaired thirst due to hypothalamic
injury or patients unable to regulate their own intake (eg,
those who have developmental disability or are dependent on
gastrostomy tubes), the usual strategy for DDAVP dosing is to
provide maximal antidiuresis in concert with a fluid pre-
scription. Maximal antidiuresis allows for approximately 0.5
mL/kg per hour of urine output, and the corresponding fluid
prescription provides replacement of urine output plus insen-
sible losses. Initial titration of such a regimen almost always
requires an inpatient stay with careful monitoring of intake
and output as well as frequent serum sodium measurement.
CONCLUSION
Hypopituitarism is a rare but complex diagnosis in the
pediatric patient that requires thorough evaluation and
treatment. It can result from a multitude of causes, including
mass effect, trauma (mechanical, chemical, or radiological),
autoimmune/autoinflammatory or infiltrative disease, and/
or infection. Among pediatric patients with hypopituitarism,
some of the most common causes are craniopharyngioma,
SOD, and brain tumors (including treatment). Treatment
involves the physiologic replacement of the end-organ hor-
mones that are deficient, with close monitoring for adequacy
of replacement.
Summary
• On the basis of observational studies, (1)(2)(3)(4)(5)(6)(7)(8)
hypopituitarism has an increasing prevalence with increasing
age.
• On the basis of case reports and observational studies, (3)(4)
septo-optic dysplasia is the most common congenital cause of
hypopituitarism.
• On the basis of epidemiologic studies, (1)(2)(3)(4)(5)(6)(7)(8)(9)
(10)(11) other causes of hypopituitarism include genetic or
anatomic abnormalities (including midline facial defects), trauma,
mass effect, infection, and autoimmune and infiltrative diseases.
• On the basis of case reports and expert opinion, single detected
pituitary hormone deficiencies are rarely isolated and should
prompt evaluation of the other pituitary hormones. Pituitary
hormone values may be inappropriately normal in the setting of
end-organ hormone deficiency.
• On the basis of expert opinion and case reports, (9) clinical
features of hypopituitarism can initially be subtle and vary based
on the hormones involved, although poor linear growth is a
prominent finding in many deficiencies and should prompt
consideration of further testing.
• On the basis of expert opinion, diabetes insipidus is characterized
by loss of free water from an inability to concentrate the urine that
results in hypernatremic dehydration if untreated.
References for this article are at http://pedsinreview.aappublications.
org/content/37/9/370.
Vol. 37 No. 9 SEPTEMBER 2016 375
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1. You are preparing a medical student to see a 16-year-old boy with a history of injury to the REQUIREMENTS: Learners
posterior pituitary as a result of head trauma associated with basilar skull fracture. Of the can take Pediatrics in
following, you explain that this region of the pituitary is responsible for the production of: Review quizzes and claim
A. Antidiuretic hormone (ADH). credit online only at:
B. Corticotropin. http://pedsinreview.org.
C. Gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]).
D. Growth hormone (GH). To successfully complete
E. Thyrotropin. 2016 Pediatrics in Review
articles for AMA PRA
2. A term newborn presents with hypoglycemia and poor visual fixation. Magnetic resonance Category 1 CreditTM,
imaging (MRI) of the brain shows absence of the septum pellucidum, and laboratory learners must
evaluation demonstrates deficiency of multiple pituitary hormones. Which of the following demonstrate a minimum
is the most appropriate diagnosis for this newborn’s presentation? performance level of 60%
A. Birth trauma. or higher on this
B. Congenital syphilis. assessment, which
C. Genetic deletion resulting in deficient production of anterior pituitary hormones. measures achievement of
D. Kallmann syndrome. the educational purpose
E. Septo-optic dysplasia. and/or objectives of this
activity. If you score less
3. A 12-year-old girl presents with exophthalmos and a lytic lesion in the skull. She is than 60% on the
diagnosed with Langerhans cell histiocytosis. Which of the following pituitary disorders is assessment, you will be
most commonly associated with this condition? given additional
A. Central adrenal insufficiency (corticotropin insufficiency). opportunities to answer
B. Central hypothyroidism (thyrotropin deficiency). questions until an overall
C. Delayed puberty due to gonadotropin deficiency. 60% or greater score is
D. Diabetes insipidus (ADH deficiency). achieved.
E. Hyperprolactinemia (overproduction of prolactin).
This journal-based CME
4. A 7-year-old male with septo-optic dysplasia is scheduled for bilateral indirect hernia activity is available
repair. Which of the following hormone levels is the most important to assess prior to through Dec. 31, 2018,
surgery? however, credit will be
A. GH. recorded in the year in
B. Insulin-like growth factor-1. which the learner
C. LH. completes the quiz.
D. Cortisol.
E. FSH.

5. A 6-year-old boy presented with growth failure, headaches, personality changes, and
visual field deficits. MRI of the brain revealed a tumor involving the pituitary gland. The
tumor was recently resected. In regards to subsequent GH replacement therapy, the most
appropriate statement is that GH therapy:
A. Is associated with an unacceptable risk of adverse events in childhood.
B. Is monitored by measuring random GH concentrations.
C. Should be deferred until 6 months after surgery.
D. Should begin in the immediate postoperative period.
E. Should not be given in the setting of active malignancy.

376 Pediatrics in Review

 Chronic and Recurrent Abdominal Pain
*Louisiana State University Health Sciences Center and Children’s Hospital of New Orleans, New Orleans, LA.
AUTHOR DISCLOSURE Dr Hyman has
disclosed no financial relationships relevant to
this article. This commentary does contain a
discussion of an unapproved/investigative
use of a commercial product/device.
Paul E. Hyman, MD*
Education Gap
The past 20 years have witnessed a transition in clinical understanding of
childhood bellyaches. The recently published third iteration of pediatric
Rome criteria provides updated and accurate criteria for symptom-based
diagnosis of chronic and recurrent abdominal pain. In many cases,
primary care clinicians can make symptom-based diagnoses and initiate
treatment on the first visit.
Objectives After completing this article, readers should be able to:
1. Make symptom-based diagnoses of functional abdominal pain
disorders.
2. List a variety of treatment options for children with functional
abdominal pain.
3. Recognize warning signs that discriminate disease from functional
abdominal pain.
4. Understand how psychosocial factors play a role in disability associated
with functional abdominal pain.
EPIDEMIOLOGY
By definition, chronic or recurrent abdominal pain must occur at least 4 times
each month for at least 2 months. Abdominal pain complaints begin as soon as a
child can provide an accurate pain history, usually around age 7 years but occa-
sionally younger. Before that age, children have difficulty separating emotional
distress from physical pain. The differential diagnosis of child and adolescent
abdominal pain is unrelated to age.
One in 10 children visits a clinician because of chronic or recurrent abdominal
pain. (1) How can a clinician screen quickly for disease? The first consideration is
the duration of each episode. If the pain lasts less than 5 minutes, even if it occurs
many times daily, the pain is unlikely to be worrisome. Abdominal pains lasting
just a few minutes may be abdominal wall muscle cramps or high-amplitude-
propagating colon contractions. High-amplitude-propagating contractions are
waves of muscle contraction starting in the ascending colon, with pressures
greater than 60 mm Hg, that move colonic contents through the colon to the
rectum. (2) High-amplitude-propagating colon contractions are normal, but they
cause an urge to defecate for about 2 minutes several times daily. Children who
Vol. 37 No. 9 SEPTEMBER 2016 377
 are sensory-sensitive or children who refuse to defecate may
experience abdominal pain with normal high-amplitude-
propagating contractions. The second consideration is loca-
tion. The closer the pain location is to the umbilicus, the less
likely it is due to disease. The final consideration is the time
of the pain complaints. Children with functional (non-
organic) abdominal pain often complain either upon awak-
ening or when going to sleep, but they seem relatively
symptom-free during daily activities. Waking up and going
to sleep share the characteristic that in those quiet min-
utes children assess their bodies for discomfort. Once
active in the day, healthy children are less aware of body
sensations.
Most chronic or recurrent abdominal pain is not caused
by disease. In a study of Norwegian children with abdominal
pain, 87% met diagnostic criteria for 1 or more functional
gastrointestinal disorders (FGIDs) on their first visit (Fig 1).
(3) Diagnoses change over time to an organic disease in only
1% to 2% of those diagnosed with an FGID. Inflammatory
bowel disease occurs in about 1 in 1,000 children. (4) Celiac
disease is found in 1 in 150 children, but most affected
children are asymptomatic. (5) Thus, the chances are slim
that the next child who comes to the office with a bellyache
has a disease.
HISTORY AND PHYSICAL EXAMINATION
A series of simple questions can provide valuable informa-
tion when taking a history from a patient complaining of
pain. The first question should address whether the pain
is constant or intermittent. Constant pain is unrelated to
Figure 1. Functional gastrointestinal disorders dominate diagnoses in
Norwegian children with abdominal pain. FAP¼functional abdominal
pain. IBS¼irritable bowel syndrome.
378 Pediatrics in Review
physiologic events such as eating or defecation and likely
reflects central nervous system (CNS) origins for pain. If the
pain comes and goes, ask how often the episodes occur and
how long they last. The next question is, “Does eating make
your pain better, worse, or no different?” Pain that worsens
with eating suggests that the cause is stretching of the
stomach (dyspepsia) or the gastrocolonic response increas-
ing pressures in the colon. Next on the question list is, “Does
defecation make your pain better, worse, or no different?” If
defecation relieves the pain, the diagnosis is likely to be
irritable bowel syndrome (IBS). This can be followed with,
“Does exercise make your pain better, worse, or no differ-
ent?” If eating and defecation have no effect but exercise
makes the pain worse, the diagnosis may be abdominal wall
pain, unrelated to gastrointestinal factors. If the pain is
unchanged by eating, defecation, exercise, or any other
physiologic event, it is a disorder termed “functional
abdominal pain not otherwise specified.” A helpful fol-
low-up question is, “What can you do to make your pain
better?” This question provides an opening for discussion of
how the patient copes, with possibilities such as medicines,
foods, rest, and distractions. It also is important to ask about
what makes the pain worse, with possibilities such as food,
exercise, academic struggles, bullying, and family stressors
(eg, psychological or physical abuse in the home or separation
from a loved one by death or relocation).
The patient’s physical appearance is helpful in assessing
the degree of distress at the time of examination. Those
suffering from chronic pain may appear to be in no distress
but when queried, they rate their pain as an 8 or 9 out of 10.
Clinicians should never challenge a patient’s pain rating
because chronic pain differs from acute pain in its pheno-
type and challenging the patient’s story can result in a failed
therapeutic alliance. The patient who has an acute abdomen
appears ill, with tachycardia, flexed legs, and a facial gri-
mace. The patient experiencing chronic pain may look sad
but rarely looks acutely ill. The adolescent might state, “No
one believes that I am in pain because I look normal.” A
comment to facilitate the therapeutic alliance might be, “I
am sorry you are feeling so much pain, but maybe I can
help.”
PATHOPHYSIOLOGY OF CHRONIC AND RECURRENT
ABDOMINAL PAIN
Basic and clinical research has exploded over the past 25
years, resulting in understanding of chronic and recurrent
abdominal pain. Chronic pain is often caused by a sensiti-
zation of primary visceral afferent nerves to pressure and
stretch (primary hyperalgesia) and amplification of pain
messages by deep brain nonspecific arousal systems (sec-
ondary hyperalgesia) (6). When the pain impulse in the
arousal center is strong enough, pain messages ascend to
perception in the sensory cortex on the anterior and mid-
cingulate gyrus (Fig 2). In individuals with healthy coping
skills, signals from frontal lobes in the brain may reduce
pain transmissions from the arousal centers in the midbrain
to the sensory cortex. In contrast, past pain experiences,
poor coping skills, expectations for pain, anxiety, and depres-
sion transmissions from the frontal lobes may increase pain
transmission from the deep brain arousal centers and heighten
pain perception in the sensory cortex. Children with poor
coping skills, academic or social stress, or a coexisting mental
health disorder may be at risk of disability from abdominal
pain. Treatment for chronic pain may target peripheral or CNS
mechanisms or both.
Chronic abdominal pain includes a CNS component,
characterized by altered pain pathways and structural
changes in the brain. (6)(7)(8) Although evidence exists
about how food, infection, inflammation, intestinal per-
meability, and the microbiome all contribute to trigger-
ing symptoms, pain- or nausea-associated FGIDs often
respond better to treatments targeting the CNS than
drugs working outside the brain. Hypnosis, (9) cognitive
behavioral therapy, (10) and citalopram (11) trials in chil-
dren were more successful than the promotility drugs
cisapride and tegaserod, the gastric acid inhibitor famotidine,
or the antibiotic used for bacterial overgrowth, rifaximin,
(12) for IBS.
Efferent and afferent nerves connect brain and gut, each
modulating the other, which provides a rationale for the use
of psychotropic drugs for abdominal pain treatment. More-
over, recent evidence from brain imaging demonstrated
Figure 2. Afferent chronic pain pathways. From Hussain SZ, Hyman PE.
Psychotropic medications for pediatric functional gastrointestinal
disorders. J Pediatr Gastroenterol Nutr. 2014;59(3):280-287. Reprinted with
permission from Wolters Kluwer Health.
changes in cortical thickness and white matter pathways
associated with chronic pain. (13) CNS amplification of
peripheral pain and nausea signals is a feature of chronic
pain physiology. Finally, the disability associated with FGIDs
may be related to a child’s prediction error or catastroph-
ization; that is, the child believes that the symptoms are
severe and hopeless. In such cases, patients may exaggerate
symptoms and believe that they cannot cope. (14) Improving
children’s self-efficacy, their belief that they can help them-
selves get better, may be an important factor in symptom
resolution.
Early childhood acute pain events predispose to the later
onset of chronic and recurrent abdominal pain. An event as
innocuous as passing a nasogastric catheter in the delivery
room to aspirate gastric contents was associated with a two-
fold increase in hospitalizations for abdominal pain during a
child’s first decade. (15) Other early life stressors associated
with development of FGIDs include cow milk protein hyper-
sensitivity, pyloric stenosis, urinary tract infections, (16) Henoch-
Schönlein purpura, and umbilical hernia repair. (17) Acute
bacterial gastroenteritis is followed by functional abdominal
pain in approximately 30% of children. (18)
Chronic pain in parents also increases the risk of func-
tional abdominal pain in their offspring. Finally, func-
tional abdominal pain may occur together with disease.
For example, a teenager with Crohn disease may have
coexisting IBS. Despite histologic remission of the Crohn
disease, the patient still may suffer with abdominal pain
associated with diarrhea that is relieved by defecation.
FUNCTIONAL GASTROINTESTINAL DISORDERS
Most abdominal pain is associated with one or more FGIDs.
Functional symptoms are not imaginary or feigned, but they
occur without easily discovered pathology. For example, a
runner’s cramp may cause intense pain and shivering when
cold is an uncomfortable sensation, but both of these
functional symptoms are within the expected range of
normal body functioning. In gastroenterology, functional
disorders are defined by symptom-based diagnostic criteria.
The first diagnostic criteria for pediatric FGIDs were created
in the late 1990s, when a group of international thought
leaders met in Rome to create them. Because the meeting
was in Rome, the diagnostic criteria are known as Rome
criteria. The first pediatric Rome criteria were based on the
personal experiences of the experts, but the publication of
criteria stimulated an explosion of research, such that
scientific evidence is accruing about the validity, epidemi-
ology, pathophysiology, and treatment of FGIDs. Some of
the original diagnostic criteria have been modified based on
Vol. 37 No. 9 SEPTEMBER 2016 379
 new data. The Rome 4 criteria for pediatric abdominal pain
disorders are listed in Table 1. (19) Rome criteria replaced
Apley’s concept of recurrent abdominal pain, (1) which had
been the standard for 50 years.
In the past, medical schools taught that every symptom
had a cause, and the physician’s job was to find and fix the
cause for pain. Children with chronic or recurrent abdom-
inal pain were thoroughly evaluated, even overinvestigated,
for disease. (20) Most of these children were without ob-
jective pathology and were labeled as having “recurrent
abdominal pain.” Families and physicians were often frus-
trated and dissatisfied with each other when there was no
answer as to what was causing the pain other than excluding
serious disease. Families rejected the idea that the pain was
“all in her head.” An alternative to the traditional medical
model is the biopsychosocial model, which recognizes that
symptoms may be influenced by disease, psychological ill-
ness, developmental challenges, social factors, genetics, and
functional disorders. Instead of the dualistic approach that
implies if there is no disease of the body, then the pain is
imaginary, the biopsychosocial model integrates mind-body
interactions into an understanding of a whole person. Symptom-
based diagnostic criteria are symptom clusters that occur
with regularity in a population with functional abdominal
pain. Validation studies have proved that the symptom-based
criteria “breed true.”(21)
An important advantage of symptom-based diagnostic
criteria is that a clinician may arrive at a diagnosis on the
first visit. For example, the clinician may say, “You have had
abdominal pains for several hours almost every day for the
past 3 months that are associated with straining to defecate
and infrequent passage of hard stools. There has been no
blood in your stools, no fevers, and no weight loss. Therefore,
you meet criteria for a diagnosis of constipation-predominant
irritable bowel syndrome. We know what it is. It is not dan-
gerous. It comes and goes. There are options for treatment.”
A second advantage of symptom-based diagnosis is a reduc-
tion in the costs for evaluating the symptoms. (20) Instead of
ruling out disease with laboratory tests and endoscopy, it is
possible to make a positive diagnosis with symptom-based
criteria. The clinician can explain that the patient’s symptoms
are diagnostic for an FGID, but if symptoms fail to improve
with treatment, new symptoms develop, or symptoms change
in character, the clinician provides reassurance that he/she is
available and always willing to re-evaluate.
TESTING
Sometimes testing is necessary to assess for disease. For
example, dyspepsia defined by upper abdominal pain or
380 Pediatrics in Review
other discomfort such as nausea may be due to peptic
disease, eosinophilic gastroenteritis, or giardiasis. Endos-
copy may be necessary to assess for mucosal disease in
dyspepsia. However, 85% of those undergoing endoscopy
for dyspepsia have no mucosal disease and are diagnosed
with functional dyspepsia. (22) Because most children with
dyspepsia have no organic disease, an acceptable approach
is to educate the family about dyspepsia and initiate a
therapeutic drug trial with a proton pump inhibitor, cypro-
heptadine, or tricyclic antidepressant. If symptoms resolve
in the subsequent month, there is no need for endoscopy. If
symptoms persist, an endoscopy and biopsies may be
undertaken.
Testing should be limited and focused to rule out a
specific diagnosis. Testing is needed when the child pre-
sents with alarm features (Table 2) that suggest disease.
Testing may be necessary to assuage caregiver fears. On the
other hand, each negative result may reinforce caregiver
belief that something is being missed.
DIFFERENTIAL DIAGNOSIS
School Phobia and Separation Anxiety
Physical symptoms may arise from emotional distress.
School phobia and separation anxiety are two common
entities that may present with abdominal pain. Clinicians
must obtain a history of when the pain episodes occur and
how long they last for both conditions. With school phobia,
symptoms are most prominent in the mornings before
school and improve as the day progresses. Symptoms
may be absent on weekends. The clinician should ask about
bullying and assess the patient’s sense of academic and
social competence. “What is harder for you at school: doing
the schoolwork or getting along with the other kids?” Once
the source of stress is identified, it can be managed. Com-
munication and collaboration among school, parents, and
clinician are helpful in resolving school phobia.
Separation anxiety disorder is an anxiety disorder of
middle childhood (peak onset between 7 and 9 years) that
is characterized by developmentally inappropriate and exag-
gerated fear of separation. Gastrointestinal symptoms of
periumbilical pain, nausea, and vomiting intensify when
separation from the caregiver is imminent. Situations
involving loss, such as moving to a new home or school,
divorce, or death of a family member; stressors such as
academic challenges and difficult peer relationships; and an
overprotective parenting style increase the risk for onset or
exacerbation of separation anxiety. Children with separation
anxiety may develop symptoms and refuse to go to school or
camp or spend any time away from their major attachment
TABLE 1. Rome Criteria for the Pediatric Pain-associated Functional
Gastrointestinal Disorders (15)*
FUNCTIONAL DYSPEPSIA (FD)

