Kittikorn

Duangkam 13rd Jan, 2011

NORMAL GROWTH
Growth is complex and involves the interaction of

multiple factors.

Phases of growth The infantile phase

rapid but decelerating growth in rst 2 years of life

The childhood phase growth at constant velocity of 5 - 7 cm/yr The pubertal phase

growth spurt of 8 to 14 cm/yr due to the synergistic eects of increasing gonadal steroid and GH secretion

Phases of growth
The pubertal phase

The infantile phase

The childhood phase

Deni;on of short stature

Short stature dened as height that is o < 2 SD of the mean height for age and sex. (Less than the 3rd percentile) OR o < 2 SD below mid-parental height Thailand : Male < 154 cm

Female < 145 cm

History
Birth history Medical history Family history Dietary history Medication history Development Growth data

Growth data
Predicted or Target height Growth velocity

Predicted height
1.Projected height
For children with delayed or accelerated growth, using

the skeletal age (bone age) rather than the

chronologic age.

Skeletal age X-Ray the bones of hand and wrist

Greulich and Pyle Atlas Tanner-Whitehouse (TW2) method

Predicted height
2.Midparental height

13) / 2 Female = ( + 13) / 2

8.5 cm = 3rd - 97th percentiles for anticipated adult height.

Male = (

+ +

Growth velocity
Growth velocities depend on age and pubertal status.

Physical examina;on
Vital signs Height , BW ,BMI General examination Dysmorphic features Pubertal examination Body proportions

Is the child short?

Body propor;ons :Upper segment to lower segment (US/LS ra;o)

The lower segment = top of the symphysis pubis

plantar surface of the foot () The upper segment = Total height - lower segment
qUS/LS ratio qBirth 1.7 q3 years 1.33 q5 years 1.17 q10 years 1.0

q >10 years <1.0

Body propor;ons :Upper segment to lower segment (US/LS ra;o)

The US/LS ratio in rickets, achondroplasia, and

Turner syndrome (because of limb length)

The US/LS ratio in Scoliosis ,Morquio ( trunk

length) or in Marfan syndrome (because of limb length)

Body propor;ons : Arm span to height

Arm span = distance between tips of middle

ngers in a horizontal position At 10 yrs boys / 12 yrs girls, , arm span > height
The arm span-to height ratio identify a

disproportion between the limbs and the trunk

eg, Marfan syndrome, which the arm span > height at

least 5 cm

Tanner Stage

Laboratory evalua;on
Endocrine function TSH, FT4, Prolactin IGF-1 and IGF-binding protein 3 or GH stimulation tests Bone age : X-Ray the bones of hand and wrist Greulich and Pyle Atlas Tanner-Whitehouse (TW2) method Chromosome study esp. all female to rule out Turner's

syndrome.

Short stature :

EVALUATION

EVALUATION

EVALUATION
1. Is the child short? 2. Dysmorphic features Syndrome? 3. Disproportionate short stature? 4. Proportionate short stature?

Approach

1. Familial short stature 2. Constitutional delayed growth

Approach
Short stature

Proportionate

Dysmorphic feature

Disproportionate

Idiopathic

secondary

Short Limbs

Short Trunk

Short stature
Dysmorphic feature

Proportionate

Disproportionate

Idiopathic

secondary

Short Limbs

Short Trunk

Dysmorphic features
E S PE C l a s s i f icat ion
A1: Clinically dened syndromes
Turner syndrome DiDeorge syndrome (velocardiofacial syndrome) Down syndrome Noonan syndrome Prader-Willi-Labhart syndrome Von Recklinghausens disease (neurobromatosis type 1) Cornelia de Lange syndrome Silver-Russell syndrome

Dysmorphic features
Chromosomal abnormalities
Down syndrome Turners syndrome Prader-willi or Laurence-moon-biedl

Nonchromosomal
Noonan syndrome Russell-silver

Intrauterine growth restriction Intrauterine infections Maternal exposures : toxins, smoking,

alcohol, and systemic illness

Short stature and Hypogonadism

Male Prader-willi Laurence-moon-biedl Female Turners syndrome

Down syndrome

95% = trisomy 21, other translocation, and mosaicism 1 in 600 live births Growth failure begin and continues postnatal Delayed skeletal maturation and a delayed and incomplete pubertal growth spurt

Etiology of growth failure is unknown It is more likely due to a generalized biochemical abnormality of the epiphyseal growth plate.
Marginal levels of GH secretion and low serum levels of IGF-I have

been reported

GH tx. will augment growth velocity

 Head and neck Brachycephaly Upslanting palpebral ssures Epicanthic folds Small low set ears Protruding enlarge tongue Furrowed tongue Web neck

Extremities Short broad hands Hypoplastic mid phalanx of 5th nger Transverse palmar crease First web space of foot Hyperexibility of joints

Mental retardation Refractive error 35 76 % Cardiovascular

Endocardial cushion defect (Atrioventricular septal defect) 45% VSD 35% ASD 8%

Prader-Willi-Labhart syndrome
Deletion in chromosome 15q11-13 Undened hypothalamic dysfunction IGF deciency

syndrome Growth failure Growth pattern

Growth failure may be evident at birth and is more

impressive postnatal. Adult heights < 2 SD and almost always < the midparental height

With advancing age, hyperphagia obesity and its

complications become prominent approved indication

GH treatment of growth failure in PWS is now an FDA-

In children 3 yrs and adults Dx : 8points ( 5 major criteria)

Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993; 91:398. Copyright 1993 American Academy of Pediatrics.

