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Micrognathia
Published in Amar Bhide, Asma Khalil, Aris T Papageorghiou, Susana Pereira, Shanthi Sairam, Basky Thilaganathan, Problem-Based Obstetric Ultrasound, 2019
Amar Bhide, Asma Khalil, Aris T Papageorghiou, Susana Pereira, Shanthi Sairam, Basky Thilaganathan
Smith–Lemli–Opitz Syndrome (SLOS): A deficiency of 7-dehydrocholesterol reductase is a causative factor of the SLO syndrome. There is evidence of pre-natal onset of growth restriction. Ambiguous genitals and sex reversal in male fetuses are seen. Polydactyly and microcephaly are often present. Mental retardation is present. Inheritance is autosomal recessive.
Endocrinology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Mehul Dattani, Catherine Peters
This condition usually presents with tall stature and excessively long legs (Figs 13.27, 13.28). The patients tend to be slim initially, but can be obese as adults. Other features include hypogonadism with small testes and inadequate virilisation, infertility and gynaecomastia (Fig. 13.28). More severe disorders of sex development have been reported, including complete sex reversal. Children with this condition can have a low intelligence quotient (IQ) with poor school performance. Diabetes mellitus is commoner in adults with Klinefelter syndrome than in the general population. Investigations should include a karyotype and serum LH and follicle stimulating hormone (FSH), which are usually elevated (hypergonadotrophic hypogonadism). The serum testosterone is consequently low. A pelvic ultrasound scan is indicated if cryptorchidism is a feature.
Sex Chromosome Anomalies
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
L. Hamerton John, A. Evans Jane
SRY is a transcription factor whose function is to initiate testicular differentiation in mammalian embryogenesis. The protein contains a high mobility group box (HMG), a DNA binding motif conserved among a broad class of nuclear proteins. Almost all of the published mutations associated with sex reversal in 46,XY females are located in the HMG box and affect the structure of the DNA binding domain (146). Other loci involved in XY sex reversal include SOX9 at 17q24, a transcription factor whose duplication leads to XX sex reversal, while mutations lead to XY gonadal dysgenesis and campomelic dysplasia. Mutations in SF1 at 9q33 result in adrenal insufficiency and XY gonadal dysgenesis. Mutations in DMRT1 at 9p24 result in XY gonadal dysgenesis. Mutations at the DAX1 locus, an antitestis gene at Xp21.3, result in congenital adrenal hypoplasia, while duplications of a 160 kb region result in XY gonadal dysgenesis (158). Clearly, extensive genetic heterogeneity exists in both XX and XY sex reversal. The process of sex determination is clearly highly complex and only partially understood (153,158-160).
The use of in silico extreme pathway (ExPa) analysis to identify conserved reproductive transcriptional-regulatory networks in humans, mice, and zebrafish
Published in Systems Biology in Reproductive Medicine, 2023
Overall, ExPa analyses indicated a considerable conservation of reproductive TRNs between mammals and zebrafish. Factor analysis across all aggregated life-stages also supported this observation (Figure 5). Given the reliance of zebrafish sex differentiation on germ cell numbers established during the bipotential stage (Kossack and Draper 2019), the conserved reproductive TRNs between zebrafish and mammals were mostly for the maintenance of sexual differentiation (once it is established). As a result, regardless of a lack of sex determination genes in zebrafish the TRNs responsible for canalizing male vs. female sexual differentiation were conserved with mammalian taxa. The discrete dynamics of gene activations over ontogeny precludes the predominance of hierarchical ‘master’ regulators. In so much is evident whereby knock-outs or mutations of either sex determination or differentiation genes result in sex reversal or reproductive functional dysgenesis (Ono and Harley 2013; Ohnesorg et al. 2014). Therefore evolutionarily, control appears distributed with ‘parliamentary’ decision-making resting with ensembles of genes active at particular developmental stages (albeit their activations being dependent upon those of preceding genes) (Capel 2017). Finally, limitations of the in silico and in vivo model systems are considered below.
Prenatal diagnosis of campomelic dysplasia due to SOX9 deletion
Published in Journal of Obstetrics and Gynaecology, 2019
Gulsum Kayhan, Pınar Calis, Deniz Karcaaltincaba, Esra Tug
CD caused by a SOX9 deletion is a rare condition. The deletion detected in the present foetus included the entire SOX9 gene and its upstream region, about 880kb. The foetus showed XY sex reversal and skeletal findings of CD. At present, only three CD cases have been reported with complete deletion of SOX9 gene. All three cases, as well as our case, carried the major skeletal findings of CD and were intubated due to respiratory insufficiency (Olney et al. 1999; Pop et al. 2004; Smyk et al. 2007). One of these patients had the 46, XY karyotype and no sex reversal. Therefore, our case diagnosed in the prenatal period is the fourth CD case with a SOX9 deletion, as well as the first with a 46, XY sex reversal and SOX9 deletion. The CD cases with sex reversal or ambiguous genitalia usually have bisexual internal genitalia. If they survive, gonadectomy should be recommended for these cases because of the risk of gonadoblastoma (Thomas et al. 1997).
WAGR, Sex Reversal, Bilateral Gonadoblastomas, and Intralobar Nephrogenic Rests: Uncertainties of Pre-Biopsy Chemotherapy in a High Risk Syndrome for Nephroblastoma.
Published in Fetal and Pediatric Pathology, 2023
Randall Craver, Matthew Stark, Stephanie Moss, Sarah Long, Pinki Prasad, Christopher C. Roth
At this time, other genetic factors contributing to sex reversal in WT1 deletion (less commonly associated with sex reversal than WT1 mutations) are unknown. Syndromes known to be associated with bilateral nephroblastomas also are associated with nephrogenic rests. Without histologic confirmation, there is a risk of premature chemotherapy for nephroblastoma, however the current standard of care for children with a cancer predisposition syndrome is to treat with pre-biopsy or pre-operative chemotherapy allowing the possibility of nephron-sparing surgery.