Trisomy 7 mosaicism, maternal uniparental heterodisomy 7 and Hirschsprung's disease in a child with Silver–Russell syndrome

Abstract

Prenatal trisomy 7 is usually a cell culture artifact in amniocytes with normal diploid karyotype at birth and normal fetal outcome. In the same way, true prenatal trisomy 7 mosaicism usually results in a normal child except when trisomic cells persist after birth or when trisomy rescue leads to maternal uniparental disomy, which is responsible for 5.5-7% of patients with Silver-Russell syndrome (SRS). We report here on the unusual association of SRS and Hirschsprung's disease (HSCR) in a patient with maternal uniparental heterodisomy 7 and trisomy 7 mosaicism in intestine and skin fibroblasts. HSCR may be fortuitous given its frequency, multifactorial inheritance and genetic heterogeneity. However, the presence of the trisomy 7 mosaicism in intestine as well as in skin fibroblasts suggests that SRS and HSCR might possibly be related. Such an association might result from either an increased dosage of a nonimprinted gene due to trisomy 7 mosaicism in skin fibroblasts (leading to SRS) and in intestine (leading to HSCR), or from an overexpression, through genomic imprinting, of maternally expressed imprinted allele(s) in skin fibroblasts and intestine or from a combination of trisomy 7 mosaicism and genomic imprinting. This report suggests that the SRS phenotype observed in maternal uniparental disomy 7 (mUPD(7)) patients might also result from an undetected low level of trisomy 7 mosaicism. In order to validate this hypothesis, we propose to perform a conventional and molecular cytogenetic analysis in different tissues every time mUPD (7) is displayed.

Trisomy 7 mosaicism prenatally misdiagnosed and maternal uniparental disomy in a child with pigmentary mosaicism and Russell– Silver syndrome

“…This pigmentary mosaicism has to be differentiated from café au lait patches that are common in RSS or matUPD7 (9). The trisomic clone was present in fibroblast karyotyping, even in the five cases without pigmentary anomaly (6,13,16,23).…”

“…Dysmorphic features were noted in 9 of the 16 mosaic cases, but highly variable and without a precise clinical picture. Nevertheless, dysmorphism described in matUPD7/RSS (triangular‐shaped face, broad forehead, small chin and low‐set ears) was found in several cases, notably in the two cases for which matUPD7 was proven (13, 14).…”

“…Two patients with RSS related to matUPD7 associated with mosaic trisomy 7 diagnosed antenatally have been reported in the literature (12–14). We report on a new patient with mosaic trisomy 7 and matUPD7, presenting growth retardation with mild RSS phenotype.…”

Visualization of uniparental inheritance, Mendelian inconsistencies, deletions, and parent of origin effects in single nucleotide polymorphism trio data with SNPtrio

“…This occurs when bivalent chromatids fail to separate during meiosis I. A mixture of iUPD and hUPD is also possible, due to meiotic recombination [Flori et al, 2005].…”

Effects of RET, NRG1 and NRG3 Polymorphisms in a Chinese Population with Hirschsprung Disease

“…Through linkage mapping and mouse model analysis, a series of susceptible genes were found to contribute to the development of the ENS, including RET (OMIM 164761), EDNRB (OMIM 131244), GDNF (OMIM 600837), ECE1 (OMIM 164761), NRTN (OMIM 602018), PHOX2B (OMIM 603851), SOX10 (OMIM 602229), EDN3 (OMIM 131242), ZFHX1B (OMIM 605802), L1CAM (OMIM 308840), TCF4 (OMIM 602272), and KBP10 (OMIM 609367)6910111213141516171819. These genes encode transcription factors, receptors, ligands, and other cellular elements involved in the development of ENS20. During the past several years, studies have revealed molecular anomalies or novel genes associated with HSCR, such as copy number variation521, polymorphisms in the 3′ untranslated region22, and gene-gene interactions23, as well as microRNA interactions24.…”