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Paediatrics: Genetic disorders of growth

Assessment of growth plays an important role in deciding whether a child may have an underlying genetic disorder.

Genetic disorders of growth


Assessment of growth plays an important role in deciding whether a child may have an underlying genetic disorder. Measurements <0.4th centile or >99.6th centile nearly always merit further assessment, unless there is a clear explanation. Measurements between the 0.4th and 2nd centiles or 98th and 99.6th need to be interpreted in context and may be clinically significant. If in doubt, discuss with a senior colleague.


Intrauterine growth retardation (IUGR)


Silver–Russell syndrome


   Incidence is unclear (1/3000–100 000 births). Equal sex ratio.

   710% of children have maternal UPD7.

   Genetically heterogeneous condition characterized by intrauterine and postnatal growth retardation with short stature and FTT. Typically, babies have disproportionately large head (OFC usually 3rd–25th centile), triangular facies, down-turned mouth, some asymmetry of limbs.

   About 30–50% of cases will show hypomethylation of the paternal chromosome at the IC1 (imprinting centre) on 11p15.5.


Cornelia de Lange syndrome


   Rare; incidence 71/50,000 live births.

   Intrauterine and postnatal growth impairment, limb anomalies, microcephaly, hirsutism, and distinctive facial features (neat arched eyebrows, short upturned nose, thin lips with down-turned corners of the mouth).

   Approximately 60% of affected children have mutations in the gene NIPBL on chromosome 5p13.


Short stature


Turner syndrome


   Affects 71/2500 females.

   Most girls have a single X chromosome (45, X), usually due to non-disjunction.

   As well as short stature, the typical phenotype includes: broad neck; ptosis; wide carrying angle at elbows (cubitas valgus); widely spaced hypoplastic nipples; low posterior hairline, excessive pigmented naevi. Puffiness of the hands and feet is a common neonatal finding.

   Associated abnormalities include: congenital heart disease (15–50%), especially coarctation of the aorta and VSD; structural renal anomalies (730%), e.g. horseshoe kidney or unilateral renal agenesis; hypoplastic ‘streak’ ovaries (p amenorrhoea and infertility).

   The phenotype can be very subtle and is easily missed, and so a chromosome analysis is usually offered to all girls with unexplained short stature.


Tall stature


Marfan syndrome




Bardet–Biedl syndrome (BBS)


Rare condition; incidence in the UK population <1/100 000.


Genetically heterogeneous with at least 8 genes identified to date. In the majority of families inheritance is autosomal recessive.


Features include: pigmentary retinopathy; postaxial polydactyly; obesity; cognitive impairment; renal defects.


Prader–Willi syndrome (PWS)


Affects 71/10 000 individuals.

Caused by disruption to the paternally derived imprinted domain on 15q11–13.

Babies are floppy with feeding difficulties and may fail to thrive in infancy. There is rapid weight gain between the ages of 1 and 6yrs.

Older children have truncal obesity, mild/moderate learning difficulties, and short stature. Typically children have an insatiable appetite with food-foraging and other behavioural problems.

Diagnosis is by molecular genetic analysis (SNRPN methylation assay).




Beckwith–Wiedemann syndrome


·Incidence 71/14,000.

Genetic basis is complex; it is caused by disruption of the imprinted region on chromosome 11p15.

Usually presents in the perinatal period with macrosomia. Birth weight is usually >97th centile and length is usually > +2SD. Polyhydramnios or preterm delivery commonly occur.

There may be associated congenital anomalies: exomphalos/umbilical hernia; dysmorphic features (e.g. ear lobe creases, port wine stain, macroglossia (large tongue)); visceromegaly; hemihypertrophy.

Neonates are at risk for severe hypoglycaemia and should be monitored closely.

Macrosomia continues through early childhood and then becomes less dramatic with increasing age.

Some children with BWS are at increased risk for Wilms’ tumour.

In 750% diagnosis can be confirmed by molecular genetic testing. Uniparental disomy 11p15 analysis requires blood testing of child and both parents.


Sotos syndrome


Incidence 71/15 000 children.

Due to mutation or deletion in the NSD1 gene on chromosome 5q35. Most are isolated de novo mutations but familial cases do occur.


Characterized by prenatal overgrowth (birth weight 74200g in males; 74000g in females), which persists in childhood, especially through the pre-school years. Final adult height is often in the upper normal range. OFC is also increased and bone age is advanced. Affected children typi-cally have a tall skull with a prominent broad forehead and pointed chin. Developmental delay is almost always present, but varies from mild to severe. Some children have seizures.


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