Silver-Russell Syndrome

Excerpt

Clinical characteristics: Silver-Russell Syndrome (SRS) is typically characterized by gestational growth restriction resulting in affected individuals being born small for gestational age, with relative macrocephaly at birth (head circumference ≥1.5 standard deviations [SD] above birth weight and/or length), prominent forehead with frontal bossing, and frequently body asymmetry. This is typically 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, growth failure is proportionate and head growth typically 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 imprinting control region 1 (ICR1) at 11p15.5 causes SRS in 35%-67% of individuals, and maternal uniparental disomy of chromosome 7 (upd(7)mat) 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 30%-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, including early referral to an endocrinologist. Treatment may include growth hormone therapy. Hypoglycemia should be prevented or aggressively managed. Strategies for feeding issues include nutritional and caloric supplementation, medication for gastroesophageal reflux, therapy for oral motor problems and oral aversion, cyproheptadine for appetite stimulation, and enteral tube feeding as needed. Lower limb length discrepancy exceeding 2 cm requires intervention. In the majority of affected older children, distraction osteogenesis is recommended. 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 a referral to a multidisciplinary disorders of sex development (DSD) center. Physical, occupational, speech, and language therapy with an individualized education plan are used to treat developmental delays. Psychological counseling can be used as needed to address psychosocial and body image issues.

Surveillance: Monitoring of growth velocity, blood glucose concentration, and urine ketones for hypoglycemia in infants and as needed in older children; evaluation of nutritional status and oral intake at each visit as well as managing tube feedings if needed; limb length assessment at each well child visit in early childhood for evidence of asymmetric growth; evaluation for scoliosis, signs of precocious puberty, genitourinary issues, dental crowding and malocclusion, and speech-language development at each visit.

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: Risk to family members: In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as a result of an apparent de novo epigenetic or genetic alteration. While the majority of families are presumed to have a very low recurrence risk, SRS can occur as the result of a genetic alteration associated with up to a 50% recurrence risk depending on the nature of the genetic alteration and the sex of the transmitting parent. Rare familial cases of SRS have been reported with several underlying mechanisms, including maternally inherited 11p15 duplications, maternally inherited CDKN1C gain-of-function pathogenic variants, paternally inherited IGF2 loss-of-function pathogenic variants, paternally inherited small deletions close to the boundaries of the ICR1, and paternally or maternally inherited deletions and intragenic pathogenic variants involving PLAG1 or HMGA2. Reliable SRS recurrence risk assessment therefore requires identification of the causative genetic mechanism in the proband.

Prenatal testing: Reliable prenatal testing for loss of paternal methylation at the 11p1.5 ICR1 H19/IGF2 region is not possible. Prenatal testing for the following SRS-related genetic mechanisms is possible provided the genetic mechanism has been demonstrated to be causative in an affected family member: upd(7)mat, SRS-related chromosomal abnormalities, intragenic CDKN1C, IGF2, HMGA2, or PLAG1 pathogenic variants, and deletions involving HMGA2 or PLAG1. The prenatal finding of a genetic alteration consistent with SRS cannot be used to reliably predict clinical outcome because children with SRS demonstrate varying responses to growth hormone, variable late catch-up growth, and variable developmental outcomes.