Electronic Letters to:

Endocrine Care: Irène Netchine, Sylvie Rossignol, Marie-Noëlle Dufourg, Salah Azzi, Alexandra Rousseau, Laurence Perin, Muriel Houang, Virginie Steunou, Blandine Esteva, Nathalie Thibaud, Marie-Charles Raux Demay, Fabienne Danton, Elzbieta Petriczko, Anne-Marie Bertrand, Claudine Heinrichs, Jean-Claude Carel, Guy-André Loeuille, Graziella Pinto, Marie-Line Jacquemont, Christine Gicquel, Sylvie Cabrol, and Yves Le Bouc 11p15 Imprinting Center Region 1 Loss of Methylation Is a Common and Specific Cause of Typical Russell-Silver Syndrome: Clinical Scoring System and Epigenetic-Phenotypic Correlations J Clin Endocrinol Metab 2007; 92: 3148-3154 [Abstract] [Full text] [PDF]

eLetters: Submit a response to this article

Electronic letters published:

11p15 imprinting center region 1 loss of methylation: evidence for a widening of the phenotype

Claire L. Turner, H. Bullman, M. Lever, D.J.G Mackay, J.H. Davies, I.K. Temple   (4 February 2008)

11p15 imprinting center region 1 loss of methylation: evidence for a widening of the phenotype 4 February 2008
Claire L. Turner, Specialist registrar clinical genetics University Southampton, H. Bullman, M. Lever, D.J.G Mackay, J.H. Davies, I.K. Temple Send letter to journal: Re: 11p15 imprinting center region 1 loss of methylation: evidence for a widening of the phenotype clsturner1{at}yahoo.co.uk Claire L. Turner, et al.	We read with interest the paper by Netchine et al. regarding loss of methylation (LOM) at 11p15, imprinting control region 1 (ICR1) in Russell Silver syndrome (RSS). Using their own clinical scoring system to define RSS patients, they detected this epimutation in 64% (1). Conversely, this aberration was absent in all their patients designated as non-RSS. Patients were examined by an endocrinologist or a geneticist, but it is not clear whether phenotypic features, not normally considered part of RSS, were actively sought. Our own experience suggests that patients with LOM at ICR1 may have features beyond classic SRS, reflecting others’ findings (2). The Wessex Regional Genetics Laboratory offers diagnostic testing for methylation abnormalities at 11p15 using methylation specific PCR, and multiplex ligation dependent probe amplification (MLPA) to confirm abnormalities. While our methods differ from those used by Netchine et al. they are validated. Phenotypic details, accompanying referred samples allow simple genotype-phenotype correlations. Over 18 months, 65 samples from patients with suspected RSS were tested. A LOM at ICR1 was identified in 12 patients (18%). Of these 12 cases, three (25%) had additional features beyond classic-RSS: A male with hypospadias and a chordee; a female with a cleft palate; A male (monozygotic twin) with hypospadias, a large exomphalos, a cleft palate, and dysplastic cardiac valves. Of note, the other twin had no unusual phenotypic features and normal methylation studies at ICR1. In the group of 53 patients with no LOM at ICR1, there were only two children (3.7%) with features that fell outside classic SRS, both with cardiac septal defects. Thus the group showing LOM at ICR1 appear more likely to have additional extra-RSS features (<0.03 with Fisher’s Exact test). An advantage of our study is that the phenotypic information used to perform genotype-phenotype correlations was prospectively acquired. The referring physician performing the phenotype was effectively masked to molecular results: however, the limited phenotypic information accompanying some samples may compromise genotype-phenotype correlations. Our data suggest an association of LOM at ICR1 with abnormal genitalia, already reported with increased incidence in RSS, occurring in up to 20% of males with RSS (3), and specifically in those with LOM at ICR1 (2). We speculate that other phenotypic features maybe associated with LOM at ICR1: two of 12 were known to have a cleft palate prior to testing; an additional patient, re-examined following testing, was noted to have a broad uvula. It is plausible that the exomphalos in one patient is relevant since this is frequent in other syndromes due to aberrations at imprinted loci including Beckwith Wiedemann syndrome (BWS), and transient neonatal diabetes mellitus (TNDM). Theoretically, the wider phenotype may reflect more global hypomethylation at other loci, as suspected in other prototype imprinting disorders including BWS and TNDM (4, 5). Alternatively, variable expression or tissue specific LOM (mosaicism) may account for phenotypic-variation. To summarize, our data suggest that it is premature to exclude patients with atypical RSS from imprinting studies at 11p15. References 1. Netchine, I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, Houang M, Steunou V, Esteva B, Thibaud N, Demay MC, Danton F, Petriczko E, Bertrand AM, Heinrichs C, Carel JC, Loeuille GA, Pinto G, Jacquemont ML, Gicquel C, Cabrol S, Le Bouc Y. 2007 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab 92:3148-3154 2. Bliek J, Terhal P, van den Bogaard MJ, Maas S, Hamel B, Salieb-Beugelaar G, Simon M, Letteboer T, van der Smagt J, Kroes H, Mannens M. 2006 Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype. Am J Hum Genet 78:604-614 3. Price SM, Stanhope R, Garrett C, Preece MA, Trembath RC. 1999 The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet 36:837-842 4. Mackay DJ, Boonen SE, Clayton-Smith J, Goodship J, Hahnemann JM, Kant SG, Njolstad PR, Robin NH, Robinson DO, Siebert R, Shield JP, White HE, Temple IK. 2006 A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus. Hum Genet 120:262-269 5. Rossignol S, Steunou V, Chalas C, Kerjean A, Rigolet M, Viegas-Pequignot E, Jouannet P, Le Bouc Y, Gicquel C. 2006 The epigenetic imprinting defect of patients with Beckwith-Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region. J Med Genet 43:902-907