Must include 1 or more of the following bothersome symptoms at least 4 times a month for at least 2 months prior to diagnosis:
1. Postprandial fullness
2. Early satiation
3. Epigastric pain or burning not associated with defecation
4. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition
Within FD, the following subtypes are now adopted:
1. Postprandial distress syndrome includes bothersome postprandial fullness or early satiation which prevents finishing a regular meal.
Supportive features include upper abdominal bloating, postprandial nausea, or excessive belching.
2. Epigastric pain syndrome includes all of the following: bothersome (severe enough to interfere with normal activities) pain or burning
localized to the epigastrium. The pain is not generalized or localized to other abdominal or chest regions and is not relieved by defecation or
passage of flatus. Supportive criteria can include: a) burning quality of the pain but without a retrosternal component and b) commonly
induced or relieved by ingestion of a meal but may occur while fasting.
IRRITABLE BOWEL SYNDROME (IBS)
1. Abdominal pain at least 4 days per month over at least 2 months associated with 1 or more of the following:
a. Related to defecation
b. A change in frequency of stool
c. A change in form (appearance) of stool
2. In children with constipation, the pain does not resolve with resolution of the constipation (children in whom the pain resolves have
functional constipation, not IBS)
3. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition
Criteria fulfilled for at least 2 months prior to diagnosis
ABDOMINAL MIGRAINE
Must include all of the following occurring at least twice:
1. Paroxysmal episodes of intense, acute periumbilical, midline, or diffuse abdominal pain lasting 1 hour or more (should be the most severe
and distressing symptom)
2. Episodes are separated by weeks to months
3. The pain is incapacitating and interferes with normal activities
4. Stereotypical pattern and symptoms in the individual patient
5. The pain is associated with 2 or more of the following:
a. Anorexia
b. Nausea
c. Vomiting
d. Headache
e. Photophobia
f. Pallor
6. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition
Criteria fulfilled for at least 6 months prior to diagnosis
Continued

Vol. 37 No. 9 SEPTEMBER 2016 381

 TABLE 1. (Continued )

FUNCTIONAL ABDOMINAL PAIN – NOT OTHERWISE SPECIFIED

Must be fulfilled at least 4 times per month and include all of the following:
1. Episodic or continuous abdominal pain that does not occur solely during physiologic events (eg, eating, menses)
2. Insufficient criteria for IBS, FD, or abdominal migraine
3. After appropriate evaluation, the abdominal pain cannot be fully explained by another medical condition
Criteria fulfilled for at least 2 months prior to diagnosis
FUNCTIONAL CONSTIPATION
Must include 2 or more of the following occurring at least once per week for a minimum of 1 month with insufficient criteria for a diagnosis of IBS:
1. Two or fewer defecations in the toilet per week in a child of a developmental age of at least 4 years
2. At least 1 episode of fecal incontinence per week
3. History of retentive posturing or excessive volitional stool retention
4. History of painful or hard bowel movements
5. Presence of a large fecal mass in the rectum
6. History of large-diameter stools that can obstruct the toilet
7. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition

*More information is available at http://theromefoundation.org.

figure. Many cases resolve with simple interventions from the
pediatrician using a rehabilitation approach targeting 3 goals:
1) reducing fear and avoidance of separation, 2) increasing the
child’s participation in age-appropriate activities, and 3) re-
directing attention to the child’s competent behavior (partici-
pating in school activities, helping others). (23)
The goal of management for both school phobia and
separation anxiety is to help the child learn positive methods
of coping with and transcending the fear. Caregivers should
receive clear instructions from the clinician on how to get
the child back to school. The longer the child is out of school,
the more difficult becomes the return.
Functional Constipation
Sometimes there may be overlap between constipation-
predominant IBS (c-IBS) and functional constipation (Table 1).
Many patients have abdominal pain and constipation. If the
patient says that the constipation is worse than the pain, the
diagnosis is functional constipation. If pain is the most
important feature of the illness, the diagnosis is c-IBS.
Abdominal Wall Pain
Approximately 1 in 30 children presenting with bellyaches
has abdominal wall pain. Chronic abdominal wall pain
is frequently confused with visceral pain, often leading
to extensive diagnostic testing before reaching a correct
diagnosis. There may be a history of pain with movement
but not with eating or defecation. Stretching exercises,
bending, and rotating the trunk may elicit the pain. Carnet’s
test is said to discriminate anterior cutaneous nerve entrap-
ment syndrome from visceral pain. (24) After localizing an
area of maximal tenderness by palpation, the clinician
applies pressure to the tender spot and asks the patient
to tense the abdominal muscles by lifting head or legs. The
examiner releases pressure on the abdomen and reapplies
pressure on the same spot. If the pain is from the viscera, the
reapplication of pressure fails to cause intense pain. When
the pain is from cutaneous nerve entrapment syndrome,
pain upon reapplication of pressure is equivalent to that of
the first palpation. Abdominal wall pain is usually a benign
condition, but if persistent, it may be treated by a pain
specialist with injections of local anesthesia and corticoste-
roids. (25)
Celiac Disease and Non-celiac Gluten Sensitivity
Celiac disease occurs in about 1 in 180 individuals, although
the ratio of symptomatic-to-asymptomatic patients is 1:7.
The most common presenting complaint in childhood
celiac disease is abdominal pain. (26) Screening for celiac
disease with serologic testing is reasonable in many children
with abdominal pain. Celiac disease is not more frequent in
patients with FGIDs than it is in the general population.

