Paediatrics JC119: The Short Child: Child Growth And Development

Question 1

Growth disorders

Answer 1

1. Short stature
2. Tall stature

Normal growth:
- Adequate lengthening of skeleton replies upon complex interaction between variables
1. **Genetic
2. **Hormonal
3. ***Nutritional
4. Psychological

Newborn’s size determined by intrauterine environment:
1. **Maternal size
2. **Nutrition
3. General health
4. Social habits (e.g. smoking status)

Question 2

Growth velocity during childhood

Answer 2

• Greatest in late fetal life
  —> ↓ until **estrogen-mediated epiphyseal fusion occurs in adolescence
  —> except during **pubertal growth spurt (升翻上去)
• Growth rate ~ in both genders until puberty (boys **later pubertal growth spurt but **higher velocity)
• HK Average height: 171cm for male, 158cm for female

Felix Lai:
- Growth failure is likely in the following
1. Height-for-age curve has deviated downwards across 2 major height percentile curve
2. Child is growing slower than the following rates
- Age 2-4: HV <5.5 cm/year
- Age 4-6: HV <5 cm/year
- Age 6-puberty: HV <4 cm/year (males) or HV <4.5 cm/year (females)

Question 3

Short stature

Answer 3

Important to determine whether due to **normal variant of growth / **underlying pathological condition

2 normal variants with short stature:
1. **Familial short stature
2. **Constitutional delay in growth / development

Constitutional delay vs Familial short stature
1. Height: Short vs Short
2. Midparental height: Normal vs Short
3. Bone age: **Delayed vs Not delayed
4. Growth rate: Slow vs Normal
5. Height prognosis: **Good (遲早長高翻) vs Poor

Question 4

***History taking in Short stature

Answer 4

***記: Birth, Immunisation, Feeding, Developmental

1. Maternal pregnancy history
2. Birth + ***Perinatal history
3. ***Birth weight, length
4. Onset + Duration of **catch-up / **catch-down growth after birth
5. Serial height measurements documented over time on a growth chart
   —> assess **Prepubertal, **Pubertal growth velocity
6. ***Nutritional history
7. **Family heights + **Maturation history
   - **Midparental height (MPH)
   —> Boys: (Father + (Mother+13)) / 2
   —> Girls: ((Father-13) + Mother) / 2
   —> 3rd / 97th centile for child are **8.5 cm to either side of MPH
   - Family history of delayed growth / pubertal developmental (e.g. age of menarche of mother, age of growth spurt)
8. Systems review for chronic illness
9. Psychosocial history

Question 5

Physical examination in Short stature

Answer 5

1. Body height, BW, Head circumference
2. ***Body proportions
   - Arm span
   - Upper to Lower segment ratio
3. ***Dysmorphism
4. Dentition + Midline defects (e.g. Septo-optic dysplasia (SpC Revision))
5. ***Visual fields + Fundoscopic examination (if suspected pituitary tumour)
6. ***Thyroid assessment
7. Specific systems screening

Question 6

Investigations of Short stature

Answer 6

1. Blood
   - CBP
   - ESR
   - LRFT
   - Electrolytes
   - **Bone profile
   - **Thyroid function
   - ***IGF-1
2. ***Bone age
   - X-ray of left hand
3. ***Karyotype for Girls
   - rule out Turner syndrome (∵ presence of mosaicism —> no classical phenotype features): complete / partial absence of 1 X chromosome
4. ***Provocative GH testing

Question 7

Features suggestive of pathological cause of Short stature

Answer 7

1. ***Body height <1st centile
2. ***Abnormally short for family heights
3. History / P/E suggestive of chronic illness
4. ***Abnormal growth velocity
5. ***Abnormal body proportions
6. ***Dysmorphic features / Midline defects

Question 8

**Pathological causes of short stature: **Endocrine PICNICS
(Psychological, Iatrogenic, Chronic illness, Nutritional, IUGR, Chromosomal, Skeletal dysplasia)

Answer 8

1. Endocrine
   - **Hypothyroidism
   - **GH deficiency
   - ***Cushing syndrome (inhibit GH action)
2. Psychological
   - Deprivation
3. Iatrogenic
   - ***Glucocorticoid usage
   - Spinal radiation
4. ***Chronic illness
5. Nutritional
6. ***IUGR (Intrauterine growth restriction —> SGA)
   - Unknown etiology
   - Part of a syndrome (e.g. Russell-Silver syndrome)
7. ***Chromosomal
   - Turner syndrome
   - Noonan syndrome
   - Down syndrome
   - Prader-Willi syndrome
8. ***Skeletal dysplasia
   - Achondroplasia
   - Hypochondroplasia

