Case English I To whom respectfully

Dr. Fitriyana Mr/Mrs ...................

VITAMIN D DEFICIECY AND RICKETS

INTRODUCTION

Vitamin D is a prohormone that is essential for normal absorption of calcium from the gut,
and deficiency of vitamin D is associated with rickets in growing children and osteomalacia
in adults. Rickets is the failure of mineralization of growing bone and cartilage. Daniel
Whistler and Francis Glisson in England provided initial descriptions of rickets as early as
the 17th century.1 Rickets is disorder of a growing child arising from disorders that result
in impaired apoptosis of hypertrophic cells and delayed mineralization of the growth plate.
Rickets can be secondary to disorders of the gut, pancreas, liver, kidney, or metabolism;
however, it is mostly due to nutrient deficiency.2,3

The most common cause of rickets is still vitamin D deficiency, which is also
responsible for other problems. Disorders of vitamin D metabolism or responsiveness may
also cause similar issues.4 Rickets due to nutritional causes remains an important global
problem. Nutritional rickets has traditionally been attributed to vitamin D deficiency
relating to reduced exposure to sunlight, resulting from crowded living conditions under
skies polluted by the detrimental products of industrialization.5

Nutritional rickets results from inadequate vitamin D and/or calcium nutrition,

because both nutrients are essential for bones to become mineralized. Rickets is generally
accompanied by osteomalacia, i.e. defective mineralization of preformed osteoid in bone,
fragility fractures and muscle weakness.6 The clinical consequences of nutritional rickets
can include stunted growth, developmental delay, lifelong deformities, pneumonia,
hypocalcemic seizures, cardiomyopathy, and even death.7

In this case report, we presented patient with deformities over the limb due to
rickets, complicated with developmental delay and seizure. The propose of presenting this
case is to highlight the vitamin D deficiency and rickets in children.

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CASE ILLUSTRATION

A five year and eleven months children was admitted to outpatient department in
September 23, 2016 with bowleg since two years old.

History of present illness:

Bowleg since two years old, the parent noticed the thought she could not walk. No fracture
history. No fever, cough, breathless, vomit, she had also good appetite. Urinating and
defecation were normal.

She got generalized afebrile seizure at 2 years old, 12 times, only few seconds, and
conscious after seizure. No head trauma.

At the time, she could walk at 2 years old speak several syllables likely ma or pa. Her
abilities at the time was changing clothes and writing likely scribble ones. At some
occasion, she could not control her emotional support by throwing thing and head banging.

Past illness history:

She has been diagnosed epilepsy asymptomatic undergone EEG with abnormal III general
epileptiform discharge and also treated by valproic acid regularly.

History of pregnancy and childbirth:

She was second child, spontaneous vaginal delivery without complication during
pregnancy and labor, a full term baby, cried immediately after birth, no cyanotic,
breathlessness, jaundice and seizure.

Immunization history: none

Growth and development history:

She was below the 3rd percentile for both height and weight at her age. Her father and
mother are normal stature. She failed at Denver test in all four domains. Impression of
growth and development was disturbance.

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Social economic and environmental history:

The fathers 34 years old, elementary school graduation, work as labor, with salary
approximately Rp. 500.000-1.000.000,-/ mount. The mother is 31 years old, bachelor
graduation, and a teacher, with salary approximately Rp. 1.500.000,-/ mount. They lived in
semi-permanent house with moderate hygiene and sanitation.

Nutritional history:

She got breastfeed until 2 years old, never consumed cow milk, with porridge at 6 months,
soft meal until 1 years than family meal. Impression: nutritional intake of quality and
quantity were adequate.

Physical examination:

At the clinical examination, she was moderately ill and alert. Her vital sign otherwise stable.
Her blood pressure was 90/60 mmHg, pulse rate was 110x/min, respiration rate was
26x/min and body temperature was 370C. The body weight 14 kg and body height was 88
cm. BW/A was 71,4% (< 3rd percentile), BH/A 77,2% (< 3rd percentile), BW/BH 107%.
Her real HA was 2,5 years old. She was of with failure to thrive at this visit. Upper segment
length 48 cm. There were no cyanotic, edema, anemia or jaundice. On her head, she had
frontal bossing, and head circumference was 48 cm (< -2 SD standard Nell Haus).
Epicanthic index was 0,08. The conjunctiva was not pale, sclera was not icteric, no sunken
eyes and pupil reflex was normal. No abnormalities found of ears and nose. On her lip and
mouth, she had macroglosia and dental caries. Her cardiac, respiratory, gastrointestinal and
genitourinary were within normal limits. On extremities, she presented deformity, curved
or bowing at her leg, warm acral and refilling capillary was normal.