382 Pediatrics in Review


TABLE 2. Alarm Signs and Symptoms
Prompting Testing for Disease
• Pain localized to the right upper or right lower quadrants
• Blood in the stools
• Weight loss
• Slow or delayed growth and delayed puberty
• Odynophagia
• Dysphagia
• Persistent vomiting
• Family history of inflammatory bowel disease or celiac disease
• Fevers
• Arthritis
• Perianal disease: skin tags, fissures, fistulae
Some patients report symptoms caused by wheat and/or
gluten ingestion, even though they do not have celiac
disease or wheat allergy, as indicated by negative celiac
disease serologies and immunoglobulin E-mediated assays.
Most of these patients report both gastrointestinal and non-
gastrointestinal symptoms, and all report symptom im-
provement with a gluten-free diet. This condition has
been named non-celiac gluten sensitivity. The clinical response
to a gluten-free diet may be caused by a variety of mechanisms,
including placebo effect, FODMAP (fermentable oligo-
di-monosaccharides and polyols) reduction, and gluten sensi-
tivity. Thus, a diagnosis of non-celiac gluten sensitivity should
be approached with caution and not be based on a short-term
improvement in symptoms on a gluten-free diet.
Peptic Ulcer Disease and Helicobacter pylori Infection
Peptic ulcer disease is uncommon during childhood, with
prevalence estimates of 1 in 2,000 children. Ulcers may present
with abdominal pain, although 50% of childhood ulcers present
with a complication of bleeding, obstruction, or perforation.
Gastric H pylori infection is the most common bacterial
infection worldwide. It is most prevalent in low-income
populations. H pylori is associated with acute and chronic
gastritis, duodenal ulcer disease, and increased risk for gas-
tric cancer. H pylori antigens in a stool sample are 95%
accurate for diagnosis. It is prudent to eradicate the infec-
tion with a course of acid suppression and multiple antibi-
otics. However, H pylori may be an incidental finding in
patients with functional abdominal pain, and eradication of
H pylori may not result in pain reduction. There are evi-
dence-based guidelines for assessing and treating H pylori in
children. (27)
Lactase Deficiency
Carbohydrate malabsorption causes pain because the osmotic
load of luminal carbohydrate draws in water from the intes-
tinal walls, thus increasing the luminal volume, stretching the
bowel wall, and activating stretch and pain receptors located
in the bowel wall. Fermentation of unabsorbed carbohydrate
in the colon results in gas and another osmotic load, drawing
more water into the lumen and stretching the colon wall,
causing pain and diarrhea.
Certain ethnic groups (everyone except Northern Euro-
peans) may develop a relative lactase deficiency in the late first
or second decade. If milk causes pain, substitutes such as soy
milk do not cause symptoms. Lactase deficiency may be diag-
nosed by a breath hydrogen test using lactose as a substrate.
Sucrase Deficiency
Less common than lactase deficiency in late childhood is con-
genital sucrose deficiency, which may cause pain and other
symptoms indistinguishable from IBS. (28) Sucrase deficiency
may be detected by a breath test using sucrose as a substrate.
Fructose Malabsorption
Fructose malabsorption is less common than lactase defi-
ciency and is a cause of diarrhea and gas. (29) Fructose
deficiency may be diagnosed with a breath test using fruc-
tose as the substrate.
Biliary Dyskinesia
Biliary dyskinesia is defined in most pediatric studies by 3
criteria: chronic upper abdominal pain, delayed excretion
of radionuclide on a gallbladder emptying study, and ab-
sence of gallstones. Biliary dyskinesia is treated by chole-
cystectomy. A growing trend in many communities is to
refer children and adolescents to surgeons for evaluation
of chronic or recurrent upper abdominal pain. However,
chronic and recurrent abdominal pain is not the same as
biliary colic, the intense episodic pain required for a biliary
dyskinesia diagnosis in adults. Moreover, there is no evidence
that hepatobiliary iminodiacetic acid (HIDA) scan results are
valid or reliable for diagnosing biliary dyskinesia in children.
In adults, IBS and functional dyspepsia are associated with
delayed gallbladder emptying, but there are no data in chil-
dren. Pediatric studies of biliary dyskinesia use symptoms
consistent with functional dyspepsia to diagnose biliary dys-
kinesia. Leaders in the pediatric gastroenterology commu-
nity stress that dyspepsia responds to nonsurgical treatment.
In the author’s opinion, clinicians should avoid screening
for biliary dyskinesia and instead treat chronic and recurrent
upper abdominal pain or nausea as dyspepsia.
Vol. 37 No. 9 SEPTEMBER 2016 383
 TREATMENT FOR FUNCTIONAL ABDOMINAL PAIN
Treatment for abdominal pain varies with the style of the
clinician, patient/caregiver preferences, and availability of
the variety of modalities. The clinician should establish a
therapeutic alliance with the family before the family will
accept a symptom-based diagnosis and agree to suspend the
search for disease. Treatment of functional abdominal pain
disorders should always include reassurance, empathy, and
education. Children and families should be assured that the
clinician believes the pain is real. The clinician explains that
in children, abdominal pain without disease is more common
than abdominal pain with disease. Although pharmacologic
treatment is common, cognitive behavioral therapy (CBT) and
hypnotherapy have been shown to be effective for abdominal
pain. The success of psychological interventions as well as
the powerful effect of placebos demonstrates the complemen-
tary influences between the brain and the gut and the impor-
tance of the CNS in the pathophysiology of abdominal pain.
Education
Making a symptom-based diagnosis and providing a lucid
explanation for symptoms is usually sufficient to reduce
the spoken and unspoken fears that prompted the visit.
Patients and families want to know the answers to 4 ques-
tions: What is wrong? Is it dangerous? Will it go away? What
can we do about it? The clinician should state the answers
to each question clearly. In gastroenterology clinic, 9% of fam-
ilies are satisfied with a clear diagnosis and a promise of con-
tinuing availability, and they decline other treatment. (30)
Diet Changes
A minority of patients identifies specific foods as a source
for pain, such as fried foods, red sauces, and milk. Patients
should eliminate the offending foods from their diets. There
is no evidence that a lactose-, gluten-, histamine-, or carbonic
acid-free diet; increased fluid intake; or prebiotics have effects
on pain-associated FGIDs. Probiotics have generally been
ineffective for abdominal pain with 2 exceptions in adult
studies. Probiotics VSL#3 (31) and Lactobacillus GG (32) may
be effective in some cases of abdominal pain associated with
bloating and diarrhea. Extra fiber is not helpful in most cases.
Pharmacologic Treatment
There are no drugs approved by the U.S. Food and Drug
Administration (FDA) for treatment of abdominal pain in
children, but that does not hamper prescribing. Proton pump
inhibitors and histamine-2 receptor antagonists appear to be
the most prescribed drugs, despite symptom improvement
rates being similar to those for placebo. The rationale for
prescribing gastric acid suppression may relate to the
384 Pediatrics in Review
excellent safety profile of the drugs and the need to relieve
concerns that the pain may be caused by esophagitis,
gastritis, duodenitis, or peptic ulcer disease. Narcotics that
are a mainstay of treatment for acute pain, including abdom-
inal migraine, should not be used for chronic and recurrent
abdominal pain. Aspirin, ibuprofen, and other nonsteroidal
anti-inflammatory drugs should not be prescribed for ab-
dominal pain because they may disrupt the gastric mucosal
barrier and cause gastritis and ulcers. A recent systematic
review of pediatric randomized, placebo-controlled drug
trials for functional abdominal pain (33) found 8 studies, low
numbers of study participants, and many limitations and
biases. Meta-analyses suggest that tricyclic antidepressants
and serotonin reuptake inhibitors are effective for adults with
abdominal pain. Data supporting anticholinergic, “antispas-
modic” drugs are less robust. Overall, the quality of evidence
for pharmacologic therapy in children with chronic or recur-
rent abdominal pain is low to very low.
In randomized clinical trials, responses to placebos for
functional abdominal pain are usually about 40%. (34) For
some clinicians who are learning what works for their patients,
a 40% response rate may condition them to continue to pre-
scribe drugs that are essentially no better than placebos. (35)
These clinicians’ learned responses might be slow to extinguish
because a 40% response rate reinforces their prescribing habits.
Psychological Treatment
A recent review of nonpharmacologic treatment of func-
tional abdominal pain concluded that hypnosis and CBT
were more effective than placebo for pediatric abdominal
pain. (36) However, limited access to mental health services
is common in many communities. Identifying the stressors
triggering symptoms and working to eliminate such stres-
sors may be a key to successful management.
One study found that CBT reduced pain better than an
identical time for education and support (attention control).
In this trial, parents and children participated in 3 brief
weekly sessions that focused on relaxation training, address-
ing inappropriate thoughts about symptoms, and working
with parents to modify the family’s responses to child illness
behaviors (social learning). (10)(37)
Hypnotherapy is effective for abdominal pain. In a ran-
domized, controlled trial of 52 children, pain intensity,
frequency, and somatization were reduced after treatment
and persisted after 5 years, indicating long-term benefit.
(9)(38) Self-hypnosis through audiotapes was effective and
is a readily available, cost-effective technique. (39)
There is weak evidence to recommend complementary
and alternative interventions such as acupuncture or yoga
for abdominal pain.
Abdominal Migraine
Abdominal migraine is 1 of 3 paroxysmal brain/gut disor-
ders, along with cyclic vomiting syndrome and migraine
headaches. Paroxysmal brain/gut disorders are named by
the dominant symptom: abdominal pain, vomiting, or head-
ache. Abdominal migraine accounts for about 0.5% of ab-
dominal pain patients in a pediatric gastroenterology clinic,
making it the least common of the pain-associated FGIDs. A
most important aspect of abdominal migraine is recogniz-
ing the symptom-based criteria to make a proper diagnosis.
Often children with abdominal migraine visit emergency de-
partments, are evaluated for acute abdomen, and receive no
diagnosis and no relief from pain because emergency depart-
ment clinicians do not want to mask symptoms. The child
suffers needlessly. In the author’s opinion, a diagnosis of acute
abdominal migraine frees the clinician to titrate narcotics to
restful sleep, with repeat doses as needed until the episode
passes. After the episode is over, future episodes are usually
prevented with amitriptyline 1 mg/kg per day.
DRUG TREATMENT FOR FUNCTIONAL DYSPEPSIA
(TABLE 3)
There are no FDA-approved drugs for children with func-
tional dyspepsia. Cyproheptadine is commonly used for dys-
pepsia in children. (40) In another trial, cyproheptadine
reduced the episodes and severity of functional abdominal
pain. (41)
There are no prospective randomized treatment trials for
pediatric functional dyspepsia. Extrapolation from adult
data suggests that acid blockade with histamine receptor
antagonists and proton pump inhibitors can be offered to
older children and adolescents for pain-predominant
symptoms. (42) If cure of functional dyspepsia is defined
as complete symptomatic relief after 4 weeks of treat-
ment, omeprazole is superior to ranitidine, famotidine,
and cimetidine. (43) Although convincing data are lacking
in children, low-dose tricyclic antidepressant therapy with
agents such as amitriptyline and imipramine is often
considered in difficult cases.
A recent trial in adults showed amitriptyline to be
superior to placebo and citalopram in the epigastric pain
subtype but not the postprandial distress subtype. (44)
Extrapolating these data to pediatrics might be risky,
but one approach might be to treat epigastric pain with
amitriptyline and postprandial distress with another
drug. Two drugs that improve gastric receptive relaxation
and treat nausea and early satiety are buspirone and
mirtazapine. Buspirone, an anxiolytic, requires multiple
dosing daily but has no black box warning about suicide.
(45) Mirtazapine, an antidepressant, requires only a
single bedtime dose and facilitates restful sleep in addi-
tion to treating postprandial distress, anxiety, panic, and
depression. (46) For chronic daily or constant nausea,
mirtazapine is superior to antiemetics such as prome-
thazine or ondansetron.
TREATMENT FOR IRRITABLE BOWEL SYNDROME
The Low FODMAP Diet
The FODMAPs include fructose (fruits, honey, high-
fructose corn syrup), lactose (dairy), fructans (wheat, garlic,

TABLE 3. Drug Treatment for Functional Dyspepsia

FUNCTIONAL DURATION OF
DISORDER DRUGS DOSE MEDICATION CLASS TREATMENT ADVERSE EFFECTS COMMENTS

Functional Epigastric pain: 10-50 mg qhs Tricyclic Until the pain goes Constipation, sedation; Start at 10 mg and increase
Dyspepsia Amitriptyline antidepressant away plus 6 months nightmares if patient by 10 mg/wk until pain
misses a dose resolves or 50 mg
Postprandial distress: 0.25-0.5 mg/kg per day Histamine-1 and Until the discomfort goes Fatigue, dizziness, Increased appetite in
Cyproheptadine divided bid or tid serotonin-1 away plus 6 months weight gain about 50% of children
antagonist lasts about 3 weeks

Irritable Bowel d-IBS: Amitriptyline 10-50 mg qhs Tricyclic Until the pain goes away Constipation, sedation, ECG unnecessary in
Syndrome antidepressant plus 6 months nightmares if patient individuals with
misses a dose no heart disease
Alosetron 0.5-1 mg qd or bid Serotonin-3 receptor Indefinite Constipation Very effective; expensive
antagonist
c-IBS: Imipramine 10-50 mg qhs Tricyclic Until the pain goes away Sedation Imipramine is less
antidepressant plus 6 months constipating and sedating
than amitriptyline
Lubiprostone 8-24 mg qd or bid Chloride channel Indefinite Diarrhea, nausea Expensive
activator

bid¼twice daily, c-IBS¼constipation-predominant irritable bowel syndrome, d-IBS¼diarrhea-predominant irritable bowel syndrome,
ECG¼electrocardiography, qd¼daily, qhs¼every bedtime, tid¼thrice daily