Question 9

***4 Major groups of Short stature

Answer 9

1. Dysmorphism with recognisable syndrome
   - **Down syndrome
   - **Turner syndrome
   - **Noonan syndrome
   - **Russell-Silver syndrome
2. Disproportionate short stature (usually need a **skeletal survey for diagnosis)
   - Short back + limbs
   —> Spondyloepiphyseal dysplasia (short trunk, kyphoscoliosis)
   —> **Mucopolysaccharidosis

• Short limbs (e.g. Rhizomelic shortening (shortening of proximal long bone i.e. humerus, femur))
  —> **Achondroplasia
  —> **Hypochondroplasia
  (—> Thanatophoric dysplasia type 1 / 2 (SpC Revision))

3. Short but thin (need to search for **chronic illness)
   - **CVS disease
   - **Respiratory disease (e.g. **Cystic fibrosis)
   - ***Malabsorption / Chronic IBD
   - Chronic renal failure
   - Psychosocial deprivation
   - Anorexia nervosa
   - Rickets
   - Thalassaemia
4. Short + Fat (suggestive of **endocrine cause)
   - **Panhypopituitarism
   - **Isolated GH deficiency
   - **Hypothyroidism
   - Pseudohypoparathyroidism
   - **Cushing’s syndrome
   - **Prader-Willi syndrome

Question 10

Down syndrome

Answer 10

1. Flat facial profile
2. ***Flat occiput
3. ***Prominent Epicanthic fold
4. ***Upward slanting eyes
5. ***Flat nasal bridge
6. Protruding tongue
7. ***Simian crease in hands
8. Clinodactyly (歪指)
9. Gap between 1st / 2nd toes (Sandal gap toes)
10. Developmental delay
11. Hypotonia
12. ***AVSD, VSD, PDA

Question 11

Turner syndrome

Answer 11

Phenotype highly variable
1. Short stature
2. **Low posterior hairline
3. **Low set ears
4. Narrow, high arched palate
5. **Webbed neck
6. **Broad chest with widely-spaced nipple
7. **Cubitus valgus (↑ carrying angle)
8. **Left-sided cardiac lesions (e.g. **Coarctation of aorta, **Bicuspid aortic valve)
9. ***Horseshoe kidney
10. Streak ovaries, amenorrhoea, infertility
11. Hypothyroidism
12. Concave hypoplastic nail (SpC Revision)

(Normal intelligence)

SpC Revision:
- Sporadic disorder with complete / partial absence of 2nd X chromosome
- Incidence 1 in 2000-2500 live female births
- Should be considered in short girls, even in the presence of pubertal signs (∵ can have Mosaic turner)
- Marked serum gonadotropins from as early as 8-9 years (∵ lack of negative feedback)
- Pure XX and XY gonadal dysgenesis both present with delayed puberty, ↑ Gonadotropins + ↓ Sex steroids
- The XY gonadal dysgenesis group reared as girls have high risk of gonadal tumours, thus need surgery for removal of gonads

Question 12

Noonan syndrome

Answer 12

• Autosomal Dominant (Vinson Cheng)
• Genetic mutation (e.g. ***PTPN11 mutation (SpC Revision))
• a ***RASopathies (along with Costello syndrome, CFC (Cardiofaciocutaneous syndrome)

1. Atypical facial appearance
   - **(Orbital) Hypertelorism
   - **Downward slanting eyes
   - ***Low set, abnormally shaped / posteriorly rotated ears
2. Short stature
3. ***Broad / Webbed neck
4. Heart defects
   - **Hypertrophic obstructive cardiomyopathy
   - ASD, VSD
   - **PS
5. Vision problems
6. Hearing loss
7. Abnormal bleeding / bruising
8. ***Pectus excavatum / carinatum
9. Mild developmental delay / Intellectual disability

Question 13

Russell-Silver syndrome

Answer 13

Cause:
- Largely unknown
- mat dup 11p15.5 (also implicated in Beckwith-Wiedemann syndrome)
- matUPD7

1. Born SGA / Low birthweight (< -2 SD) (IUGR-related (SpC Revision))
2. Short stature (< -2 SD)
3. ***Relative macrocephaly (Normal head circumference which may appear large ∵ small body size)
4. ***Triangular face
5. ***Broad forehead
6. ***Pointed chin
7. ***Clinodactyly of 5th finger (尾指歪左)
8. ***Limb / body / facial asymmetry / hemihypertrophy
9. Hypospadias
10. ***Feeding difficulty during infancy
11. Hypoglycaemia (need GH supplementation for low glucose + poor growth)
12. Normal head circumference (SpC Revision)
13. Developmental delay
14. Urogenital features (e.g. Hypospadias, Urethral valves, Horseshoe kidneys, Cryptochidism)