Laboratory result:

Hemoglobin 11,4gr/dl, white blood cell 9500/mm3, differential counts 0/3/0/46/50/1.

Urinalysis was within normal limit.

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List of problem:

Bowleg
Global developmental delay
Failure to thrive
Epilepsy

Diagnosis:

Suspect Rickets
Global developmental delay
Epilepsy
Suspect Congenital hypothyroid

Management:
1. Suspect Rickets
a. Diagnosis:
Electrolyte, calcium, alkali phosphatase, vitamin D 25-OH, parathyroid
hormone (PTH).
Bone survey, bone age
b. Therapy:
Calcium supplement 3 x 250 mg
Vitamin D supplement 3 x 400 IU
c. Education:
The parent was given an information about diagnosis, management,
complication and prognosis of the disease
2. Global developmental delay:
a. Diagnosis:
History of developmental milestone
Denver II
b. Therapy:
Consul to medical rehabilitation consultant
Physiotherapy
c. Education:

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 The parent was given an information about diagnosis, management,
complication and prognosis of the disease
3. Epilepsy:
a. Diagnosis:
History of seizure
EEG
b. Therapy:
Valproic acid 2 x 2,8 cc (140 mg)
Folic acid 1 x 1 mg
c. Education:
The parent was given an information about diagnosis, management,
complication and prognosis of the disease
4. Suspected Congenital hypothyroid
a. Diagnosis:
History
FT4-TSH
b. Therapy:
Levothyroxine sodium 1 x 25 g
c. Education:
The parent was given an information about diagnosis, management,
complication and prognosis of the disease

Follow up:

Sodium 144 mmol/L (N: 135-145 mmol/L), potassium 4,1 mmol/L (N: 3,3-4,6 mmo/L),
calcium 9,5 mg/dl (N:8,8-10,8 mg/dL), alkali phosphatase 365 u/L (N: 145-420 u/L),
magnesium 1,7 mg/dl (N: 1,5-2,3 mg/dL). Calcium ion 1,11 mmol/L (N: 2,2-2,7 mmol/L),
vitamin D 25-OH total 18,9 ng/mL (N: 30-100 ng/mL). FT4 1,08 ng/dL (0,81-1,74 ng/dL),
TSHs 5,62 IU/mL (0,8-6,26 IU/mL).

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Bone survey:

Schaedel AP-Lat: within normal limit

Thoracolumbosacral: within normal limit
Chest x ray: none of rachitic rosary
Upper extremities bilateral: appeared bowing at femur bilateral bones

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Lower extremities bilateral: within normal limit
Conclusion: Bowing at femur bones due to suspected rickets

Bone age:
A girl with 5 years and 6 months old.
Regarding the bones age was 3 years 6 months until 7 years 6 months old
Patient bone age was in appropriate with girl 2 years old
Good bone modelling
Conclusion: retarded girl

LITERATURE REVIEW

Vitamin D deficiency is considered the most common nutritional deficiency and also one
of the most common undiagnosed medical conditions in the world. Vitamin D has evolved
into a hormone that is active throughout the body not only to regulate calcium and bone
metabolism but also to reduce the risk of chronic diseases including autoimmune diseases,
malignancies, cardiovascular and infectious diseases. It has been estimated that 1 billion
people worldwide have vitamin D deficiency or insufficiency.8

Rickets is a condition associated with bone-deformity due to inadequate

mineralization in growing bones. While some cases relate to hereditary syndromes, renal
disease, or use of medication, rickets in the world mostly stems from nutritional
insufficiency. Nutritional rickets is prevalent throughout much of the developing world and
is again being increasingly seen in more affluent countries.5,9