Vol. 37 No. 9 SEPTEMBER 2016 385


Figure 3. Preteens and teens with functional symptoms associated with
disability fall into a gap between conventional medicine and
conventional mental health. They require a clinician who understands
functional symptoms and a rehabilitation approach to treatment.
onion, inulin), galactans (legumes such as beans, lentils,
soybeans), and polyols (sweeteners containing isomalt, man-
nitol, sorbitol, xylitol, stone fruits such as avocados, apricots,
cherries, nectarines, peaches, plums). FODMAPs may not be
digested or absorbed well and could be fermented by bacteria
in the intestinal tract when eaten in excess. Typical IBS
symptoms of diarrhea, constipation, gas, and bloating may
improve with a low FODMAP diet. (47) A low FODMAP diet
is best initiated in consultation with a dietitian to assure that
the diet meets the child’s nutritional needs.
Medical Foods
Two medical foods are on the market to treat IBS. IBGast is
peppermint oil in an enteric-coated capsule. In one pediatric
randomized, controlled trial, peppermint oil was effective
386 Pediatrics in Review
for treating IBS. (48) Dosing is 1 capsule for symptoms 1 to
3 times daily. Bovine serum immunoglobulin taken twice
daily was effective for diarrhea-predominant IBS (d-IBS)
in adults. (49)
Drugs (Table 3)
There are no FDA-approved drugs for treatment of chil-
dren with IBS. Randomized clinical trials are missing for
most drugs used for childhood IBS. For example, despite
their routine use by clinicians, there is no evidence that
acid suppression with histamine-2 receptor antagonists
or proton pump inhibitors is helpful in IBS.
Tricyclic antidepressants are effective treatment for
IBS in adults, (50) but 2 randomized, controlled trials in
children were unsatisfying because placebo-treated chil-
dren did as well as amitriptyline-treated children. (51)(52)
However, amitriptyline dosing in the pediatric trials may
have been too low to achieve a response. Amitriptyline and,
to a lesser extent, imipramine are sedating and consti-
pating. If the patient has abdominal pain, diarrhea, and
insomnia, a tricyclic antidepressant may be a good choice
(Table 3).
In children with d-IBS who are unable or unwilling
to take amitriptyline because of concerns about cardiac
arrhythmias, seizures, or mood effects, the serotonin-3
receptor antagonist alosetron is effective. Clonidine may
be a good choice for d-IBS and disordered sleep.
There are several alternatives for children with c-IBS.
A clinician might choose to treat the constipation with
polyethylene glycol titrated to soft stools together with a
Figure 4. Pathogenesis of pain-associated
disability syndrome (PADS). PADS may be
triggered by factors causing autonomic
arousal in a preteen or teen with a functional
gastrointestinal disorder. From Hyman PE,
Bursch B, Sood M, Schwankovsky L, Cocjin J,
Zeltzer LK. Visceral pain-associated disability
syndrome: a descriptive analysis. J Pediatr
Gastroenterol Nutr. 2002;35(5):663-8.
Reprinted with permission from Wolters
Kluwer Health.
tricyclic antidepressant or serotonin reuptake inhibitor for
pain. Lubiprostone binds to small intestinal epithelium,
activating chloride channels to facilitate secretion of chlo-
ride and water. Lubiprostone is approved by the FDA for c-
IBS and functional constipation in women, but there are
scant data in children. (53) Adherence may be better with 1
or 2 tablets of 24-mg lubiprostone per day compared to
asking a teenager to mix and drink polyethylene glycol.
Lubiprostone should be taken with food to reduce the
chances of nausea.
WHEN TO SEE A SPECIALIST
Children should be referred to a pediatric gastroenterologist
for further testing and/or treatment in the event of:
• Treatment failure
• Prolonged school absence
• Presence of alarm features
• Abnormal laboratory test results (including abnormal
celiac tests)
DISABILITY ASSOCIATED WITH FUNCTIONAL
ABDOMINAL PAIN
Children with abdominal pain may miss school. Care-
givers should understand that staying home from school
is considered a disability in the same way that staying
home from work is considered a disability for adults. The
more missed school, the more difficult it is to return.
Staying home leads to greater disability, increased focus
Figure 5. Multidisciplinary biopsychosocial
rehabilitation model for treating disability
associated with functional gastrointestinal
disorders. From Hyman PE, Bursch B, Sood M,
Schwankovsky L, Cocjin J, Zeltzer LK. Visceral
pain-associated disability syndrome: a
descriptive analysis. J Pediatr Gastroenterol
Nutr. 2002;35(5):663-8. Reprinted with
permission from Wolters Kluwer Health.
on pain, and fewer opportunities for distraction and social
interaction. In addition, children who stay at home for long
periods of time may become physically deconditioned and
less secure in their ability to interact with their peers.
Children who stay at home sometimes adopt a sick role that
makes rehabilitation difficult.
Pain-associated disability syndrome (PADS) is defined
as a preteen or teen with at least 2 months of abdominal
pain or other symptom such as nausea that is unresponsive
to acute management strategies. (54) Doctors do many
tests but find no disease, yet symptoms interfere with the
patient’s routine activities, such as attending school, eat-
ing, and sleeping. The symptoms and disability are out of
proportion to the clinicians’ findings. Physicians some-
times admit that they find nothing wrong and refer
families to mental health professionals. Mental health
professionals usually find no overt psychopathology dur-
ing the first interview because the patient converts emo-
tional distress into physical symptoms and denies
symptoms of a mood disorder. PADS patients fall into
a gap between conventional medicine and conventional
mental health (Fig 3).
PADS appears to be a downward spiral of disability and
pain that has 3 continuously interacting features: abnormal-
ities in gastrointestinal motility, abnormalities in sensory
experience such as pain and nausea, and dysregulation in
the autonomic nervous system (Fig 4).
Every PADS patient meets diagnostic criteria for 1
or more FGIDs that are diagnosed with symptom-based
criteria. FGIDs, which occur in approximately 25% of the
Vol. 37 No. 9 SEPTEMBER 2016 387
 population, are associated with minor abnormalities in
gastrointestinal motility and sensation, but nearly all
affected patients cope with such disorders without
becoming disabled. In PADS, a developmental, family,
or mental health problem causes sustained autonomic
arousal. The intensity of symptoms and the degree of
disability are proportional to the severity of emotional
distress. PADS severity is inversely correlated with
an individual’s assessment of his or her own academic
or social competence. PADS patients often feel helpless.
Catastrophization, the belief that symptoms can only
worsen and the patient is helpless, further activates auto-
nomic arousal. Similarly, an external locus of control, the
belief that the suffering can be reduced only from outside
sources, interferes with coping and amplifies arousal. Treat-
ment for teens with PADS encompasses a shift away from
the medical model, in which a doctor does something to
cure a passive patient, to a rehabilitation model, in which
clinicians teach the child the necessary skills to return to a
normal lifestyle.
Treatment includes physical therapy, psychotherapy,
and drugs to treat coexisting mental health issues and
sleep disruptions (Fig 5). Psychotherapy and hypnosis have
the advantage of effects that last long after the treatment
period compared to drug effects that last only as long as
treatment continues. Drugs have the advantage of not
requiring a psychotherapist. However, strong evidence
for drug efficacy in children with pain related to FGIDs
is missing. Treatment requires a multidisciplinary biopsy-
chosocial team approach that must include the family.
When the child or family does not accept the diagnosis
or challenges the treatment, management fails. When the
child, family, and team of professionals are in step, treat-
ment succeeds.
Parent Resources from the AAP at HealthyChildren.org
Chronic and Recurrent Abdominal Pain
• https://www.healthychildren.org/English/health-issues/conditions/abdominal/Pages/Abdominal-Pain-in-Children.aspx
• Spanish: https://www.healthychildren.org/spanish/health-issues/conditions/abdominal/paginas/abdominal-pain-in-children.aspx
• https://www.healthychildren.org/English/health-issues/conditions/abdominal/Pages/Abdominal-Pains-in-Infants.aspx (English only)
388 Pediatrics in Review
Summary
• On the basis of strong research evidence, most chronic and
recurrent abdominal pain in children and adolescents is
functional, meaning that symptoms are not feigned, but there is
no easily detected disease.
• Symptom-based diagnostic criteria facilitate rapid diagnosis for
most children and adolescents with functional abdominal pain.
For most children who meet diagnostic criteria for a functional
disorder and have no warning signs for disease (weight loss,
fevers, blood in stool), no testing is necessary or desirable.
• On the basis of strong epidemiologic evidence, irritable bowel syndrome
(IBS), defined by chronic or recurrent abdominal pain associated with
diarrhea or constipation or alternating diarrhea and constipation, is the
most common of the functional gastrointestinal disorders.
• Because of the very few prospective randomized, controlled trials
in children, there is no generally accepted safe and effective
treatment for IBS in this population. On the basis of strong
research evidence, treatments for IBS in adults include tricyclic
antidepressants and cognitive behavioral therapy.
• On the basis of strong research evidence, the placebo response
rate in functional abdominal pain is approximately 40%; this
response rate ensures that any treatment works some of the time.
• On the basis of some research evidence and consensus, disability
from a functional disorder is proportional to comorbid psychological
distress from a mental health disorder or learning disability.
• On the basis of primarily consensus, due to lack of prospective
studies, treatment for those disabled by functional abdominal
pain requires shifting from an acute medical to a rehabilitation
model and involves a team approach that includes cognitive
behavioral therapy, medication to regulate sleep and reduce
autonomic arousal, and physical therapy. Refusal to engage with
mental health treatment is associated with treatment failure.
References for this article are at http://pedsinreview.aappublications.
org/content/37/9/377.
PIR Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link under the article title in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://www.aappublications.
org/content/journal-cme.

1. A 10-year-old girl is brought by her parents to see you for the first time for evaluation of a 1- REQUIREMENTS: Learners
year history of abdominal pain that she has been experiencing several times a week. You can take Pediatrics in
know that chronic recurrent abdominal pain is common among children across the world. Review quizzes and claim
You also know that most such pain is not caused by isolated organic disease, but rather credit online only at:
reflects a symptom sparked by a combination of overlapping physical, physiological, http://pedsinreview.org.
mental, and social factors. Which of the following characteristics of the pain will prompt
you to initiate an immediate search for an organic explanation?
To successfully complete
A. Has a consistent periumbilical distribution. 2016 Pediatrics in Review
B. Is associated with a 10-lb weight loss. articles for AMA PRA
C. Occurs primarily upon awakening. Category 1 CreditTM,
D. Occurs primarily upon going to sleep. learners must
E. Occurs several times a day, lasting less than 5 minutes for each episode. demonstrate a minimum
2. Over the past 25 years, the uncovering of a better understanding of the pathophysiology of performance level of 60%
chronic and recurrent abdominal pain has: or higher on this
A. Decreased the need for mental health counseling for the complaint. assessment, which
B. Increased the clinician’s ability to use history and physical examination to reliably measures achievement of
differentiate one functional disorder from another. the educational purpose
C. Increased the need for primary care physicians to refer patients with such pain to and/or objectives of this
gastroenterologists. activity. If you score less
D. Increased the requirement for sophisticated diagnostic laboratory testing. than 60% on the
E. Raised doubt about the role of social stress as a contributing cause. assessment, you will be
given additional
3. Since starting kindergarten, an 8-year-old boy has had frequent periumbilical pain and
opportunities to answer
nausea in the morning. He occasionally vomits. Which of the following statements would
questions until an overall
strongly suggest that he suffers from separation anxiety?
60% or greater score is
A. He has postbreakfast fullness, bloating, and belching. achieved.
B. He feels fine soon after being permitted to stay home from school.
C. His symptoms are present both on weekdays and weekends.
D. His symptoms are relieved by defecation. This journal-based CME
E. His symptoms improve at school as the day goes on. activity is available
through Dec. 31, 2018,
4. A 12-year-old girl has experienced daily periumbilical abdominal pain lasting several hours for
however, credit will be
the past 2 years. She rarely misses school. She has gained weight normally and experienced
recorded in the year in
normal menarche. She strains to defecate and passes small hard stools every 2 days, after which
which the learner
she experiences some relief from pain but no complete resolution. Treatment with polyethylene
completes the quiz.
glycol has failed to resolve the problem. Her physical examination yields normal results. Based
on her history and examination, which of the following is the most likely diagnosis?
A. Abdominal migraine.
B. Functional constipation.
C. Functional dyspepsia.
D. Irritable bowel syndrome.
E. Postprandial distress syndrome.

