A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome

Abstract

BackgroundMultiple clinical scoring systems have been proposed for Silver-Russell syndrome (SRS). Here we aimed to test a clinical scoring system for SRS and to analyse the correlation between (epi)genotype and phenotype.Subjects and methodsSixty-nine patients were examined by two physicians. Clinical scores were generated for all patients, with a new, six-item scoring system: (1) small for gestational age, birth length and/or weight ≤−2SDS, (2) postnatal growth retardation (height ≤−2SDS), (3) relative macrocephaly at birth, (4) body asymmetry, (5) feeding difficulties and/or body mass index (BMI) ≤−2SDS in toddlers; (6) protruding forehead at the age of 1–3 years. Subjects were considered to have likely SRS if they met at least four of these six criteria. Molecular investigations were performed blind to the clinical data.ResultsThe 69 patients were classified into two groups (Likely-SRS (n=60), Unlikely-SRS (n=9)). Forty-six Likely-SRS patients (76.7%) displayed either 11p15 ICR1 hypomethylation (n=35; 58.3%) or maternal UPD of chromosome 7 (mUPD7) (n=11; 18.3%). Eight Unlikely-SRS patients had neither ICR1 hypomethylation nor mUPD7, whereas one patient had mUPD7. The clinical score and molecular results yielded four groups that differed significantly overall and for individual scoring system factors. Further molecular screening led identifying chromosomal abnormalities in Likely-SRS-double-negative and Unlikely-SRS groups. Four Likely-SRS-double negative patients carried a DLK1/GTL2 IG-DMR hypomethylation, a mUPD16; a mUPD20 and a de novo 1q21 microdeletion.ConclusionsThis new scoring system is very sensitive (98%) for the detection of patients with SRS with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum.

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

“…Among these latter, 11 were clinically diagnosed according to Weksberg classification [1], while diagnosis was only suspected in the remaining five. We also studied seven cases with SRS (SRS 1–7) and ICR1 LOM: three of these cases achieved the Netchine-Harbison criteria for clinical diagnosis of SRS [2], while diagnosis was only suspected in the remaining four.…”

“…Beckwith-Wiedemann (BWS, OMIM #130650) and Silver-Russell (SRS, OMIM #180860) syndromes are paired imprinting disorders (IDs) caused by opposite molecular defects at the 11p15.5 chromosomal region, which harbors two imprinted domains, IGF2/H19 and CDKN1C/KCNQ1OT1 , regulated by different imprinting control regions, ICR1 and ICR2, respectively [1,2]. Loss of methylation (LOM) at ICR1 accounts for over 50% of SRS cases, while gain of methylation (GOM) at ICR1 and LOM at ICR2 trigger BWS in approximately 10% and 60% of cases, respectively.…”

“…BWS is an overgrowth condition characterized by macrosomia, macroglossia, hemihyperplasia, visceromegaly with consequent abdominal wall defects, and increased risk of embryonal tumors [1]. Conversely, growth restriction, relative macrocephaly, peculiar small and triangular face, the fifth finger clinodactyly, and hemihypoplasia are characteristic of SRS [2]. …”

Prenatal molecular testing for Beckwith–Wiedemann and Silver–Russell syndromes: a challenge for molecular analysis and genetic counseling

“…Additionally, 10% of the latter patients show a maternal uniparental disomy of chromosome 7 (upd(7)mat). Furthermore, in patients exhibiting features of the two disorders aberrations not involving chromosomes 7 and 11p15.5 [6][7][8][9] are reported.…”

“…17,18 Furthermore, the number of SRS patients with reported molecular defects in 14q32 corresponding to Temple syndrome (TS14) is increasing. 6,7,19 For patients with BWS features, aberrations of other chromosomal regions and genes have rarely been reported. 8,9,20 Up to 60% of SRS patients show a DNA hypomethylation of the ICR1 in 11p15; in addition, in single cases complete or partial maternal duplications of 11p15 have been identified (for a review, Begemann et al 21 ).…”