Rickets can be classified into three main types depending on the biochemical
profile: calciopenic, phosphopenic and inhibited mineralization. Typically, calciopenic
rickets is associated with an elevated plasma parathyroid hormone concentration (PTH) in
response to low plasma calcium, which results in internalization of phosphate transporters
in the kidneys and decreased renal phosphate reabsorption. Phosphopenic rickets is
associated with a chronically low plasma phosphate with normal PTH and results from
increased production or gain-of-function of FGF23, a phosphaturic hormone, or from renal
disorders that compromise phosphate reabsorption. In both cases, the result is urinary
phosphate loss and hypophosphatemia, leading to reduced apoptosis of hypertrophic
chondrocytes in the growth plate and rickets. The third category, inhibition of

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mineralization, refers to rickets where the mineralization process in the growth plate is
directly affected and typically, the plasma concentrations of calcium and phosphate are
normal. There are varieties of underlying causes responsible for the various forms of
rickets, including genetic disorders, such as autosomal dominant hypophosphatemic rickets
(ADHR) and X-linked hypophosphatemic rickets (XLH), tumors, organ malfunction, drugs
and exposure to toxic agents such as aluminum and fluoride.2,6

Etiology

Nutritional rickets has been attributed primarily to vitamin D deficiency, resulting in

impaired calcium absorption and secondary phosphorus depletion. Vitamin D is
metabolized to 25-hydroxyvitamin D (25(OH) D), then to 1,25-dihydroxyvitamin D, which
acts primarily on vitamin D receptors in the gut to increase calcium absorption. The serum
concentration of the intermediate metabolite, 25(OH) D, is the best indicator of vitamin D
status. Measurement of 25(OH)D has been possible over the last 30 years, but reliable
measurement requires radio-immunoassay.9

Vitamin D deficiency is defined as serum levels of 25(OH) D less than 20 ng/dL

whereas 21- 29 ng/dL is considered insufficient by US Endocrine Society. This has been
done to utilize full advantage of all the health benefits of vitamin D.8

Table 1. US Endocrine Society classification10

Vitamin D status Levels

Deficiency <20 ng/mL (50 nmol/L)
Insufficiency 21-29 ng/mL (52.572.5) nmol/liter
Sufficiency >30 ng/mL
Toxicity >150 ng/mL

Risk factors for vitamin D deficiency can be divided into non-modifiable risk
factors such as age and skin color, modifiable risk factors such as sunscreen use and low
vitamin D intake, and non-patient factors such as living at high latitude and low altitude
(further away from the sun). A study in US found that older age, female sex, non-White
ethnicity, obesity, less frequent milk drinking, and watching over 4 h of television, video
or computer per day were associated with 25(OH)D levels below 15 ng/ml.11

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Epidemiology

Immigrant and refugee children typically come from countries with a high incidence of
nutritional rickets. Many of these countries are in the tropics with abundant sunshine. The
highest prevalence of nutritional rickets is found in children in the Middle East, Africa, and
South Asia, corresponding to the sites of origin for many immigrants. In the UK at 2006, a
survey of pediatricians identified 24 cases of symptomatic vitamin D deficiency in children
less than 5 years of age. The overall annual incidence was 7.5 per 100,000, but children of
South Asian ethnic origin had a five-fold greater incidence of 38 per 100,000, and those of
black African or African-Caribbean ethnic origin had an incidence of 95 per 100,000.7,12

Vitamin D-deficiency rickets usually presents in the 1st 18 months of life, whereas
calcium deficiency typically presents after weaning and often after the 2nd year of life.

Table 2. Children with nutritional rickets.9

Pathophysiology

In a vitamin D sufficient state or when the serum 25-hydroxyvitamin D (25(OH)D) level is

above 20 ng/mL (50 nmol/L), intestinal Ca absorption can be as high as 80% of the intake,
especially during periods of active growth. On the other hand, in a vitamin D deficient state,
intestinal Ca absorption can decrease to as low as 10-15% and there is also a decrease in
total maximal reabsorption of phosphate. In this state, the low serum ionized Ca++ level

9
stimulates parathyroid hormone (PTH) secretion, which leads to release of Ca++ and
phosphorus (P) from bone in an attempt to maintain normal Ca++ levels. Increased PTH
levels also lead to increased urinary P excretion. Finally, the decreased levels of serum P
and Ca++ result in decreased bone mineralization. In addition, the low serum P levels cause
failure of the expected apoptosis of hypertrophic chondrocytes and this results in cellular
ballooning and disorganization of the growth plate.13

