Silver-Russell Syndrome

Clinical characteristics: Silver-Russell Syndrome (SRS) is typically characterized by asymmetric gestational growth restriction resulting in affected individuals being born small for gestational age, with relative macrocephaly at birth (head circumference ≥1.5 SD above birth weight and/or length), prominent forehead usually with frontal bossing, and frequently body asymmetry. This is followed by postnatal growth failure, and in some cases progressive limb length discrepancy and feeding difficulties. Additional clinical features include triangular facies, fifth-finger clinodactyly, and micrognathia with narrow chin. Except for the limb length asymmetry, the growth failure is proportionate and head growth normal. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean. The Netchine-Harbison Clinical Scoring System (NH-CSS) is a sensitive diagnostic scoring system. Clinical diagnosis can be established in an individual who meets at least four of the NH-CSS clinical criteria – prominent forehead/frontal bossing and relative macrocephaly at birth plus two additional findings – and in whom other disorders have been ruled out.

Diagnosis/testing: SRS is a genetically heterogeneous condition. Genetic testing confirms clinical diagnosis in approximately 60% of affected individuals. Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes SRS in 35%-50% of individuals, and maternal uniparental disomy (mUPD7) causes SRS in 7%-10% of individuals. There are a small number of individuals with SRS who have duplications, deletions or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in CDKN1C, IGF2, PLAG1, and HMGA2 have been described. However, approximately 40% of individuals who meet NH-CSS clinical criteria for SRS have negative molecular and/or cytogenetic testing.

Management: Treatment of manifestations: Multidisciplinary follow up and early, specific intervention are necessary for optimal management of affected individuals. Treatment may include growth hormone therapy. Hypoglycemia should be prevented or aggressively managed. Strategies for feeding disorders include nutritional and caloric supplements, medication for gastroesophageal reflux, therapy for oral motor problems and feeding aversion, cyproheptadine for appetite stimulation, and enteral tube feeding as needed. Lower-limb length discrepancy exceeding 2 cm requires intervention. In older children, distraction osteogenesis is recommended for most individuals. Physical, occupational, speech, and language therapy with an individualized education plan are used to treat delays. Psychological counseling can be used as needed to address psychosocial and body image issues. Severe micrognathia or cleft palate should be managed by a multidisciplinary craniofacial team. Males with cryptorchidism or hypospadias should be referred to a urologist. Males with micropenis and females with internal genitourinary anomalies benefit from referral to a multidisciplinary disorders of sex development center.

Surveillance: Monitoring of: growth velocity; blood glucose concentration and urine ketones for hypoglycemia in infants and as needed in older children; limb length at each well-child visit in early childhood for evidence of asymmetric growth; evaluation for scoliosis, signs of premature central puberty, dental crowding and malocclusion, and speech/language development.

Agents/circumstances to avoid: prolonged fasting in infants and young children because of the risk for hypoglycemia; elective surgery whenever possible due to risk of hypoglycemia, hypothermia, difficult healing, and difficult intubation.

Genetic counseling: SRS has multiple etiologies and typically has a low recurrence risk. In most families, a proband with Silver-Russell syndrome (SRS) represents a simplex case (a single affected family member) and has SRS as the result of an apparent de novo epigenetic or genetic alteration (e.g., loss of paternal methylation at the 11p15 ICR1 H19/IGF2 imprinting center 1 or maternal uniparental disomy for chromosome 7). SRS may also occur as the result of a genetic alteration associated with up to a 50% recurrence risk (e.g., a copy number variant on chromosome 7 or 11 or an intragenic pathogenic variant in CDKN1C, IGF2, PLAG2, or HMGA2) depending on the nature of the genetic alteration and the sex of the transmitting parent. Accurate assessment of SRS recurrence therefore requires identification of the causative genetic mechanism in the proband.