Silver-Russell Syndrome

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Silver-Russell Syndrome

Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder, characterized by severe pre/postnatal growth retardation, characteristic facies, skeletal asymmetry, and other congenital anomalies. The incidence is estimated as 1:50,000–1:100,000 live births.

GENETIC/BASIC DEFECTS

1. Inheritance

a. Sporadic occurrence in majority of cases

b. 19% of cases with more than one affected individuals in the family, providing evidence for a genetic cause c. A genetically (and clinically) heterogeneous disorder

i. Autosomal recessive (17.4%) ii. Autosomal dominant (8.7%) iii. X-linked dominant (74%) 2. Chromosomal basis

a. Small number of cases with Silver-Russell syndrome reported in association with numerous chromosomal abnormalities

i. R(15) and deletion of 15q ii. Diploid–triploid mixoploidy iii. 45,X/46,XY

iv. XXY

v. Trisomy 18 mosaicism vi. Del(8)(q11-q13) vii. Del(18p)

viii. Dup(1)(q32.1-q42.1) ix. Dup(7p12.1-p13)

x. Distal chromosome 17q

a) Balanced translocation (17;20)(q25;q13) inherited from clinically normal father b) De novo translocation (1;17)(q31;q25) with

breakpoint recently cloned and localized to 17q23.3-q24

c) Heterozygous deletion of the chorionic somatomammotrophin hormone 1 (CSH1) gene located within the growth hormone and CSH gene cluster on 17q24.1. The deletion was inherited from the father who appeared clinically normal but had short stature

b. Maternal uniparental disomy (UPD) for chromosome 7 (about 7–10% of cases)

i. Inheritance of both chromosomes 7 from the mother

ii. A possible novel imprinted region at 7p12-p14, 7q32, and 7q31-ter: UPD can disrupt the balance between imprinted genes and thereby lead to phenotypic manifestations

iii. Strong evidence of disruption of imprinted gene expression rather than mutation of a recessive

gene underlying the Silver-Russell phenotype in these cases

c. The majority of the cases, however, have a normal karyotype

CLINICAL FEATURES

1. Diagnostic criteria: Presence of three major features plus one or more minor features is generally required for a positive diagnosis.

a. Major criteria

i. Low birth weight (intrauterine growth retardation)

ii. Proportionate short stature (postnatal growth retardation): mature height about –3.6 standard deviation scores in both sexes

iii. Small triangular face iv. Fifth finger clinodactyly b. Minor criteria

i. Relative macrocephaly due to sparing of cranial growth

ii. Ear anomalies

iii. Skeletal asymmetry (face, limb, or body) iv. Brachydactyly of the fifth fingers

v. Bilateral camptodactyly with terminal interpha- langeal contractures

vi. Syndactyly

vii. Transverse palmar crease

viii. Downward slanting corner of the mouth ix. Muscular hypotrophy/hypotonia

x. Motor/neurological delay xi. Irregular spacing of the teeth xii. Café-au-lait spots

xiii. Precocious puberty xiv. Squeaky voice

xv. Genital abnormalities xvi. Speech delay xvii. Feeding difficulties 2. Other manifestations

a. Significant cognitive impairment (50%) b. Gastrointestinal symptoms (77%)

i. Gastroesophageal reflux disease (34%) ii. Esophagitis (25%)

iii. Food aversion (32%) iv. Failure to thrive (63%) c. Skeletal anomalies

i. Large anterior fontanelle (delayed closure) ii. Absence of asymmetry

iii. Syndactyly of the toes d. Genitourinary anomalies

i. Hypospadias

ii. Posterior urethral valves

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900 SILVER-RUSSELL SYNDROME

e. Cardiac defects f. Various tumors

i. Craniopharyngioma ii. Testicular seminoma iii. Hepatocellular carcinoma

iv. Wilms tumor

g. Essentially normal pattern of puberty and adolescent growth

h. Fertility not necessarily impaired, at least in females i. Other features

i. Blue sclera ii. Café-au-lait spots iii. Excessive sweating

iv. Hypoglycemia

DIAGNOSTIC INVESTIGATIONS

1. Increased serum or urinary gonadotropin levels in the pre- pubertal age

2. Hypoglycemia

3. Growth hormone studies

4. Metabolic acidosis due to renal tubular acidosis in a few patients

5. Radiography

a. Delayed bone age b. Limb asymmetry

c. Ivory epiphyses of the distal phalanges d. Clinodactyly of the fifth fingers e. Short fifth middle phalanges

f. Pseudoepiphyses at the base of the second metacarpal 6. Chromosome analysis to define chromosome basis 7. UPD study using microsatellite markers on chromosome 7

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sibs

i. Not increased in a non-genetic sporadic case ii. Increased depending on the inheritance pattern b. Patient’s offspring

i. Not increased in a non-genetic sporadic case ii. Increased depending on the inheritance pattern 2. Prenatal diagnosis by ultrasonography of fetus at risk by

family history

a. Delayed fetal skeletal growth may not be evident until late second trimester

b. Asymmetry of fetal limbs may not be evident until the third trimester

3. Management

a. Growth deficiency

i. Optimize caloric intake

ii. Consider nasogastric or gastrostomy feeding for severe gastroesophageal reflux and failure to thrive iii. Consider growth hormone treatment in patients

with documented growth hormone deficiency b. Dental cares for overcrowding of teeth

c. Orthopedic management for asymmetry of legs d. Early intervention programs including physical thera-

py for developmental delay due to hypotonia e. Special education for learning disabilities

f. Psychological counseling related to body image and peer relationship

REFERENCES

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Fig. 1. An infant with Silver-Russell syndrome showing prenatal and postnatal growth deficiency, triangular face, and asymmetry of legs.

Fig. 2. A girl with Silver-Russell syndrome showing prenatal and post- natal growth deficiency, triangular face, and clinodactyly of the 5th fingers.

Fig. 3. A girl with Silver-Russell syndrome showing prenatal and post- natal growth deficiency with brachydactyly and clinodactyly of the 5th fingers.