Figure.1 Schematic representation of the pathogenesis of vitamin D deficiency and

dietary calcium deficiency rickets.14
During ossification of the cartilage tissue, chondrocytes differentiate into sequential
morphological cell zones with well-defined margins in the epiphyseal growth plate. These
are known as resting zone, proliferative zone, hypertrophic zone and ossification zone of
chondrocytes. The hypertrophic chondrocytes are subject to calcification of the
surrounding matrix to form the primary center of ossification before apoptosis. This is
followed by vascularization of the calcified tissue and arrival of osteoclasts and osteoblasts
to the site. Modelling of bone tissue subsequently takes place. In this way, secondary
ossification centers are formed and longitudinal healthy bone growth is ensured until the
epiphyses are closed by ossification of the cartilage tissue in the growth plate.15,16

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 In rickets, failure of apoptosis of the hypertrophic chondrocytes results in
irregular and deformative expansion of the cartilage tissue formed by hypertrophic
chondrocytes in the growth plate (Figure 2). This condition leads to cupping and to a brush-
like appearance of the epiphyseal ends on radiograms. The nonoccurrence of apoptosis of
hypertrophic chondrocytes is reported to be correlated with hypophosphatemia and leads
to enlarged unmineralized osteoid tissue seen in the growth plate.15

Figure 2. In rickets, the growth cartilage formed by hypertrophic chondrocytes is not

resorbed due to the defective apoptosis and the irregularly calcified growth plate expands.13

Clinical features

The clinical features of rickets are similar around the world, but the age of presentation and
the risk of hypocalcaemia symptoms, such as tetanic, vary depending on the age of
presentation and the relative importance of vitamin D (versus calcium) deficiency in
different populations. In areas where vitamin D deficiency is more common, rickets usually
presents in the first year of life often with clinically significant hypocalcaemia.5

Rickets is the disease of a growing organism; therefore, the deformities and clinical
findings are more specific to the bone tissue that is undergoing rapid growth at the age of
onset of rickets. The growth rate decreases in cases of malnutrition and hypothyroidism,
leading to less definite clinical findings. The clinical presentation of NR is stage-dependent
and most likely due to the duration of VDD. Hypocalcemia symptoms are predominant in

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stage I. Skeletal deformities become obvious in stage II and worsen in stage III. Clinical
findings of rickets comprise those that are specific to and those that are not specific to the
bone tissue. Accordingly, if there is suspicion of rickets, a complete physical and dental
examination should be carried out, and the entire skeletal system should be palpated to
identify possible sensitivity and deformities.13

Growth plates become soft because of diminished mineralization. With weight-

bearing, gravitational pressure causes, soft bones to curve in response to forces exerted
across joints. Thus, the long bones of the leg curvebecoming bow legs or, show up later
onset of rickets in the form of knocked knees. The use of specific physical examination
criteria for a diagnosis of rickets is, however, difficult. Determination of wide wrists and
beaded ribs is a subjective experience in subtle cases. There are broad ranges of normal
lower limb curvature, fontanel closure, and tooth eruption.2,5

Radiologic signs are seen at rapidly growing ends of long bones (e.g. at the distal
rather than the proximal end of the femur). The earliest radiologic sign of rickets is the loss
of the crisp line, produced by the zone of provisional calcification at the interface of the
epiphyseal growth plate, and metaphysis of long bones is lost. This zone becomes frayed
or brush like, and in more advanced stages of rickets it becomes concave or cup shaped.
The metaphyseal area also becomes wider than normal. Radiologic features of secondary
hyperparathyroidism include generalized osteopenia, sub periosteal bone resorption, and
periosteal reaction along the diaphysis.2

Table 3. Biochemical marker of vitamin D deficiency 8

Treatment

Several therapeutic regimens have been attempted for deficiency of vitamin D. Short term
administration of vitamin D2 or D3 2000 units daily or vitamin D2 50,000 units weekly
has yielded equivalent outcomes in the treatment of hypovitaminosis D in young children.
Common recommendations include vitamin D 1000- 5000 units/day for several weeks or
single IM injection of 6 lakh units (Stoss therapy) or 50,000U of vitamin D2 weekly for 8

