Journal Article

Chromosome 14q32.2 imprinted region disruption as an alternative molecular diagnosis of Silver-Russell Syndrome

Harbison, Madeleine D, Salem, Jennifer, Esteva, Blandine, Pienkowski, Catherine, Naud-Saudreau, Catherine, Chantot-Bastaraud, Sandra, Steunou, Virginie, Isidor, Bertrand, Netchine, Irène, Dufourg, Marie-Noëlle, Fradin, Mélanie, Oliver Petit, Isabelle, Busa, Tiffanny, Azzi, Salah, Tauber, Maithé, Afenjar, Alexandra, Heide, Solveig, Canton, Ana P, Morice Picard, Fanny, Brioude, Frédéric, Philip, Nicole, Geneviève, David, Rio, Marlène, Vu-Hong, Thuy-Ai, Dubern, Béatrice, Geoffron, Sophie, Linglart, Agnès, Rossignol, Sylvie, Thevenon, Julien, Giabicani, Eloïse, Abi Habib, Walid, Chalouhi, Christel

2018

Overview

Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.

• Publisher: Copyright Oxford University Press,Oxford University Press,Endocrine Society
• Subject: Adolescent / Adult / Body mass index / Book publishing / Child / Child, Preschool / Chromosome 14 / Chromosome Deletion / Chromosome Disorders - diagnosis / Chromosome Disorders - genetics / Chromosomes / Chromosomes, Human, Pair 14 - genetics / Cyproheptadine / Development and progression / Diagnosis / Diagnosis, Differential / DNA / DNA methylation / DNA Methylation - genetics / Dwarfism / Endocrinology and metabolism / Female / Genes / Genetic aspects / Genetic diversity / Genetic research / Genomic imprinting / Genomic Imprinting - genetics / Growth rate / Health aspects / Human health and pathology / Humans / Intercellular Signaling Peptides and Proteins - genetics / Life Sciences / Male / Medical schools / Membrane Proteins - genetics / Methylation / Pediatrics / Phenotype / Preadipocyte factor 1 / Pregnant women / Proteins / Puberty / Puberty, Precocious - genetics / Retrospective Studies / RNA, Long Noncoding - genetics / Russell-Silver syndrome / Silver-Russell Syndrome - diagnosis / Silver-Russell Syndrome - genetics / Syndrome / Uniparental Disomy / Young Adult