The Laurence-Moon syndrome

Laurence-Moon-Biedl syndrome Autosomal recessive

 Short stature Retinitis pigmentosa

progressive visual impairment, caused by rod-cone dystrophy

Hypogonadism Mental retard Spastic paraplegia lower

part Obesity in early childhood Renal abnormalities.

Turner syndrome
(Gonadal dysgenesis)
45,XO or 46,XX with mosaicism Short stature is the single most common feature (95%-100%) >

delayed puberty and another

The cause of growth failure in Turner's syndrome remains

unclear

Haploinsucient for the SHOX gene (short stature homeobox-

arm of the X chromosome. They have many features of a skeletal dysplasia Most patients have normal GH and IGF levels during childhood

containing gene) located in the pseudoautosomal region of the short

Turner syndrome
(Gonadal dysgenesis)
Growth pattern Slow growth recognized during early infancy and falling to -3 SD by 3 years of age Progressive height velocity from age 3 yrs until 14 yrs Delayed onset of the childhood phase of growth Prolonged adolescent growth phase followed by delayed epiphyseal fusion partial return normal height (nal patient height

correlate with Parental height )

Posterior web neck

Noonan syndrome
Autosomal dominant(50% =sporadic) 4disease-causing genes (PTPN11, SOS1, RAF1, and KRAS)

have been identied regulator of cell growth

Turner-like syndrome and male Turner syndrome.

distinction. The sex chromosomes are normal Both males and females may be aected

Shares certain phenotypic features with Turner's syndrome but clear

Growth pattern similar to Turner's syndrome Mental retardation of variable degrees is present in

approximately 25% to 50%

Down-slant palpebral fissures

Anterior web neck

Turner syndrome VS Noonan syndrome

Turners
Female Normal intelligence Coarctaion of aorta Hypogonad Infertility Posterior webbed neck

Noonans
Both sex (AD) Mental retardation VHD: PS Normal sex character Fertility Anterior webbed neck

DiGeorge syndrome (velocardiofacial syndrome)

Deletion in 22q11.2 leads to a deletion of the TBX1

(a T-box transcription factor ) gene

pouches

Abnormal development of the pharyngeal arches and

AD, AR, and X-linked fashions Classical triad of DGS is Conotruncal cardiac anomalies Hypoplastic thymus Hypocalcemia (resulting from parathyroid hypoplasia).

 Facies Hypertelorism Micrognathia Short philtrum with sh-mouth appearance Antimongoloid slant Telecanthus Short palpebral ssures. Otolaryngic Low-set ears Defective pinna Cleft palate Submucous cleft Velopharyngeal insuciency.

Russell-Silver syndrome
No genetic or biochemical basis for this disorder has

been identied IUGR Postnatal growth failure Congenital hemihypertrophy Small, triangular facies

Nonspecific findings include Clinodactyly of the 5th finger Precocious puberty Delayed closure of the fontanels Delayed bone age

McCune-albright syndrome
Somatic mutations of the GNAS gene Denition Triad of Polyostotic brous dysplasia of bone (FD) Hyperfunctioning endocrinopathies caf-au-lait skin pigmentation

 Diagnosis of MAS clinical triad

Polyostotic brous dysplasia of bone (FD)
Plain X-ray sucient to diagnosis of FD but

denite by biopsy

Typical expansile lesions with endosteal

scalloping and thinning of the cortex with the matrix of the intramedullary tissue demonstrating a "ground glass appearance

 caf-au-lait skin pigmentation

Endocrinopathies
Precocious puberty Hyperthyroidism GH excess --Acromegaly Renal phosphate wasting with or

without rickets/osteomalacia Cushing syndrome

Other organ involvement

liver, cardiac, parathyroid, pancreas

Pseudohypoparathyroidism
PTH resistance Hypocalcemic and Hyperphosphatemic AND Albright's hereditary osteodystrophy (AHO) clinical features ;

Short stature Rounded face Shortened 4th and other metacarpals Obesity Subcutaneous calcications

Short stature

Proportionate

Dysmorphic feature

Disproportion ate

Idiopathic

secondary

Short Limbs

Short Trunk

Disproportionate
Short Limbs
A3:Skelatal dysplasia Rickets Achondroplasia Hypochondroplasia Dyschondrosteosis (Leri-