Question 14

Mucopolysaccharidosis (MPS)

Answer 14

MPS subtypes share common characteristics + is a progressive multisystemic disorder
- MPS type 6: Maroteaux-Lamy syndrome
- MPS type 4a: ***Morquio syndrome
- MPS type 1: Hurler syndrome

Facial features:
1. Broad nose
2. Flat nasal bridge
3. **Prominent eyes
4. Enlarged tongue + lips
5. **Prominent forehead
6. ***Macrocephaly
7. Coarse hair

Extra-skeletal symptoms:
1. **Chronic rhinitis / otitis media
2. Obstructive airway disease
3. Skin thickening
4. **Corneal clouding
5. **Hearing loss
6. Enlarged tongue
7. **Valvular heart disease
8. Hepatosplenomegaly
9. ***Umbilical / Inguinal hernia (need to reduce early otherwise later on when develop hepatosplenomegaly will be difficult to operate)
10. Developmental delay
11. Abnormal facial features

Skeletal / Joint symptoms:
1. **Evolving joint contracture without signs of inflammation —> Fixed joint deformity early in life
2. **Cervical spine stenosis / Cord compression
3. **Pectus carinatum
4. **Kyphosis / Scoliosis
5. Bilateral hip dysplasia
6. Genu valgum
7. Waddling gait / Reduced mobility
8. ***Short stature of unknown reason
9. Idiopathic carpal tunnel syndrome
10. Multiple joint pain

Question 15

Rhizomelic shortening: Achondroplasia

Answer 15

• Autosomal dominant (AD) inheritance
• ***FGFR3 gene gain-of-function mutation
• Short stature at birth
• ***Rhizomelic shortening of arms + legs (can be diagnosed antenatally)
• ***Head disproportionately large + Prominent forehead
• ***Thoracolumbar kyphosis (gibbus)
• ***Trident hand with brachydactyly (short fingers)
  —> short digits + wide hands
  —> hand resembles a trident (三叉戟) (thumb + 2nd/3rd finger + 4th/5th finger)
  —> characteristics of both achondroplasia + hypochondroplasia

Skeletal survey (SpC Revision):
- Excessive skinfold
- Trident hand
- Narrow sciatic notch
- Widened metaphysis
- Spikes at metaphysis

Question 16

Rhizomelic shortening: Hypochondroplasia

Answer 16

• ***FGFR3 gene mutation (SpC Revision)
• Short-limbed short stature
• Considerable shortening of upper + lower limb
• Marked bowing of legs
• **In contrast to Achondroplasia, Head size + Facial features are **normal

Question 17

3. Short but thin (need to search for chronic illness)

Answer 17

Chronic disease:
1. **CVS disease
2. **Respiratory disease (e.g. **Cystic fibrosis)
3. **Malabsorption / Chronic IBD
4. Chronic renal failure
5. Psychosocial deprivation
6. Anorexia nervosa
7. Rickets
8. Thalassaemia

Question 18

4. Short + Fat (suggestive of endocrine cause)

Answer 18

Endocrine cause:
1. **Panhypopituitarism
2. **Isolated GH deficiency
3. **Hypothyroidism
4. Pseudohypoparathyroidism
- **short 4th, 5th metacarpals
- target organ resistance to PTH
- **HypoCa —> Carpopedal spasm
- ↑ PO4
- ↑↑ PTH
- Short stature, obesity, developmental delay
- **Calcification of basal ganglia in deep white matter of brain

5. ***Cushing’s syndrome
6. ***Prader-Willi syndrome

DDx of Obesity + Mental retardation (Vinson Cheng):
- Pan-hypopituitarism
- Hypothyroidism
- Prader-Willi syndrome

Question 19

Prader-Willi syndrome

Answer 19

• Short stature
• ***Long + Narrow head at birth
• ***Narrow face
• ***Distinct almond shaped eyes
• Small mouth + corners curved downward
• Thin upper lip
• Small upturned nose
• ***Small hands + feet
• ***Hypogonadism leading to genital hypoplasia (Felix Lai)
  —> Cryptorchidism
  —> Scrotal hypoplasia
  —> Labia minor / Clitoral hypoplasia
• ***Obese (not a must) (Vinson Cheng)
• ***Mental retardation
• **Genomic Imprinting: deletion of the **paternal copies of SNRPN and Necdin genes
• Dolichocephaly (SpC Revision)
• ***Hypotonia + Poor feeding —> Failure to thrive
• Treatment: ***GH injection (Growth promoting effect + Lipolytic effect)