Vol. 37 No. 9 SEPTEMBER 2016 389

 5. The caregivers of children and adolescents diagnosed with functional abdominal pain in
your practice ask you about options for treatment and their effectiveness. Assuming that you
already have established a therapeutic alliance with patients and families, provided them
with assurances that you believe that the pain is real, and offered empathy, education, and
reassurance, which of the following proposed treatment options currently promises the best
treatment outcome for children and adolescents with functional abdominal pain?
A. Acupuncture.
B. Changes in diet.
C. Cognitive behavioral therapy.
D. Intensive personal psychotherapy.
E. Prescription of U.S. Food and Drug Administration-approved medications.

390 Pediatrics in Review


EDITOR’S NOTE
We invite readers to contribute Index of
Suspicion cases at: Submit and Track My
Manuscript.
AUTHOR DISCLOSURE Drs Shah and Lee
have disclosed no financial relationships
relevant to this article. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
Constipation, Irritability, and Poor Feeding in
1 2-month-old Boy
Nidhi A. Shah, MD,* Henry C. Lee, MD*
*Department of Pediatrics, Division of Neonatal and Developmental Medicine,
Stanford University, Stanford, CA.
PRESENTATION
A 2-month-old boy, who had been born at term, presents to the emergency
department with irritability and poor feeding. The infant had been healthy with no
temperature instability until approximately 2 weeks ago, when he became fussier
than usual. Yesterday he refused to breastfeed and had a decreased number of wet
diapers. His last stool was 5 days ago. His parents report that the infant is drooling
more and appeared to choke on his secretions today.
The pregnancy was unremarkable and was completed with a normal vaginal
delivery. The infant is exclusively breastfed, with good weight gain and normal
development. Family members were ill with a stomach virus 10 days ago, but the
infant appeared unaffected. His only medications are probiotics, chamomile, and
an herbal supplement. Recent travel includes camping along the coastline. The
infant has not received any vaccines.
Vital signs are as follows: temperature of 36.7°C (98.1°F), heart rate of 166
beats per minute, respiratory rate of 75 breaths per minute, blood pressure of
85/43 mm Hg, and oxygen saturation of 95%. On physical examination, the boy is
grunting and has increased work of breathing, with subcostal retractions and
nasal flaring. Pupils are equal, round, and reactive to light; extraocular movements
are intact; and facial muscles appear symmetric. He has an absent gag reflex and
absent bowel sounds. Passive tone appears to be normal, and deep tendon reflexes
cannot be elicited, which may be due to agitation and difficulty of examination.
Laboratory evaluation reveals the following:
• White blood cell count 9,910/mL (9.91  109/L)
• Hemoglobin 12 g/dL (120 g/L)
• Platelet count 454  103/mL (454  109/L)
• Sodium 142 mEq/L (142 mmol/L)
• Potassium 5.4 mEq/L (5.4 mmol/L)
• Chloride 110 mEq/L (110 mmol/L)
• Serum carbon dioxide 11 mEq/L (11 mmol/L)
• Blood urea nitrogen 20 mg/dL (7.1 mmol/L)
• Creatinine 0.5 mg/dL (44.2 mmol/L)
• Glucose 55 mg/dL (3 mmol/L)
A chest radiograph yields unremarkable results, and a plain abdominal
radiograph (kidneys, ureter, bladder) shows substantial air in the bowel (Figure).
Vol. 37 No. 9 SEPTEMBER 2016 391

Figure. Abdominal radiograph (kidneys, ureter, bladder) showing diffuse
intestinal dilation.
The infant is intubated for airway protection. Blood and
urine are sent for culturing, and empiric antibiotics are
initiated. Stool tests ultimately lead to a diagnosis.
DISCUSSION
Based on the infant’s presentation of respiratory distress
and abnormal neurologic findings, the differential diagno-
sis included sepsis, meningoencephalitis, inborn error of
metabolism, exposure to or ingestion of toxin, and congen-
ital neuromuscular disease. The findings of constipation,
difficulty handling secretions, and absent gag reflex also
raised the possibility of infantile botulism.
Stool tests were ordered for botulinum toxin, but samples
could not be obtained efficiently due to ileus. A saline ene-
ma was performed, and stool was obtained on the second at-
tempt. The stool was sent to the state laboratory for botulinum
testing. Because of the delay in sending the stool and the
high suspicion for infantile botulism, botulism immuno-
globulin (BabyBIG) was administered empirically. The infant
showed improved spontaneous movement within hours of
treatment and was able to be extubated 2 days later. The state
laboratory confirmed the diagnosis of infantile botulism 1 day
after treatment was initiated. The infant was discharged from
392 Pediatrics in Review
the hospital 5 days after treatment with completely normal
neurologic function.
The Condition
In the United States, an average 145 cases of botulism are
reported annually, of which 65% are cases of infantile
botulism. Botulism is caused by Clostridium botulinum, a
gram-positive, spore-forming bacterium that produces a
toxin which blocks cholinergic transmission on the presyn-
aptic side of ganglia and neuromuscular junctions. Although
infantile botulism is most commonly associated with inges-
tion of raw honey, most cases actually occur from the inges-
tion of spores found in dust and dirt. Of the 4 subtypes of C
botulinum, types A and B are responsible for most cases.
Type A botulism is believed to be more severe than type B.
Infantile botulism affects infants up to 12 months of age,
although the median age of onset is 3 to 4 months. Older
children are believed to be less susceptible to botulism due
to their mature gastrointestinal tracts, which can excrete the
spores before they germinate. The condition most com-
monly presents with constipation and poor feeding, fol-
lowed by progressive descending weakness and hypotonia.
Infants can rapidly decompensate because cranial nerve
function is compromised, leading to a loss of suck and
gag reflexes and eventually respiratory failure.
Diagnosis
Diagnosing infantile botulism can be difficult. The most
sensitive test for diagnosis is identification of toxin in the
stool. Because constipation is present in almost all affected
infants, however, stool can be difficult to obtain. Serum mar-
kers are often negative.
Management
Supportive treatment is the mainstay of the therapy. Infants
with respiratory failure must be intubated to protect the
airway and placed on mechanical ventilation. Paralysis may
progress rapidly, and heightened vigilance is required to
prevent sudden deterioration. During the period of ileus,
nasogastric decompression along with parenteral nutrition
may be required.
BabyBIG is a safe and effective therapy to treat both types
A and B infantile botulism. It contains primarily immuno-
globulin G that is pooled from donors. Because of the lack
of adverse effects associated with the treatment, infants
with clinical presentations consistent with infantile botulism
should be empirically treated with BabyBIG even before
confirmation of the diagnosis. Systemic antibiotics should
be discontinued because they might lead to lysis of C botu-
linum in the intestines, resulting in further release of toxin.
 In a randomized, controlled study, administration of
BabyBIG reduced length of hospital admission, duration of
intensive care, and duration of mechanical ventilation for
treated infants compared to those who were not treated with
BabyBIG.
• Infantile botulism almost always presents with feeding
difficulty and constipation, followed by a descending
paralysis.
• Botulism immunoglobulin should be administered early,
even without the results of confirmatory tests.

Lessons for the Clinician

• Infantile botulism is most commonly caused by ingestion Suggested Readings for this article are at http://pedsinreview.
of spores found in dirt and dust. aappublications.org/content/37/9/391.

Parent Resources from the AAP at HealthyChildren.org

Case 1: Constipation, Irritability and Poor Feeding in a 2-month-old Boy
• https://www.healthychildren.org/English/health-issues/conditions/infections/Pages/Botulism.aspx
• Spanish: https://www.healthychildren.org/spanish/health-issues/conditions/infections/paginas/botulism.aspx

Vol. 37 No. 9 SEPTEMBER 2016 393


AUTHOR DISCLOSURE Drs Shah and Angelilli
have disclosed no financial relationships
relevant to this article. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
394 Pediatrics in Review
Acute Respiratory Distress and Facial
2 Petechiae in a 4-month-old Boy
Alpa Patel Shah, DO,* Mary Lu Angelilli, MD*
*Children’s Hospital of Michigan, Detroit, MI.
PRESENTATION
A 4-month-old twin infant boy presents to the emergency department (ED) with a
10-hour history of increased work of breathing, poor feeding, and decreased
activity. Prior to arrival, the patient’s mother administered 2 albuterol treatments
via nebulizer, which helped transiently. Then she took the child to his pediatri-
cian’s office, where he was given an additional albuterol treatment and sub-
sequently referred to the ED for persistent respiratory distress. The infant has had
2 hospital admissions for bronchiolitis. His parents deny any history of fever,
cough, wheezing, runny nose, or vomiting. His twin brother remains asymptomatic.
In the ED, the child is alert but tachypneic, with intercostal and subcostal
retractions and nasal flaring. His initial vital signs include a temperature of 37.8°C
(100°F), heart rate of 174 beats per minute, respiratory rate of 34 breaths per
minute, blood pressure of 111/53 mm Hg, and pulse oximetry of 80% in room air.
He weighs 4.8 kg (less than the third percentile). Findings on physical exami-
nation include a reddish discoloration on both sides of the neck and petechiae
on the right cheek. A subconjunctival hemorrhage is also noted in the right eye.
His lungs are clear to auscultation bilaterally, without wheezing, stridor, rales,
or crackles, despite persistent and severe retractions. Auscultation of the heart
reveals a regular rate and rhythm without a murmur. Capillary refill is less than 2
seconds. The remainder of the physical examination yields unremarkable results.
DISCUSSION
The initial evaluation for respiratory distress included chest radiography, which
was negative for any cardiopulmonary process; a capillary blood gas analysis that
revealed a pH of 7.32, PCO2 of 41 mm Hg, PO2 of 57 mm Hg, and bicarbonate of
19 mEq/L (19 mmol/L); a complete blood cell count and electrolyte panel, which
documented no findings of note; coagulation studies, which were within normal
limits; computed tomography (CT) scan of the head, which was negative for
hemorrhage or any intracranial pathology; and electrocardiography and echocar-
diography, the results of which were within normal limits. The patient progressed
to respiratory failure and ultimately required intubation and transfer to the
pediatric intensive care unit.
Due to the petechiae and discoloration around the child’s neck as well as the
right subconjunctival hemorrhage, which raised suspicion for trauma, the child
protection team (CPT) was consulted and a bone survey,
ophthalmology examination, and magnetic resonance im-
aging (MRI) of the brain and cervical spine were re-
commended. MRI of the brain documented soft-tissue
thickening at the C2/C3 level. MRI of the cervical spine
demonstrated subluxation of C2 over C3, with an epidural
hematoma causing compression of the spinal cord and
edema in the lateral masses of C2 and C3. A CT scan of
the cervical spine showed bilateral pars fractures of C2 with
widening of the C2-C3 intervertebral disc spaces consistent
with a hangman’s fracture (Figure). Ophthalmologic exam-
ination yielded negative results, and the bone survey did not
document any additional fractures. Child physical abuse
was diagnosed.
Differential Diagnosis
The differential diagnosis in a previously healthy infant
presenting with acute respiratory failure in the presence
of bruising of the face and/or neck includes both non-
accidental and accidental trauma to the spine and/or spinal
cord. Nonaccidental trauma may specifically result from
strangulation injury or intentional smothering leading to
asphyxia.
The Condition
A hangman’s fracture is a traumatic spondylolysis of C2.
The term originates from the fact that this injury was
commonly seen as a consequence of judicial hangings.
Today, hangman’s fractures refer to bilateral C2 pars inter-
articularis fractures and are usually the result of a sudden
deceleration injury. This is seen in motor vehicle crashes
Figure. Computed tomography scan of the cervical spine. A. Anteroposterior image showing bilateral pars interarticularis fractures of C2. B. Lateral
image showing C2 pars interarticularis fracture.
and involves a powerful combination of hyperextension,
compression, and/or distraction forces. Although rare,
hangman’s fractures have been reported in the setting of
child physical abuse. However, the mechanism of injury in
abuse is unknown because the perpetrator does not always
disclose information regarding the abuse.
Even in the case of known child physical abuse, clinicians
must distinguish a traumatic hangman’s fracture from a
congenital C2 spondylolysis. A few factors that point to
abusive trauma are: disruption of the intervertebral discs,
ligamentous injury or hematoma on MRI, and the presence
of callous formation or other evidence of healing on serial
imaging. In this case, there was evidence of ligamentous
injury, an epidural hematoma, widening of the C2/C3
disc space, and edema of the lateral masses. This com-
bination, along with the concerning area of ecchymosis
around the patient’s neck, petechiae on the cheek, and
subconjunctival hemorrhage, is worrisome and should
immediately alert a clinician to the possibility of child
physical abuse.
Management
The management of a patient with a suspected hangman’s
fracture requires close collaboration with the neurosurgical
team. Cervical spine immobilization and observation are
most important, although neurosurgical repair may be
indicated in select cases. Physical therapy is a crucial com-
ponent of treatment to ensure appropriate rehabilitation,
and serial cervical spine images are recommended. The
remainder of the management is case-dependent and focused
on supportive care.
Vol. 37 No. 9 SEPTEMBER 2016 395
 Patient Course and Outcome
The CPT made a referral to child protective services and the
patient was evaluated by a neurosurgeon. The cervical spine
was stabilized using a cervical collar followed by an infant
restraining device. The neurosurgery team noted weakness
in the left upper extremity on their examination, for which
he was evaluated by a neurologist and treated by both
physical and occupational therapy services. Nasogastric tube
feedings were started to maintain adequate nutrition.
On the sixth day of admission, the patient’s father re-
quested a meeting with the CPT physician. He disclosed
that he placed his thumbs around the front of the patient’s
neck and dug his fingers into the back of the neck as he threw
him onto the bed. The father stated that he became frustrated
because the baby was crying despite his efforts to feed and
change him. The incident was promptly referred to local officials.
The patient continued to improve with cervical spine
immobilization, physical therapy, and occupational therapy.
Within several days of placing him in a cervical collar, his
oromotor skills improved and nasogastric tube feedings
were discontinued. He was also successfully weaned
396 Pediatrics in Review
off of mechanical ventilation. He was discharged to his
maternal grandmother in stable condition with outpatient
physical and occupational therapy services. The patient was
followed with serial cervical spine images, which showed
evidence of healing.
Lessons for the Clinician
• Child physical abuse must be considered in any infant
who presents with unexplained bruises.
• Unexplained bruises on the neck should alert the clinician
to the possibility of a cervical spine injury.
• Although uncommon, bilateral C2 pars fractures have
been reported specifically in cases of abusive head and
neck trauma.
• It is important to distinguish a primary spondylolysis or
persistent synchondrosis from a traumatic spondylolysis.
• Maintaining a high index of suspicion for neck injury with
early cervical spine immobilization is crucial.
Suggested Readings for this article are at http://pedsinreview.
aappublications.org/content/37/9/394.