Short Trunk
Scoliosis Morquio

Weill and other defects in the SHOX gene) Osteogenesis imperfecta I VI

Short Limbs = bone disease

Rickets RTA Vitamin D deciency Skeletal dysplasia Achondroplasia Hypochondroplasia

Rickets
Hypovitaminosis D Failure of osteoid to calcication in a

childrens, occurs before closure of the epiphyses

Autosomal Dominant Hypophosphatemic

Rickets (ADHR)
deciency)

mutation of the gene encoding FGF23 -- RTA --- Phosphate loss(Ca2 and PO4

 Craniotabes manifests

early in infants Frontal bossing and delays the closure of the anterior fontanelle
Rachitic rosary along the

costochondral junctions Harrison groove Weight bearing produces deformities such as bowlegs Vertebral softening leads to kyphoscoliosis

Rachitic rosary

Harrison groove

Achondroplasia
Autosomal dominant , 80-90% are new mutations Mutation gene for broblast growth factor receptor 3 (FGFR3) Chromosome 4 (4p16.3)

Aects many tissues, most strikingly the cartilaginous

growth plate in the growing skeleton

Diminished growth velocity present from infancy, short

stature may not be evident until after 2 years

Mean adult heights in males and females

are 130 and 120 cm

Achondroplasia

Short Limb ,big head Normal IQ May have various skeletal abnormalities

Achondroplasia
Megalocephaly Low nasal bridge Lumbar lordosis Short trident hand Rhizomelia (shortness of
the proximal legs and arms)

with skin redundancy

Rhizomelia

Short Trunks
Scoliosis Morquio
Autosomal recessive Normal retardation Pectus carinatum

MPS IV Morquio MPS IVA =galactose 6-sulphatase def MPS IVB = beta-galactosidase. def

Short stature

Proportionate

Dysmorphic feature

Disproportionate

Idiopathic

Secondary

Short Limbs

Short Trunk

Propor;onate
B1 Insucient nutrient intake B2 Disorders in organ systems

Secondary growth disorders

Idiopathic

1. Familial short stature 2.Constitutional

B3 Growth hormone deciency B4 Other disorders of the growth

delayed growth

hormone-IGF axis (primary B5 Other endocrine disorders

Cushing syndrome Hypothyroidism

Diabetes mellitus (poorly controlled)

B6 Metabolic disorder B7 Psychosocial B8 Iatrogenic

Endocrine Regula;on of Growth

1.GH 2.IGF Actions of GH mediated by IGF peptides

GH stimulates precursor cells dierentiate Dierentiated cells secrete IGFs IGF act as mitogens and stimulate clonal expansion

Endocrine Regula;on of Growth

3.Gonadal Steroids Gonadal steroid is an important of the pubertal growth spurt
Gonadal steroid excess before epiphyseal fusion cause

rapid linear growth and skeletal maturation

4.Thyroid Hormone

a major contributor to postnatal growth a direct eect on epiphyseal cartilage a permissive eect on GH secretion

Growth hormone deciency

IGFD can be divided into primary and secondary causes Secondary IGFD results from defects of GH production, on either a

hypothalamic or pituitary basis

Secondary IGFD can be the consequence of damage to the

hypothalamus and/or pituitary resulting from

Trauma Infection Tumors Radiation Inammation

Clinical Features of IGF Deciency

Congenital IGF deciency Near-normal birth size, reecting the largely GH-independent nature of IGF production in utero Growth failure may present in several months of postnatal age Skeletal proportions relatively normal but correlate better with bone age than with chronologic age Acquired GHD Bone age = chronologic age Weight/height ratios tend to be increased Facial bone growth retarded underdeveloped nasal bridge and frontal bossing

 + fat mass lean mass High LDL May impair cardiac func;on Osteoporosis Psychologic distress Increase mortality

Hypothyroidism
Cretinism The most prominent manifestation of acquired

hypothyroidism is growth failure

Body disproportion with The US/LS ratio Skeletal age is usually markedly delayed Pubertal growth and maturation and nal adult

height are normal in well-treated CH

 Short stature Sutures - separated ,big

posterior fontanelle Low hairline Dry, brittle hair Short thick neck Hoarse-sounding voice

Broad hands with short

ngers Myxedema

Cushing syndrome
Glucocorticoid excess Impairs skeletal growth Inhibiting osteoblastic activity, and enhances bone resorption Probably eect at the level of the epiphysis Fall linear growth in children receiving prednisone >

0.35 mg/kg/day

Idiopathic Short Stature

Variants of normal growth The etiology of the slow growth and delayed

pubertal spurt has not been established. This is the largest group of short children.
Familial (genetic) short stature Constitutional Delay of Growth

Familial short stature

Growth 3 th percentile In target of family

height Normal growth velocity Normal onset and progression of puberty The GH-IGF system is normal

Cons;tu;onal Delay of Growth

Normal variant of maturation Short stature at 2 yrs of age Normal growth velocity during childhood (2 yrs ) Delayed puberty with a late pubertal growth spurt Prolong childhood growth normal adult height Some call transient GH deciency or to a lazy

pituitary