ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 4.8 | DOI: 10.1530/ey.15.4.8

ESPEYB15 4 Growth and Growth Factors Novel insights into Silver-Russell syndrome (2 abstracts)

4.8 Targeted next generation sequencing approach in patients referred for Silver-Russell syndrome testing increases the mutation detection rate and provides decisive information for clinical management

Meyer R , Soellner L , Begemann M , Dicks S , Fekete G , Rahner N , Zerres K , Elbracht M & Eggermann T


Institute of Human Genetics, University Hospital, Technical University Aachen, Aachen, Germany


To read the full abstract: J Pediatr 2017; 187:206-12

SRS is a clinically heterogeneous imprinting disorder. Although the understanding of its genetic basis has gradually advanced, about 40% of patients still have an unknown molecular defect. In subjects with unknown etiology, diagnosis is primarily clinical, based upon the Netchine-Harbison scoring system (NH-CSS) [31]. However, several diseases have signs and symptoms that overlap with the clinical features of SRS, and differential diagnosis includes a wide range of genetic disorders.

This study examined a cohort of children with a clinical diagnosis of SRS based on NH-CSS. The use of a targeted next generation sequencing (NGS) approach, comprising genes associated with differential diagnoses of SRS or proposed as SRS candidate genes, increased the detection rate of disorders overlapping with SRS. In 4 of the 15 patients with NH-CSS based clinical diagnosis, a genetic cause was identified (namely Bloom syndrome, Mulibrey nanism, KBG syndrome, IGF1R), thus leading to a detection rate for disease-causing mutations of 26.7%. These results also indicate that the application of targeted NGS analysis significantly increases the current (epi)mutation detection rate up to approximately 70% of patients with NH-CSS defined SRS. The identification of a specific molecular defect is needed not only to confirm the clinical diagnosis, but also to subdivide patients into specific molecular subgroups and offer a tailored management and therapeutic approach. The mutations detected in this cohort of SRS patients included a pathogenic mutation causing Bloom syndrome, a rare genetic disorder characterized by high likelihood of developing cancers thus representing a contraindication for GH therapy, commonly used in SRS to treat short stature. Another genetic condition detected by targeted NGS was Mulibrey nanism, a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of Mulibrey nanism is variable and may overlap with SRS [33]. Its diagnosis should prompt cardiac assessment and follow-up as cardiac complications are a characteristic feature. Moreover, in Mulibrey nanism, the risk for Wilms tumors and ovarian fibrothecomas is increased. Notably, no mutations were detected in subjects without a clinical score indicative of SRS, thus underlining the importance of a careful physical examination and precise phenotyping to drive genetic analysis.

31. Wakeling EL, Brioude F, Lokulo-Sodipe O, O’Connell SM, Salem J, Bliek J, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13:105-24.

32. Hannula-Jouppi K, Muurinen M, Lipsanen-Nyman M, Reinius LE, Ezer S, Greco D, et al. Differentially methylated regions in maternal and paternal uniparental disomy for chromosome 7. Epigenetics. 2014;9:351-65.

33. Jobic F, Morin G, Vincent-Delorme C, Cadet E, Cabry R, Mathieu-Dramard M, et al. New intragenic rearrangements in non-Finnish mulibrey nanism. Am J Med Genet A. 2017;173:2782-8.