Question 20

Treatment of Short stature

Answer 20

Depend on underlying etiology
1. Explanation + Reassurance if non-pathological cause
2. Explore issues around school, sport, family —> help encourage short children to feel comfortable with their height outcome
3. Referral to a paediatric endocrinologist if suspect pathological cause

Question 21

Tall stature

Answer 21

Far less common presenting problem than Short stature

Causes:
1. ***Familial tall stature (vast majority)

2. Endocrine causes
   - **Hyperthyroidism
   - Precocious puberty
   - **GH secreting tumours
3. Syndromal causes
   - **Klinefelter syndrome
   - **Marfan syndrome
   - **Sotos syndrome
   - **Homocystinuria (very rare, can be screened in newborn screening)
   - ***Beckwith-Wiedemann syndrome

Investigations:
1. **Serial measurement: determine duration of problem + plot against father’s + mother’s height to look at basic genetic potential
—> **Crossing centiles: more likely to have underlying pathological cause
2. **TFT
3. **IGF-1
4. **Karyotype
5. **Bone age

Question 22

1. Familial tall stature

Answer 22

1. Tall parents
2. Family history of ***early puberty
3. Bone age: helpful in demonstrating advancement in development + aid in predicting final height

Question 23

2. Endocrine causes of Tall stature

Answer 23

1. Hyperthyroidism
2. Precocious puberty
   - tall at diagnosis but ***reduced final height (∵ premature fusion of epiphyses)
3. GH secreting tumours
   - extremely rare in paediatrics

Question 24

3. Syndromal causes of Tall statures

Answer 24

1. Klinefelter syndrome
   - 47 XXY males
   - **Eunuchoid body habitus, Poor musculature, Sparse body / facial hair, **Small testes, Aggressive impulsive personality
2. Marfan syndrome
   - Autosomal dominant (AD) inheritance
   - Defect in **fibrillin (FBN1) gene —> ↑ TGFβ signalling —> Hyperextensibility, **Arachnodactyly (long fingers) (thumb (Steinburg) + wrist (Walker-Murdoch) sign), Kyphoscoliosis, Aortic root problems, **Ectopia lentis (upward + outward), **High arch palate, **Dolicocephaly
   - Patients with **MEN2B have a similar phenotype
   - DDx:
   —> Ehlers-Danlos syndrome
   —> Klinefelter syndrome (Vinson Cheng)
   —> Loeys-Dietz syndrome (LDS)
   - Diagnosis: Ghent criteria (JC122)
3. Sotos syndrome
   - ***Cerebral gigantism (characterised by rapid growth in early childhood)
4. Homocystinuria (very rare, can be screened in newborn screening)
   - **Autosomal recessive (AR) inheritance
   - similar phenotype to **Marfan syndrome with additional problems: **Poor bone density + **↑ Tendency to thrombosis (more likely to have stroke) (Ectopia lentis: downward + inward)
5. Beckwith-Wiedemann syndrome
   - Sporadic
   - **Imprinting gene disorder
   - Five distinct errors involving **11p15 have been identified
   - Fetal overgrowth syndrome with features: **Macrosomia, **Macroglossia, **Hepatosplenomegaly, **Hypoglycaemia (∵ Hyperinsulism), **Risk of malignancy esp. **Wilms’ tumour, **Hepatoblastoma (monitor AFP)
   - **Microcephaly (Vinson Cheng)
   - **Omphalocele / umbilical hernia
   - **Hemihypertrophy
   - Horizontal ear crease
   - Pathology finding: Adrenal cortex cytomegaly, Placental mesenchymal dysplasia, Pancreatic adenomatosis
   - DDx of big tongue:
   —> Hypothyroidism
   —> Storage disease (mucopolysaccharidosis)
   —> Obstructive airway disease with protruding tongue
   - Management:
   —> AFP + USG monitoring up to 8 yo for embryonal tumours

Question 25

Klinefelter syndrome (SpC Revision)

Answer 25

• Most common cause of ***hypergonadotropic hypogonadism in male
• Incidence 1 in 500-1000 live male births
• A group of chromosomal disorders with >=1 extra X chromosome added to the normal male karyotype of 46,XY
• **Eunuchoidal body habitus with sparse body and facial hair, **gynaecomastia, ↑ fat mass, **small testes and penis, ↓ verbal intelligence, with **high gonadotropins,
  **testosterone deficiency and **azoospermia
• Early introduction of testosterone prevents gynaecomastia

Question 26

Overgrowth syndromes (SpC Revision)

