First international consensus statement guides clinicians on diagnosis, management
of Silver-Russell syndrome
Hannah L.Jelley, M.D. and David H.Jelley, M.D., FAAP
Focus on Subspecialties
More than half a century after Henry K. Silver and Alexander Russell independently
described individuals with the syndrome that now bears their names, evidence from
controlled trials involving patients with Silver-Russell syndrome (SRS) is still limited.
An international consensus statement was developed to guide clinicians in the diagnosis
and management of patients with SRS (Wakeling EL, et al. Nat Rev Endocrinol.2017;13:105-124).These guidelines also contain lessons for the management of individuals born with
idiopathic small for gestational age (SGA), as there is significant overlap with SRS
SGA. These issues include postnatal growth retardation with failure to catch up to
peers, feeding problems, premature adrenarche and insulin resistance.
The diagnosis of SRS is primarily clinical, based on characteristic phenotypic features,
including pre- and postnatal growth failure, body asymmetry, relative macrocephaly,
protruding forehead and feeding difficulties or low body mass index.
The Netchine-Harbison clinical scoring system (NH-CSS) for the diagnosis of SRS (see
table) was developed using prospective data (Azzi S, et al. J Med Genet. 2015;52:446-453).The system is easy to use in a clinical setting. It has a sensitivity of 98% with
a negative predictive value of 89%. However, it has a low specificity of 39%, which
could lead to overdiagnosis when only clinical findings are considered.
The two clinical criteria from the NH-CSS that best differentiate SRS from non-SRS
SGA are relative macrocephaly at birth and a protruding forehead. Therefore, it is
recommended that if molecular testing is normal, a clinical diagnosis of SRS should
be made only if four of six criteria are met, including both relative macrocephaly
and prominent forehead.
Additional features occurring in at least 50% of individuals with SRS include triangular
face, clinodactyly of the fifth finger, shoulder dimples, micrognathia, low muscle
mass and hyperhidrosis (Wollmann, HA, et al. Eur J Pediatr. 1995;154:958-968).
Molecular testing can be useful to confirm the diagnosis of SRS. However, 40% of SRS
patients have normal molecular results using today’s techniques. Molecular testing
also can aid in the stratification into subcategories that can help direct the most
appropriate medical management.
Use of the NH-CSS is recommended to avoid unnecessary testing. The system advises
against molecular testing if the patient meets less than three of the six clinical
The two most common underlying genetic variants associated with SRS are loss of methylation
on chromosome 11p15 (30%-60% of cases) and maternal uniparental disomy for chromosome
7 (5%-10% of patients). It is recommended that first line molecular testing include
evaluation for both mutations. If initial molecular testing is normal, a clinical
decision is necessary to determine whether it is appropriate to pursue further genetic
SRS is best managed using a multidisciplinary approach given the wide scope of abnormal
physical findings and functional difficulties seen with this syndrome. The multidisciplinary
team may include a pediatric endocrinologist, gastroenterologist, geneticist, orthopedic
surgeon, craniofacial surgeon, dietitian, speech-language therapist and psychologist,
along with the child’s general pediatrician.
Given the medical complexity of patients with a diagnosis of SRS, long-term and comprehensive
medical care is required through their lives. Following are some of the management
recommendations outlined in the consensus statement:
Ensure early feeding and nutritional support.
Consult with registered dietitian.
Closely monitor and prevent hypoglycemia.
Pre-operative fasting or febrile illness may require intravenous glucose (D10) treatment.
Treat with growth hormone.
Monitor for early puberty and bone age advancement.
Consider treatment with a GnRH agonist.
Be aware of long-term metabolic complications.
Evaluate for neurocognitive problems.
Screen for orthopedic problems, including scoliosis and hip dysplasia.
Refer patients to a maxillofacial team for maxillofacial abnormalities.
In summary, children with SRS and their families encounter multiple issues, including
feeding difficulties, growth failure, recurrent hypoglycemia, premature adrenarche,
early and rapid “true” puberty, insulin resistance, and orthodontic and orthopedic
issues. Management should involve a multidisciplinary team approach and close parental
David H. Jelley, M.D., FAAP, is a member of the AAP Section on Endocrinology. His
daughter Hannah Jelley, M.D., is a second-year pediatric resident at the University
of Utah, Salt Lake City, and an AAP resident member.