RESUMEN
BACKGROUND: Wolf-Hirschhorn (WHS) is a set of congenital physical anomalies and mental retardation associated with a partial deletion of the short arm of chromosome 4. To establish a genotype-phenotype correlation; we carried out a molecular cytogenetic analysis on two Tunisian WHS patients. Patient 1 was a boy of 1-year-old, presented a typical WHS phenotype while patient 2, is a boy of 2 days presented an hypospadias, a micropenis and a cryptorchidie in addition to the typical WHS phenotype. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used. RESULTS: Results of the analysis showed that patient 2 had a greater deletion size (4.8 Mb) of chromosome 4 than patient 1 (3.4 Mb). Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. If we analyze the uncommon deleted region between patient1 and patient 2 we found that the Muscle Segment Homeobox (MSX1) gene is included in this region. MSX1 is a critical transcriptional repressor factor, expressed in the ventral side of the developing anterior pituitary and implicated in gonadotrope differentiation. Msx1 acts as a negative regulatory pituitary development by repressing the gonadotropin releasing hormone (GnRH) genes during embryogenesis. We hypothesized that the deletion of MSX1 in our patient may deregulate the androgen synthesis. CONCLUSION: Based on the MSX1 gene function, its absence might be indirectly responsible for the hypospadias phenotype by contributing to the spatiotemporal regulation of GnRH transcription during development.
RESUMEN
OBJECTIVE: To determine the genetic cause of 46,XY primary amenorrhea in three 46,XY girls. DESIGN: Whole exome sequencing. SETTING: University cytogenetics center. PATIENT(S): Three patients with unexplained 46,XY primary amenorrhea were included in the study. INTERVENTION(S): Potentially pathogenic variants were confirmed by Sanger sequencing, and familial segregation was determined where parents' DNA was available. MAIN OUTCOME MEASURE(S): Exome sequencing was performed in the three patients, and the data were analyzed for potentially pathogenic mutations. The functional consequences of mutations were predicted. RESULT(S): Three novel homozygous nonsense mutations in the luteinizing hormone receptor (LHCGR) gene were identified:c.1573 CâT, p.Gln525Ter, c.1435 CâT p.Arg479Ter, and c.508 CâT, p.Gln170Ter. CONCLUSION(S): Inactivating mutations of the LHCGR gene may be a more common cause of 46,XY primary amenorrhea than previously considered.