12
weeks. The total dose of vitamin D has been reported to be more predictive of vitamin D
sufficiency rather than the frequency of dosing (daily, weekly or monthly). Therefore,
treatment regimens for a given patient can be individualized to ensure compliance, since
no difference in the efficacy or safety was reported in these common treatment regimens.8

Calcium supplementation: Even for children who are not frankly hypocalcaemia,
calcium supplements are important for avoiding subsequent hypocalcaemia from a decrease
in bone demineralization and an increase in bone mineralization as PTH levels normalize
(hungry bone syndrome), particularly with Stoss therapy. Supplementation of elemental
calcium in a dose of 30- 75mg/kg/day in 3 divided doses is recommended. High doses of
calcium are necessary early in the course of therapy, after which doses are reduced by half
for next 1-2 weeks.

Table 4. Management of hypocalcaemia due to vitamin D deficiency 8

Complication

Other features of rickets include growth retardation, frontal bossing of the skull, and
swelling of wrists, knees, and ankles. A rachitic rosary arises due to expansion of the
costo-chondral junctions, and an inward diaphragmatic pull of soft rib cage gives rise to
Harrisons sulcus (groove). Dentition may be delayed and development of tooth enamel
impaired. Irritability, considered secondary to bone pain, is a common feature in rachitic
infants. Muscle weakness associated with vitamin D deficiency leads to hypotonia and
delay of the motor development.2

Prevention

Vitamin D deficiency and low dietary calcium intakes act synergistically in increasing the
prevalence of rickets in communities where both problems are present. Vitamin D
supplementation has been shown to be a safe and effective way of reducing vitamin D
deficiency rickets in vulnerable infants. A nationwide program of providing free vitamin D

13
drops (400 IU/d) to newborns and infants reduced the prevalence of rickets from 6% in
1998 to 0.1% in 2008 in children under 3 years of age.2,17

Calcium supplementation in children from developing countries does not appear to

improve growth and may in fact have adverse effects on final height. Bone mass increases
during calcium supplementation, but most studies have found that the benefit is lost
following cessation of the supplement.14

CASE ANALYSIS

A case presented a five years and eleven months old girl with rickets and global
developmental delay. The diagnosis was established in accordance with history, clinical
features and supportive investigation.

Rickets is a failure of normal mineralization of growing bone that should be

included in the differential diagnosis of children presenting with failure to thrive and
orthopedic abnormalities, such as leg bowing, osteopenia, or frequent fractures. Nutritional
rickets is common cause rickets in development country. Patient came with chief complaint
bowleg. The physical examination was significantly found failure to thrive and bowleg
likely O shape.

She had bowing leg since age 2 years old. A single center study in Turkey from
2006-2011, found 93 cases nutritional rickets with aged 1,5 months to 15 years old, about
74% aged 3 months-3 years. The most common physical examination finding were
widening of the wrist, rachitic beads and the O-ban deformity of the lower extremities.18
Thacher et al conducted a study including 736 (>18 months) cases of rickets and concluded
that of all clinical signs, the combined finding of enlargement of the wrists and rachitic
rosaries constituted the most sensitive physical examination finding.19

In a patient suspected to have rickets based on clinical findings, the diagnosis is

confirmed by biochemical and radiological findings.

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 Figure 3: Management algorithm of rickets20
PTH= parathyroid hormone. 25OHD=calcidiol. ALP=alkaline phosphatase. LMW=low molecular
weight. XLH=X-linked hypophosphataemic rickets. HHRH=hereditary hypophosphataemic rickets
with hypercalciuria. TmP:GFR=ratio of renal tubular reabsorption rate of phosphate to glomerular
filtration rate. HVDRR=hereditary vitamin D-resistant rickets.

Regarding laboratory investigation, there was deficiency of vitamin D 25-OH,

lower calcium ion and bow at femur bilateral bones. In accordance with the finding
deficiency of vitamin D due to low intake nutritional was either established. Blood PTH
concentration could not afford it despite of financial problem, which is not covered by
assurance.