AUTHOR DISCLOSURE Drs Kojima,
Rosenberg, and English have disclosed no
financial relationships relevant to this article.
This commentary does not contain a
discussion of an unapproved/investigative
use of a commercial product/device.
3 Sore Throat and Fever in a 4-year-old Boy
Katsuaki Kojima, MD,* Melissa Rosenberg, MD,† B. Keith English, MD*
*Departments of Pediatrics and Human Development, College of Human Medicine;
†
Department of Pediatrics, College of Osteopathic Medicine, Michigan State University,
East Lansing, MI.
PRESENTATION
A 4-year-old previously healthy and fully immunized boy presents with a 2-day
history of sore throat and a 1-day history of fever and drooling. He awakened today
with worsening sore throat, drooling, and subjective fever. He complains of pain
during swallowing and refuses oral intake. He has no cough, congestion, sick
contacts, or recent travel. His prenatal, natal, and postnatal histories contain no
significant information. His immunizations are up to date.
At initial presentation, his temperature is 39.6°C (103.4°F), heart rate is 160
beats per minute, respiratory rate is 22 breaths per minute, and oxygen saturation
is 95% in room air. Physical examination reveals an alert and interactive boy who
is drooling and appears uncomfortable. He is in the tripod position and has a
muffled voice but no stridor, nasal flaring, or labored breathing. His chest is clear
to auscultation bilaterally. His neck is supple and has no swelling, erythema, or
tenderness. His throat is not examined. Findings on the remainder of the physical
examination are unremarkable.
Results of laboratory evaluation include:
• White blood cell count 30,900/mL (30.9  109/mL), with 66% segmented
neutrophils, 22% banded neutrophils, 5% lymphocytes, and 7% monocytes
• Hemoglobin 13.9 g/dL (139 g/L)
• Hematocrit 39.1% (0.39)
• Platelet count 473  103/mL (473  109/L)
• Erythrocyte sedimentation rate, 8 mm/h
• C-reactive protein, 3.2 mg/L (30.5 nmol/L)
Blood is drawn for culture. Neck soft-tissue radiography leads to the diagnosis.
DISCUSSION
The soft-tissue neck radiograph reveals a “thumb sign.” After clinicians
administer ceftriaxone and dexamethasone, the patient is flown to a university
hospital. He is transported to the operating room for endotracheal intubation
under general anesthesia. His epiglottis is visualized and is erythematous
and swollen. Blood culture becomes positive for Haemophilus influenzae
type f after 40 hours. Repeat blood culture is negative. He receives 14 days of
antibiotic treatment with ceftriaxone. Immunodeficiency evaluation is not
performed.
Vol. 37 No. 9 SEPTEMBER 2016 397
 Condition
H influenzae type b (Hib) was historically the most common
cause of acute epiglottitis. Immunization against Hib was
introduced in 1985, although initially it was not a conjugate
vaccine and was not recommended for infants. The first Hib
conjugate vaccine was licensed in December 1987 and the
incidence of Hib epiglottitis declined by 80% to 90% af-
ter the introduction. The incidence of immunoglobulin A
deficiency and immunoglobulin G subclass deficiency are
reported to be higher in those who had Hib vaccine failure.
Epiglottitis caused by other H influenzae types (a, f, and
nontypeable), Streptococcus pyogenes, S pneumoniae, and Staphy-
lococcus aureus (including methicillin-resistant strains [MRSA])
now comprise a larger proportion of cases compared to the
prevaccine era. The median peak age of children with epiglottitis
has increased from age 3 years to ages 6 to 12 years due to the
change in etiology of the disease. Among the pediatric
population, the incidence of acute epiglottitis was 0.5
cases per 100,000 children in the United States in 2006.
Acute epiglottitis is defined as an acute inflammation of
the epiglottis and adjacent structures. The clinical presen-
tation is characterized by rapidly progressing dysphagia,
drooling, dysphonia, and distress (“the four Ds”). Other
characteristic findings include high temperature, toxic appear-
ance, and muffled speech, which is sometimes described as a
“hot potato” voice. The typical patient presents in the tripod
position of sitting upright and leaning forward with a hyper-
extended neck and chin thrust, which maximizes airway
patency. Of note, children with epiglottitis lack a cough or
hoarse voice, which are characteristic of croup.
Diagnosis
The diagnosis is based upon visualization of a large, cherry
red, swollen epiglottis or demonstration of epiglottal swell-
ing (“thumb sign”) by lateral neck radiography. Blood cul-
tures and cultures obtained from the surface of the epiglottis
help identify the causative organism. Epiglottal cultures are
positive in 30% to 70% of patients.
When a clinician has a high index of suspicion for
epiglottitis based on clinical presentation, direct visualiza-
tion of the epiglottis with laryngoscopy should be performed
by a physician skilled in intubation in a controlled setting,
such as an operating room or intensive care unit, with
preparation for subsequent artificial airway placement.
Laboratory testing and radiography should not be per-
formed on patients in whom epiglottitis is strongly sus-
pected until the airway is secured. In this case, soft-tissue
neck radiography was performed due to the unclear cause of
his respiratory distress because he had been fully immu-
nized. Agitation and anxiety may increase respiratory effort
398 Pediatrics in Review
and worsen respiratory distress. An experienced physician
with skills in airway management and intubation should be
present at all times.
Occasionally, other infections related to Hib, including
pneumonia, cervical adenopathy, or otitis media, may occur
concurrently with epiglottitis, but this is a rare finding.
Treatment
Acute epiglottitis is a medical emergency that warrants
immediate intervention to secure the airway regardless of
the degree of apparent respiratory distress. Without an
artificial airway, 6% of children die compared to less than
1% of those with an artificial airway. The airway should be
secured in a controlled setting, either an operating room or
intensive care unit, via orotracheal intubation, nasotracheal
intubation, or less frequently, tracheostomy.
The choice of antibiotics depends on local resistance
patterns. In general, a combination of a third-generation
cephalosporin and an antistaphylococcal agent against
MRSA is recommended. Once an organism is identified by
blood culture or culture of the epiglottis, antibiotics specif-
ically directed to the organism’s susceptibility should be
prescribed. The optimal duration of therapy is unknown,
although most physicians treat for 7 to 10 days. A longer
course may be required in cases of bacteremia.
Evidence to support routine use of glucocorticoids in pa-
tients with epiglottitis is insufficient. Retrospective studies do
not show an association between glucocorticoid use and re-
duced length of intensive care unit or hospital stay or duration
of intubation. Such use may be beneficial in select patients
with severe disease or in patients who are difficult to extubate.
Prognosis
Epiglottitis generally resolves after a few days of antibiotics,
and the patient may be extubated once the inflammation is
under control. Most patients recover without residual airway
problems if the airway is secured promptly and they are
treated with appropriate antibiotics.
Lessons for the Clinician
• Acute epiglottitis is a medical emergency that warrants
immediate intervention to secure the airway.
• A combination of a third-generation cephalosporin and
an antistaphylococcal agent against methicillin-resistant
Staphylococcus aureus is recommended.
• The incidence of Haemophilus influenzae type b epiglottitis
declined significantly after the introduction of vaccination.
Suggested Readings for this article are at http://pedsinreview.
aappublications.org/content/37/9/397.

EDITOR’S NOTE
This case was selected for publication from
the 10 finalists in the 2015 Clinical Case
Presentation program for Section on
Pediatric Trainees of the American
Academy of Pediatrics (AAP). Zachary Graff,
MD, resident from Texas Tech University
Health Sciences Center School of Medicine,
Amarillo, TX, wrote this case report.
Choosing which case to publish involved
considerations of the teaching value and
excellence of writing but also the content
needs of the journal. Another case will be
chosen from the finalists presented at this
year’s AAP National Conference and
Exhibition and published in the September
2017 issue of Pediatrics in Review.
AUTHOR DISCLOSURE Drs Graff, Mendoza,
Barche, and Turner have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of a
commercial product/device.
4 Two Black Eschars in a 6-year-old Girl
Zachary Graff, MD,* Geronimo Mendoza, MD,* Apurv Barche, MD,*
Curtis Turner, MD*
*Texas Tech University Health Sciences Center School of Medicine, Amarillo, TX.
PRESENTATION
A previously healthy 6-year-old Hispanic girl presents with a 4-week history of a
left lower back skin lesion and a 1-week history of a left forearm lesion. Both
lesions progressed from an initial red bump to ulceration with overlying black
crust. The lesions are mildly itchy and not painful. She denies fever, weight loss,
night sweats, lymphadenopathy, and cough. She has no history of trauma,
international travel, tuberculosis exposure, pet bites or scratches, or exposure
to animal hides. There is no family history of cancer. Social history is notable for
her father working at a dairy farm.
Physical examination reveals a temperature of 36.2°C (97.2°F), with other vital
signs within normal limits. The girl is smiling and cooperative. Examination of
the skin reveals a nontender 2.5
2-cm sharply defined ulcer with overlying black
eschar on the left lower back with edematous and erythematous borders (Fig 1)
and a similar 1-cm lesion on the left forearm (Fig 2). There is no clinically
significant lymphadenopathy or hepatosplenomegaly. The remainder of the
examination yields normal results.
She is started on doxycycline for suspected cutaneous anthrax. However,
polymerase chain reaction (PCR) for Bacillus anthracis returns negative and
the doxycycline is discontinued.
A complete blood cell count shows a white blood cell count of 6,800/mL (6.8

109/L) with 48% neutrophils, 39% lymphocytes, 11% monocytes, and 2% eosin-
ophils. Results of other laboratory studies, including a complete metabolic panel,
erythrocyte sedimentation rate, C-reactive protein, serum uric acid, and lactate
dehydrogenase, are within reference ranges. Human immunodeficiency virus
antibodies are negative and a chest radiograph is normal. A pediatric oncologist is
consulted and recommends skin biopsies.
DISCUSSION
The differential diagnosis for this girl certainly included cutaneous anthrax due to
the characteristic progression of the lesions from erythematous painless papule to
ulceration and eventually to black eschar. However, the incidence of cutaneous
anthrax in the United States is extremely rare (1-2 cases per year reported), and due
to her lack of exposure to risk factors such as animals and animal products
and negative PCR test result for Bacillus anthracis, an alternative diagnosis was
pursued.
Vol. 37 No. 9 SEPTEMBER 2016 399