Answer 26

Types:
1. Chromosomal abnormalities (e.g. Sotos syndrome)
2. Syndromes with generalised overgrowth (e.g. Beckwith-Wiedemann syndrome, Costello syndrome)
3. Segmental overgrowth syndromes (e.g. Pallister-Killian syndrome, Klippel-Trenaunay syndrome, Cloves syndrome)

Approach:
History:
- Antenatal history: Parity, Maternal obesity, Excess weight gain (>18kg), Maternal DM
- Review family history: Ethnicity, Consanguinity, Learning difficulties, Parental height + weight

P/E:
- **Segmental / Asymmetric (e.g. **Mosaicism) vs ***Generalised / Symmetric overgrowth
- Dysmorphic features: Craniofacial characteristics, Hair line, Ear pits / creases, Macroglossia
- Hands: Camptodactyly, Deep palmar creases, Loose folds of skin
- Cardiac abnormalities

Investigations:
- Chromosomal microarray if generalised overgrowth is unexplained
- Specific genetic tests according to clinical features:
—> Methylation studies of 11p5 for Beckwith-Wiedemann syndrome
—> Sequence analysis on the HRAS gene for suspected Costello
- If suspected Pallister-Killian / Asymmetric overgrowth —> Consider mosaicism

Question 27

Sotos syndrome

Answer 27

• Most common syndromic cause of congenital macrosomia
• Autosomal dominant
• Deletion / Heterozygous variant of NSD1 at chromosome 5q35
• Family history many reveal an affected parent but most cases are sporadic + de novo

Clinical features:
1. Distinct facial features
- High prominent forehead
- Sparse frontoparietal hair
- Downslanting palpebral fissures
- Small pointed chin
2. Increased birth length
3. Hypotonia
4. Variable large hands and feet
5. Joint laxity, renal abnormalities, cardiac abnormalities
6. Prognathism
7. Learning difficulties (variable) (vs ***No developmental delay in Beckwith-Wiedemann syndrome)

Question 28

Costello syndrome

Answer 28

• Autosomal dominant
• Heterozygous pathogenic variant in HRAS gene on chromosome 11
• Part of Noonan / CFC (Cardiofaciocutaneous syndrome) / Costello RASopathy spectrum

Clinical features:
- Failure to thrive (NB may present as SGA, IUGR babies; May be LGA, but many have difficulties, develop FFT and short stature later)
- Coarse facial features
—> Thick lip
—> Prominent nose
—> Wide mouth
- Loose folds of extra skin (esp. on hands + feet)
- Sparse curly hair
- Arrhythmia
- Structural heart defects
- Hypertrophic cardiomyopathy
- Later: Significant learning difficulties, increased tumour risk (***Papillomas, Rhabdomyosarcoma, Neuroblastoma, Transitional cell carcinoma)

Question 29

Klippel-Trenaunay syndrome

Answer 29

• Segmental overgrowth
• Mosaic PIK3CA mutation

Classical triad of:
1. Cutaneous capillary malformation (usually Port-wine stain)
2. Venous malformation / varicosities
3. Soft tissue / Skeletal overgrowth

Complications:
1. Coagulopathy
2. Bleeding tendency
3. Venous insufficiency
4. Limb length discrepancy
5. Kasabach-Merritt syndrome in 50% (Thrombocytopenia)

Question 30

Cloves syndrome

Answer 30

CLOVES: Congenital lipomatous overgrowth, Vascular malformations, epidermal naevi, scoliosis / skeletal and spinal syndrome
- ~ to Klippel-Trenaunay syndrome —> also caused by somatic PIK3CA mutation
- Progressive + disproportionate segmental overgrowth syndrome involving:
1. Subcutaneous
2. Muscular
3. Vascular
4. Adipose tissue
5. Skeletal overgrowth

Question 31

DiGeorge syndrome features (SpC Paed + JC118)

Answer 31

• Long face
• Upslanting eyes
• Long nose with broad nasal bridge
• Low set ears
• Truncal lesions (e.g. Tetralogy of Fallot, Pulmonary atresia with VSD, Interrupted aortic arch)

From JC118:
Patterns of infection:
- Failure to thrive
- Chronic diarrhoea
- Thrush
- ***Viral, Fungal opportunistic infections

Clinical presentations:
1. **Hypocalcaemia (Low Ca Low pH) —> Muscle cramps
2. **Low T cells (babies have low but adequate T cells for live vaccines)
3. Abnormal facies with prominent ears, small chin, short philtrum
4. ***Pcychiatric + Learning issues
5. Conotruncal heart defects

Investigation:
- **FISH: chromosome **22q deletion