A Nigerian study has given some basis for a clinical diagnosis of rickets when
alkaline phosphatase levels and wrist/knee radiographs are not available. Specifically, for
children with deformities of the lower limb, the finding of at least three of five features (age
less than 5 years, short stature, leg pain with walking, wide wrists, costal beading) identified
87% of children with active rickets.5

Vitamin D deficiency during early childhood can affect primary teeth and ensuing
caries can sometimes lead to tooth loss at a young age.21 A study in Qatar found that
prevalence of dental caries was high among those with deficient levels of vitamin D as
compared to those with optimum levels of vitamin D. In addition, deficient levels of serum
calcium were also independently associated with a number of dental caries.22 A prospective
study in North India, a total of 120 patients with positive history of rickets. Enamel

15
hypoplasia was detected in 90 (75%) cases and missing teeth were detected in 45 (37.5%)
cases.23 She had dental caries, and missing tooth, but never perform dental examinations to
the dentist.

She had recurrent afebrile seizures since 2 years old, perform the EEG investigation,
in which appropriate with epilepsy, she got valproic acid 10 mg/kgBW/day. Up to 20-25
% of patients with acute hypocalcemia present epileptic seizure and up to 70% of chronic
hypocalcemia, patients are associated with epilepsy. Common etiologies for chronic
hypocalcemia are vitamin D deficiency and parathyroid hormone (PTH) dysfunction such
as hypoparathyroidism (low PTH level) or pseudo hypoparathyroidism (ineffective
peripheral PTH receptor).24

Seizures are a frequent complication of acute hypocalcemia: they have been

reported in 2025% of patients with acute hypocalcemia, and in 3070% of patients with
idiopathic hypoparathyroidism. The main etiologies of hypocalcemia are
hypoparathyroidism, severe vitamin D deficiency (VDD) and drugs.25 Hypocalcemia
seizures may also occur in subjects with severe VDD. A study conducted in UK among
children presenting to the emergency department identified 89 patients with a low vitamin
D level (total vitamin D levels less than 50 nmol/L), with 83% of those having very low
vitamin D levels (less than 25 nmol/L), seizures were present in 17% of patients.26 Patient
with deficiency vitamin D (18,9 ng/mL), and had seizure, but at EEG examination there
was epileptiform abnormalities.

Kang, et al in Korea find out of the 17 children diagnosed as vitamin D deficient

rickets, nine patients (53%) had seizure, while eight patients (47%) did not. Serum calcium
(Ca) and 25-hydroxyvitamin D3 (25-OHD3) levels were significantly lower in the 'seizure'
group. The relative risk for seizure occurrence was 8 times higher in hypocalcemia and 17
times higher in 25-OHD3<8 ng/mL. Seizures occurred several times as generalized or focal
types, but none of them developed epilepsy nor showed developmental abnormalities later
on.27

Maryam, et al in Islamabad found that antiepileptic drugs negatively affect bone

metabolism and increase the risk of osteoporosis, fractures and rickets in children. Out of
34 cases, 11 (32.4%) cases had decreased vitamin D levels (20 g/dL) after taking
carbamazepine and valproic acid for more than 3 months.28

16
 Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral
density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone
turnover markers and fractures were reported with phenobarbital, phenytoin,
carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs
induced bone diseases are heterogeneous and include hypovitaminotic D, hypocalcemia
and direct acceleration of bone loss and/or reduction of bone formation.29 She got
antiepileptic drug after the rickets symptoms was appears, so the chances of rickets due to
the AED can be removed.

She had failure in Denver developmental milestones, and diagnosed with global
developmental delay (GDD). GDD is defined as a significant delay in 2 or more
developmental domains, including gross or fine motor, speech/language, cognitive,
social/personal, and activities of daily living.30 We suspected GDD due to congenital
hypothyroid, but laboratorial examination not suitable with hypothyroid. Regarding
Abdulmoein study for clinical presentations of vitamin D deficiency, 7,5% children
experienced delayed walking and 1,6% had developmental delay.31 Rickets and delayed
developmental milestones were seen in 7% of cases in a Canadian study.32

She treated with calcium and vitamin D. Usually calcium and phosphorus levels
become normal within 6-10 days whereas PTH, 25(OH) D levels normalize within 1-2
months and serum alkaline phosphatase by 3-6 months. Complete radiological healing
takes longer than one month although evidence of healing is seen within 4 weeks.8

17
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