Figure 1. A 2.5
2.0-cm sharply defined ulcer with overlying black
eschar on the left lower back with edematous and erythematous borders.
Also in the differential diagnosis was ecthyma. This
condition is characterized initially by grey-yellow crusted
sores under which ulcers later form, a deep form of impe-
tigo involving the dermis. There is a predilection for the
lower extremities. This is caused most commonly by the
same bacterium causing impetigo, Streptococcus pyogenes.
Due to the absence of initial grey-yellow crust, location of
lesions on the lower back and forearm, and more subacute
presentation of lesions over 4 weeks, ecthyma was a less likely
diagnosis.
She underwent full-thickness incisional resection of the
back lesion. The evaluation was negative for organisms
on Gram stain, anthrax PCR, acid-fast bacilli, aerobic and
anaerobic cultures, and fungal cultures.
Histopathology showed an atypical T-cell lymphoid
infiltrate rimming adipose tissue, with 70% of abnor-
mal lymphocytes expressing CD3, CD5, CD2, BCL2, and
Figure 2. A sharply defined 1-cm ulcer with overlying black eschar on
left forearm with edematous and erythematous borders.
400 Pediatrics in Review
CD4. The CD4:CD8 ratio was 6:1. Forty percent of the
lymphoid cells expressed CD30. The cells also expressed
anaplastic lymphoma kinase (ALK). A high proliferation
rate was noted, with 70% of cells expressing Ki67. Mono-
clonal rearrangement for T-cell receptor and gamma re-
ceptors was demonstrated by PCR. A final diagnosis of
ALKþ anaplastic large cell lymphoma (ALCL) was made.
Once the pathology report was available, imaging
(computed tomography scan of chest/abdomen/pelvis
and bone scan) and bone marrow biopsy and aspira-
tion with flow cytometry were performed and ruled out
systemic involvement. She was started on oral metho-
trexate (20 mg/m2) weekly and topical bexarotene daily
for 4 weeks. Bexarotene is a retinoid that achieves its
antineoplastic properties by binding retinoid X receptors.
Once bound, these receptors function as transcription
factors that regulate genes, which control cellular differ-
entiation and proliferation. A plastic surgeon performed
wide local excisions of both lesions, which were reviewed
by pathology and demonstrated no residual disease. The
girl remains in complete remission 2 years following
treatment.
The Condition
Primary cutaneous lymphomas (PCLs) are defined as non-
Hodgkin’s lymphomas limited to the skin. They often
mimic infectious processes such as cutaneous anthrax
and ecthyma and can be difficult to distinguish clinically.
PCLs present as solitary or multifocal red skin lesions that
do not regress and may progress to ulceration and black
eschar. They may appear on any part of the body and often
grow slowly, with a more subacute course than cutaneous
anthrax.
Within this heterogeneous group of disorders is ALCL,
which is typically defined by the immune-histochemical
expression of CD30 and lack of ALK. In contrast to systemic
ALCL, which comprises 15% of pediatric non-Hodgkin’s
lymphomas, cutaneous ALCL is rarely found in children.
In addition, the presence of ALK expression is exceedingly
rare, and some have suggested that its expression should
be considered highly suspicious for underlying systemic
involvement.
Although systemic disease with cutaneous manifesta-
tions is treated aggressively with polychemotherapy, local-
ized cutaneous disease often spontaneously regresses or is
treated locally and cured with radiation or surgery alone.
This patient received a short course of systemic chemother-
apy, in part due to the relative lack of therapeutic trials
guiding treatment decisions for this disease. In addition,
the presence of ALK expression in adults is suggestive of
systemic disease. This patient was found to have primary
cutaneous ALKþ ALCL, with no evidence of extracutaneous
involvement, suggesting that ALK expression may not
be a reliable marker of systemic disease in pediatric
patients.
Lessons for the Clinician
• Physicians must maintain a broad differential diagnosis
when confronted with unusual skin findings.
• Primary cutaneous anaplastic large cell lymphoma may be
confused with infection and is a rare diagnosis in children,
with very few reports of anaplastic lymphoma kinase (ALK)
expression.
• Although the prognosis of this disease is favorable, early
detection is important for appropriate treatment to avoid
potential systemic involvement.
• This case reinforces that ALK expression cannot be used
to distinguish systemic from localized cutaneous disease
in children, as previously thought.
Suggested Readings for this article are at http://pedsinreview.
aappublications.org/content/37/9/399.
Vol. 37 No. 9 SEPTEMBER 2016 401
 in
Brief
Pulse Oximetry and the Neonate
Philip Roth, MD, PhD*
*Staten Island University Hospital, Hofstra-North Shore/LIJ School of Medicine, Staten Island, NY.
AUTHOR DISCLOSURE Dr Roth has disclosed
no financial relationships relevant to this
article. This commentary does not contain a
discussion of an unapproved/investigative
use of a commercial product/device.
Critical Congenital Heart Disease Screening
Using Pulse Oximetry. Frank LH, Bradshaw E,
Beckman R, Mahle WT, Martin GR. J Pediatr.
2013;162(3):445–453
Diagnosis and Treatment of Pulmonary
Hypertension in Infancy. Steinhorn RH. Early
Hum Dev. 2013;89(11):865–874
Role of Pulse Oximetry in Examining
Newborns for Congenital Heart Disease:
A Scientific Statement from the AHA and
AAP. Mahle WT, Newburger JW, Matherne GP,
et al; American Heart Association Congenital
Heart Defects Committee of the Council on
Cardiovascular Disease in the Young, Council
on Cardiovascular Nursing, and
Interdisciplinary Council on Quality of Care
and Outcomes Research; American Academy
of Pediatrics Section on Cardiology and
Cardiac Surgery; Committee on Fetus and
Newborn. Pediatrics 2009;124(2):823–836
Persistent Pulmonary Hypertension of the
Newborn: Advances in Diagnosis and
Treatment. Jain A, McNamara PJ. Semin Fetal
Neonatal Med. 2015;20(4):262–271
Meconium Stained Fluid: Approach to the
Mother and the Baby. Welsh NC, Fanaroff JM.
Clin Perinatol. 2007;34(4):653–665
402 Pediatrics in Review
Evaluation of the newborn who has cyanosis requires prompt and logical as-
sessment. Although entities such as polycythemia and methemoglobinemia
must be considered, the diagnoses that must be addressed most urgently are
primary respiratory disease, congenital heart disease (CHD), and persistent
pulmonary hypertension of the newborn (PPHN). These categories of disease
are not mutually exclusive, as in the case of meconium aspiration with PPHN,
but their distinct pathophysiologic mechanisms account for different results
in diagnostic testing.
The essence of PPHN lies in the pathologic failure of pulmonary artery
pressure to decline postnatally. Although pulmonary artery pressure varies
directly with pulmonary vascular resistance (PVR), pulmonary blood flow, and
pulmonary capillary wedge pressure, the first of these plays the most prominent
role in PPHN. Persistently elevated PVR may result from the perinatal failure to
elaborate nitric oxide and/or prostaglandin I2 in addition to increased production
of phosphodiesterase-3 or -5, endothelin-1, reactive oxygen species, and rho-
kinase. The net effect is right ventricular dysfunction as well as right-to-left
shunting across fetal channels (ie, the patent foramen ovale and ductus arterio-
sus), which results in decreased pulmonary blood flow. The affected infant
develops ventilation/perfusion mismatch, hypoxemia, and acidosis that can lead
to left ventricular dysfunction, decreased output, and shock. When differentiating
PPHN from cyanotic CHD, the clinician must pay careful attention to patient
history; familial occurrence of CHD; and risk factors for PPHN, including sepsis,
perinatal asphyxia, intrauterine growth restriction, and maternal medications (eg,
selective serotonin reuptake inhibitors, indomethacin) (Table 1).
On physical examination, the clinician should auscultate for heart murmurs,
compare upper and lower extremity pulses, assess for hypotension associated
with the patient’s cyanosis, and examine the cardiac silhouette on chest radiog-
raphy. For many years, the “hyperoxia test” was used to distinguish the 3 major
causes of cyanosis. Arterial blood gases were obtained before and after infants
were placed in 100% oxygen. If an initially low PaO2 rose to equal to or greater than
150 mm Hg following hyperoxia, the likely diagnosis was respiratory disease.
Nonresponders with either cyanotic CHD or PPHN were subsequently hyper-
ventilated. Decreased PaCO2 and alkalosis would dilate the pulmonary vasculature
in PPHN, resulting in increased PaO2, which would not be the case in cyanotic
CHD. Recently, echocardiography with color Doppler directional flow has sup-
planted the hyperventilation phase of the hyperoxia test. However, use of blood
gases is limited by the technical difficulty in obtaining them by arterial puncture; a
falsely low PaO2 may result when an infant’s crying leads to increased right-to-left
shunting. Also, changes in clinical status may not be evident during the interval
between the 2 samplings. Consequently, the routine introduction of pulse
oximetry into the care of neonates has had a significant impact.
 ductal patency in CHD lesions dependent on it for oxygenation,
TABLE 1. Disorders Associated with Persistent achievement and maintenance of higher saturations are readily
Pulmonary Hypertension of the noted. In PPHN associated with meconium aspiration syn-
Newborn drome, once the shunting resolves, the effects of parenchymal
lung disease may persist for days to weeks. Consequently, every
• Idiopathic
effort should be made to minimize barotrauma through
• Meconium aspiration syndrome “gentler” ventilation, use of high-frequency oscillatory ventila-
• Respiratory distress syndrome tion to optimize lung volumes, and tolerance of lower pH (7.25-
• Transient tachypnea of the newborn 7.29) and higher PaCO2 (50-60 mm Hg) in arterial blood.
Aside from its use in the early evaluation of cyanotic
• Pneumonia/sepsis
CHD, pulse oximetry can also play a key role in the detection
• Lung hypoplasia
of critical congenital heart disease (CCHD) in asymptomatic
• Congenital diaphragmatic hernia infants. CCHD, defined as lesions that require intervention
• Medications: Indomethacin, selective serotonin reuptake inhibitors in the first postnatal year for survival, account for approx-
• Other imately 25% of CHD cases, but the condition may not be
evident initially because of incomplete transition from the
- Alveolar capillary dysplasia
fetal circulation (ie, elevated PVR and/or continued patency
- Surfactant protein B deficiency of the ductus arteriosus). Heart lesions with ductal-dependent
- ABCA3 surfactant deficiency pulmonary or systemic blood flow are most prominent in
- Pulmonary lymphangiectasia this category (Table 2). Because fetal ultrasonography
detects only about 50% of CCHDs, particularly lesions with
- Congenital lobar emphysema
- Cystic adenomatoid malformation

Adapted from Steinhorn R. Diagnosis and treatment of pulmonary

hypertension in infancy. Early Human Dev. 2013;89(11):865-74.9, with
TABLE 2. Critical Congenital Heart Disease
permission from Elsevier. Defects
• Left-sided obstructive lesions

Hypoplastic left heart syndrome

A pulse oximeter uses 2 diodes emitting light at 640 nm
(red) and 940 nm (infrared), which are selectively absorbed Interrupted aortic arch

by oxyhemoglobin and deoxyhemoglobin, respectively. Mea- Critical coarctation of the aorta

surement of red and infrared light emerging from the tissue Critical aortic stenosis
and calculation of their ratio are used to determine the
• Right-sided obstructive lesions
oxygen saturation. Because visual recognition of cyanosis
Pulmonary atresia with intact septum
requires the presence of equal to or greater than 5 g/dL of
deoxyhemoglobin, pulse oximetry allows detection of more Tricuspid atresia
subtle levels of desaturation. In addition, placement of 1 Critical pulmonary stenosis
pulse oximeter probe on a preductal site (eg, right hand) and Tetralogy of Fallot
a second on a postductal site (eg, either foot) allows detection of
• Mixing lesions
ductal shunting, which occurs in 90% of cases of PPHN.
With a threshold pre-to-postductal saturation difference of Total anomalous pulmonary venous return

equal to or greater than 10%, oximetry can be used initially at Transposition of the great arteries
diagnosis as well as to detect onset of shunting with patient Truncus arteriosus communis
agitation or clinical interventions (eg, suctioning). Unlike
Reprinted from Bruno CJ, Havranek T. Screening for critical congenital
the labile oxygenation of the infant with PPHN, patients
heart disease in newborns. Adv Pediatr. 2015;62(1):211-226, with
with cyanotic CHD have fixed low oxygen saturations. How- permission from Elsevier.
ever, once prostaglandin E1 infusion is initiated to maintain

Vol. 37 No. 9 SEPTEMBER 2016 403

 single-ventricle configurations, its overall reliability is lim-
ited. Therefore, in the absence of effective screening, delays
in diagnosis occur, leading to increased mortality, surgical
morbidity, and neurodevelopmental disability. Echocardiog-
raphy would be the gold standard for detection, but use of
this modality in every baby would be impractical and cost-
ineffective. As a result, newborn screening with pulse
oximetry has become the standard in an increasing number
of states. Recently, screening has expanded from pulse
oximetry on a single site to 2 measurements: one preductal
and the second postductal. As shown in the algorithm
(Figure), a positive result of screening when performed at
more than 24 hours of age consists of a single reading of less
than 90% on any site OR 3 consecutive hourly readings of
either 90% to 94% on any site or a difference of greater than
3% between upper and lower extremities.
This methodology for CCHD screening provides sensi-
tivity between 75% and 80%, specificity greater than 99%,
positive predictive value of 26%, and negative predictive
value of greater than 99%. Even with the fewer than 1%
404 Pediatrics in Review
of neonates who have false-positive screening results for
CCHD, echocardiography performed on these children
may reveal other clinically relevant conditions, such as
pulmonary hypertension. On this basis, CCHD screen-
ing is cost-effective; with $5 to $10 expended per child
screened, detecting 1 case of CCHD before clinical dete-
rioration offsets the cost of screening approximately 2,000
healthy newborns. Lesions that are the most difficult to
detect include aortic outflow obstruction, which often presents
later compared to other CCHDs. Further studies are required
to determine the proper timing, if any, for CCHD screening in
the NICU, where pulse oximetry is already being used for
regular monitoring and other coexisting conditions (eg, pre-
maturity, sepsis, and primary lung disease) and can complicate
analysis.
Pulse oximetry has had a dramatic impact on neonatal
care in the: 1) detection of subtle cyanosis (<5 g/dL deoxy-
hemoglobin), 2) differentiation of CHD and PPHN in the
infant with acute cyanosis, and 3) detection of CCHD in the
asymptomatic newborn.
Figure Pulse oximetry screening protocol.
Reprinted from the public domain from the U.S.
Centers for Disease Control and Prevention.
Available at http://www.cdc.gov/ncbddd/
heartdefects/hcp.html, as adapted from Kemper
AR, Mahle WT, Martin GR, et al. Strategies for
implementing screening for critical congenital
heart disease. Pediatrics. 128(5). Available at: www.
pediatrics.org/cgi/content/full/128/5/e1259.
 COMMENT: For those of us who felt like medieval tor-
turers when jabbing the radial arteries of cyanotic neonates
in a search for that arterial blood flow that seemed stub-
bornly resistant to our desperate efforts, the advent of pulse
oximetry has been akin to the alchemist’s dream of turning
lead into gold. How much easier for us, and of course, more
importantly, how much nicer for the children. Further, if we
can’t yet prevent the occurrence of critical congenital heart
disease, at least we have a safe and efficient tool for iden-
tifying affected infants before they suffer irreversible harm,
which is progress indeed!
– Henry M. Adam, MD
Associate Editor, In Brief

