Endocrine phenotype of 6q16.1–q21 deletion involving SIM1 and Prader–Willi syndrome‐like features

Abstract

Proximal interstitial 6q deletion involving Single-minded 1 (SIM1) gene causes a syndromic form of obesity mimicking Prader-Willi syndrome. In addition to obesity, Prader-Willi syndrome includes several other endocrinopathies, such as hypothyroidism, growth hormone deficiency, and hypogonadotropic hypogonadism. The endocrine phenotype of interstitial 6q deletion remains largely unknown, although clinical similarities between Prader-Willi syndrome and interstitial 6q deletion suggest endocrine abnormalities also may contribute to the interstitial 6q deletion phenotype. This report describes the endocrine phenotype in a propositus with the Prader-Willi-like syndrome associated with an interstitial 6q deletion including the SIM1 gene. Detailed endocrine evaluation of the propositus during childhood and adolescence revealed hypopituitarism, though initial endocrine evaluations during infancy were unremarkable. Our patient raises the possibility that hypopituitarism may be part of the phenotype, especially short stature, caused by interstitial 6q deletion. SIM1 plays an important role in the development of neuroendocrine lineage cells, implicating SIM1 haploinsufficiency in the pathophysiology of hypopituitarism seen in our propositus. Early identification of endocrine abnormalities can improve clinical outcome by allowing timely introduction of hormone replacement therapy. Hence, we suggest that detailed endocrine evaluation and longitudinal endocrine follow up be performed in individuals with proximal interstitial 6q deletion involving SIM1.

Mini-Review Prader-Willi-like phenotypes: a systematic review of their chromosomal abnormalities

“…If two or more articles reported the same chromosomal alterations for PW-like phenotype, the most recent was chosen. Twelve articles of 14 were case reports (Lukusa and Fryns, 2000;De Molfetta et al, 2002;Florez et al, 2003;Stalker et al, 2003;Niyazov et al, 2007;Nowicki et al, 2007;Gabbett et al, 2008;Pramyothin et al, 2010;Tsuyusaki et al, 2010;Ben-AbdallahBouhjar et al, 2012;Doco-Fenzy et al, 2013;Izumi et al, 2013) and two reported series of cases: one of 78 cases (Hosoki et al, 2009) and another of 9 cases (D'Angelo et al, 2013) ( Table 1). The patients included in this review were clinically diagnosed as bearing the PWlike phenotype because they were negative for alterations on 15q11-q13.…”

“…After the application of these techniques, the authors were able to exclude classical PWS, i.e., the syndrome caused by deficiency on 15q11-q13. They investigated further and discovered other mutations that could be associated with the PW-like phenotype, such as: a molecular pattern compatible with Angelman's syndrome (De Molfetta et al, 2002); chromosome 14 maternal uniparental disomy (Hosoki et al, 2009); monosomy of 1p36 (Tsuyusaki et al, 2010); deletion of 6q (Izume et al, 2013), 2pter deletion (Doco-Fenzy et al, 2013); and 10q26 deletion (Lukusa and Fryns, 2000); paracentric inversion (X)(q26q28) (Florez et al, 2003); 12q subtelomere deletions (Niyazov et al, 2007); Xq27-qter disomy; deletion 3p26.3 (Ben-Abdallah-Bouhjar et al, 2012); fragile X (Nowicki et al, 2007); and fragile X with 47,XYY (Stalker et al, 2003); deletion in 6q (Izumi et al, 2013); and Klinefelter syndrome karyotype, which showed a duplication of X(q21.1-q21.31) (Pramyothin et al, 2010) (Table 1). Recently, D'Angelo et al (2013) reported different copy number imbalances of chromosomes 2, 3, 6, 10, 12, 14, and X, in nine patients showing the PW-like phenotype.…”

“…It is important to emphasize that signs and symptoms of PWS could also be found in patients who show other types of chromosomal abnormalities such as a duplication of Xq (Gabbett et al, 2008), 1p36 monosomy (Tsuyusaki et al, 2010), a 6q deletion (Izumi et al, 2013), or fragile X (Stalker et al, 2003;Nowicki et al, 2007). Therefore, these patients exhibited a PW-like phenotype.…”

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

“…3, However, few of them underwent molecular characterisation of their genetic abnormalities, using either chromosomal microarray analysis, 3,13,[15][16][17][18]22,23,25 fluorescence in situ hybridisation (FISH) analysis with bacterial artificial chromosomes (BAC) clones 21 or STR analysis. 24 Two publications evaluated genotype-phenotype correlations at the 6q16 locus, but included only five and three patients, respectively.…”

Double Interstitial Deletion of the Long Arm of Chromosome 6 in a Patient with Pierre Robin Sequence, Dysmorphisms, and Severe Developmental Delay

“…For example, it was suggested that deletions in SIM1 at 6q16.3 were responsible for Prader-Willi-like phenotypes [Izumi et al, 2013], while deletions in NR2E1 and SNX3 (and likely additional genes in the 6q21 region) would contribute to microcephaly [Kumar et al, 2007;Mizutani et al, 2009], and deletions of 6q21q22.31 were associated with the acro-cardio-facial syndrome phenotype [Toschi et al, 2012;Hudson et al, 2014].…”