Parent Resources from the AAP at HealthyChildren.org

Pulse Oximetry and the Neonate
• https://www.healthychildren.org/English/ages-stages/baby/Pages/Newborn-Screening-Tests.aspx
• Spanish: https://www.healthychildren.org/spanish/ages-stages/baby/paginas/newborn-screening-tests.aspx
• https://www.healthychildren.org/English/ages-stages/baby/preemie/Pages/When-Baby-Needs-Oxygen-At-Home.aspx
• Spanish: https://www.healthychildren.org/spanish/ages-stages/baby/preemie/paginas/when-baby-needs-oxygen-at-home.aspx

CME Quiz Corrections

An error was found in the CME quiz for the December 2015 article “Pain and Symptom Management in Pediatric
Palliative Care” (Komatz K, Carter B. Pediatrics in Review. 2015;36(12):257–534, doi: 10.1542/pir.36-12-527). The correct
answer for Question 4 should be “C. Ondansetron,” with the following rationale: “Ondansetron, a serotonin 5-HT3
receptor antagonist, may be used in children older than 4 years to prevent postoperative nausea and vomiting, or that
associated with chemotherapy.” The quiz has been corrected. A correction notice has been posted with the online version
of the article. The journal regrets the error.
In the CME quiz for the August 2016 review “Inflammatory Bowel Disease” (Shapiro JM, Subedi S, LeLeiko NS.
Pediatrics in Review. 2016;37(8):337–347, DOI: 10.1542/pir.2015-0110), the correct answer for Question 3 is “A.
Endoscopy.” The quiz has been corrected. A correction notice has been posted with the online version of the article.
The journal regrets the error.

ANSWER KEY FOR SEPTEMBER 2016 PEDIATRICS IN REVIEW:

Acid-Base Disorders: 1. A; 2. B; 3. E; 4. C; 5. B.
Evaluation and Initial Management of Hypopituitarism: 1. A; 2. E; 3. D; 4. D; 5. E.
Chronic and Recurrent Abdominal Pain: 1. B; 2. B; 3. B; 4. D; 5. C.

Vol. 37 No. 9 SEPTEMBER 2016 405

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AUTHOR DISCLOSURE Mr Sorensen and
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commentary does contain a discussion of
an unapproved/investigative use of
a commercial product/device.
e38 Pediatrics in Review
Spoon Nails and Short, Brittle Hair in a
3-year-old Boy
Eric P. Sorensen, MD,* Wynnis L. Tom, MD†
*School of Medicine, University of California, San Diego, La Jolla, CA.
†
Departments of Dermatology and Pediatrics, University of California,
San Diego and Rady Children’s Hospital, San Diego, CA.
PRESENTATION
A 3-year-old boy presents for evaluation of toenails that have been abnormally
shaped since infancy and areas of hair on the scalp that are of a coarser texture
and that “never grow long at all.” There is no history of chemical or other insult to
the hair or nails. He has no known health problems and has been meeting growth
and developmental milestones appropriately. His pediatrician recommended a
trial of sulfur sulfacetamide shampoo to the scalp, but there was no improve-
ment. His older sister had similar hair findings that resolved by age 1 year. The
boy’s mother is concerned if there might be nutritional or other health concerns
because his condition has not improved. There is no other family history of hair or
nail abnormalities.
On physical examination, the well-developed and well-nourished boy has
appropriate behavior for age. All of his toenails are thin and depressed in a concave
manner (Fig 1), but all fingernails are unaffected. His hair is short, coarse, and
wiry predominately on the occipital scalp (Fig 2). Hair in all other areas appears
normal. The thyroid gland is not enlarged and the distal extremities are well
perfused, with no clubbing or cyanosis. Several strands of hair from the affected
area appear under microscopic examination in Figure 3.
DISCUSSION
Findings on physical examination and microscopic hair examination suggest the
diagnosis of koilonychia in the setting of monilethrix. According to Stone and
Maberry, causes of koilonychia (thin, concave-shaped nails) can be divided into 3
major categories: idiopathic, acquired, and hereditary in association with other ec-
todermal defects. In idiopathic cases, koilonychia is seen in an otherwise healthy
infant, and the condition tends to resolve on its own. In acquired cases, koilonychia
is often related to systemic diseases such as iron deficiency anemia and thyroid
disease. Interestingly, in children with iron deficiency, koilonychia often
presents before significant anemia develops. Therefore, early detection via this
clinical sign may help prevent progression of iron deficiency to its more severe
manifestations, such as neurodevelopmental defects and decreased immune
function. Koilonychia has been described in both hyperthyroidism (5% of
 Monilethrix is predominantly an autosomal dominant
condition, although autosomal recessive mutations have
been documented. The basic hair keratin genes (KRT81,
KRT83, and KRT86), along with the type II trichocyte keratin
genes (hHb1, hHb3, and hHb6), have been implicated in the
autosomal dominant form. Of note, mutations in hHb1 may
produce a less severe phenotype than with the other type II
keratin genes. Mutations in the desmoglein 4 (DSG4) gene,
which encodes for a protein in the desmosomal bridge
structures that help cells attach to each other, have been
found in autosomal recessive cases. The aberrancy in moni-
lethrix appears to be primarily attributable to cells in the
hair shaft cortex having dysfunction of the intracellular
cytoskeleton and cell-cell adhesion.

Differential Diagnosis
Figure 1. Thin toenails with concave curvature. Other hair shaft diseases may mimic monilethrix in appear-
ance, with the same sparse, short, dry, and fragile hair at an
cases) and hypothyroidism. Iron and thyroid studies should
early age. However, examination with light microscopy can
be considered in patients with persistent, acquired koilo-
allow differentiation, with electron microscopy used for
nychia. Correction of the systemic problem resolves the nail
further evaluation, if needed. Trichorrhexis nodosa is
changes. Other, less common systemic causes include sys-
a common congenital or acquired hair shaft disorder with
temic lupus erythematosus, hemochromatosis, and Raynaud
distinct points of splintering like two opposing broomsticks.
disease. Performing a thorough review of systems and physical
Pili torti is a hereditary hair shaft disorder characterized by
examination is important in determining if these conditions
light-colored fragile hair with a twisted appearance that can
warrant further consideration.
occur alone or as a manifestation of a syndrome, such as
The clinician should also consider the congenital ectoder-
Menkes syndrome. Wooly hair syndrome is characterized by
mal defect disorders as other potential causes of koilonychia,
tight, curly hair and has a variable inheritance pattern but
particularly if the condition is of early onset. Ectodermal-
is normally present from birth. Trichothiodystrophy refers
derived structures include the hair, teeth, nails, sweat glands,
to the sulfur-deficient brittle hair that gives a tiger-tail
cranial-facial structure, and digits. Among the congenital dis-
orders that may include koilonychia are monilethrix, palmo-
plantar keratodermas, and the ectodermal dysplasia syndromes,
where 2 or more ectodermal-derived structures are affected.
Monilethrix is a rare, heritable disorder with onset at any age,
although it predominantly begins in early childhood. Hair shafts
have areas of normal growth separated by areas of narrowing,
called nodes and internodes, respectively. Microscopic examina-
tion demonstrates regularly spaced spindlelike segments, giving
the monilethrix hair a characteristic string-of-beads appearance.
Internodes typically form soon after birth, at intervals of 0.7 to
1.0 mm. This thinning causes the hair to break at a shorter length
than normal, forming short, sparse, coarse, and wiry hairs. The
nape and occipital regions are most commonly affected, but hair
over the entire body has the potential to be involved. In more
severe cases, the condition can progress to a scarring alopecia.
Frequently associated with monilethrix are koilonychia and ker-
atosis pilaris, a common, benign condition of small, rough, follicle-
centered papules. Less commonly associated findings are other
dental and nail anomalies, juvenile cataracts, and neurologic dis-
orders, such as cognitive impairment, schizophrenia, and epilepsy. Figure 2. A transition from normal hair to coarse, wiry hair at the occiput.

Vol. 37 No. 9 SEPTEMBER 2016 e39


appearance under polarizing microscopy, seen in a group
of autosomal recessive genetic disorders with ichthyosis,
short stature, neurologic impairment, and photosensitivity.
Chemical or heat insult may also lead to brittle hair, as can
severe malnutrition (kwashiorkor, marasmus), but the other-
wise healthy boy in this case lacks such a history. Iron deficiency
and thyroid disorders do not tend to cause patterned changes
along the hair shaft, although they can lead to dry, thin hair
and diffuse shedding.
Of note, normal hair may have an appearance similar to that
of monilethrix under light microscopy as an artifact of the fixing
process. This phenomenon, called pseudomonilethrix, may be
caused by trauma from tweezers or forceps and by compressing
overlapping hairs between glass slides. It can be avoided by
cutting the hair shaft instead of plucking and minimizing
friction between the two glass slides when preparing the sample.
Management
The prognosis of monilethrix is variable; in some cases, the
findings resolve spontaneously. Several accounts report an
improvement with hormonal changes following the onset of
adolescence or pregnancy. However, in one case, hormonal
treatment only gave temporary improvement.
Currently there is no specific treatment for monilethrix.
Positive responses have been reported with topical minox-
idil and several oral medications (corticosteroids, griseo-
fulvin, N-acetyl cysteine, and the retinoids acitretin and
etretinate). However, none have been consistently effective,
and the risks versus benefits must be weighed when consid-
ering treatment. Some reports claim an exacerbation of moni-
lethrix with trauma, so minimizing trauma and damage to the
hair may help. Genetic testing for mutations does not tend to
alter management but may inform future/familial risk.
Patient Course
Examination of hair samples from affected and nonaffected
areas for the boy in this case confirmed the diagnosis of
monilethrix. Laboratory studies showed normal thyrotropin,
free thyroxine, and complete blood cell count values. Treatment
e40 Pediatrics in Review
Figure 3. A) Examination of affected and
unaffected hairs with light microscopy at 4
magnification. B) An affected hair at 40
magnification.
options were discussed, but none were chosen because data
on their usage were limited. Biotin 2.5 mg was started as
a supplement to potentially help strengthen the hair and
nails, based on use for other hair shaft disorders and for nail
fragility, along with its low risk profile.
Summary
• The causes of koilonychia (spoon nails) may be idiopathic,
acquired, hereditary, and in association with other ectodermal
defects. Acquired causes include iron deficiency anemia and
thyroid disease, and hereditary causes include monilethrix.
Performing a thorough review of systems and physical
examination helps determine which conditions are probable and
warrant further evaluation.
• Monilethrix is a predominantly autosomal dominant hair shaft
disorder characterized by sparse, short, dry, and fragile hair.
Koilonychia in this setting does not have other systemic implications.
• The distinguishing characteristic of the monilethrix hair is its beaded
appearance, caused by regularly spaced deformation of cortical hair
shaft cells and visible under light and electron microscopy.
• Literature supporting treatment options is limited to only a few
case reports, although some patients note gradual self-resolution
and others have improvement with puberty.
Suggested Readings
Farooq M, Ito M, Naito M, Shimomura Y. A case of monilethrix caused
by novel compound heterozygous mutations in the desmoglein 4
(DSG4) gene. Br J Dermatol. 2011;165(2):425–431
Gebhardt M, Fischer T, Claussen U, Wollina U, Elsner P. Monilethrix–
improvement by hormonal influences? Pediatr Dermatol. 1999;
16(4):297–300
Ito M, Hashimoto K, Katsuumi K, Sato Y. Pathogenesis of monilethrix:
computer stereography and electron microscopy. J Invest Dermatol.
1990;95(2):186–194
Leitner C, Cheung S, de Berker D. Pitfalls and pearls in the diagnosis of
monilethrix. Pediatr Dermatol. 2013;30(5):633–635
Rasmussen J. Hair loss in children. Pediatr Rev. 1981;3(3):85–90
Stone OJ, Maberry JD. Spoon nails and clubbing: review and possible
structural mechanisms. Tex Med. 1965;61:620–627