Male pseudohermaphroditism: A case study of 46,XY disorder of sexual development using whole-exome sequencing.
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ABSTRACT:
SUBMITTER: Naumova OY
PROVIDER: S-EPMC7752474 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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Male pseudohermaphroditism: A case study of 46,XY disorder of sexual development using whole-exome sequencing.
Naumova Oxana Yu OY Rychkov Sergey Yu SY Burenkova Olga V OV Solodunova Maria Yu MY Polyanskaya Irina V IV Arintcina Irina A IA Zhukova Marina A MA Ovchinnikova Irina V IV Zhukova Olga V OV Grigorenko Elena L EL
Clinical case reports 20200910 12
The study shows that whole-exome sequencing is a promising approach to detect novel variants-and gene candidates in DSD, that, as a future direction, may improve the diagnostic gene panels for this heterogeneous disorder. ...[more]
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Project description:CONTEXT:Disorders of sex development (DSD) are clinical conditions where there is a discrepancy between the chromosomal sex and the phenotypic (gonadal or genital) sex of an individual. Such conditions can be stressful for patients and their families and have historically been difficult to diagnose, especially at the genetic level. In particular, for cases of 46,XY gonadal dysgenesis, once variants in SRY and NR5A1 have been ruled out, there are few other single gene tests available. OBJECTIVE:We used exome sequencing followed by analysis with a list of all known human DSD-associated genes to investigate the underlying genetic etiology of 46,XY DSD patients who had not previously received a genetic diagnosis. DESIGN:Samples were either submitted to the research laboratory or submitted as clinical samples to the UCLA Clinical Genomic Center. Sequencing data were filtered using a list of genes known to be involved in DSD. RESULTS:We were able to identify a likely genetic diagnosis in more than a third of cases, including 22.5% with a pathogenic finding, an additional 12.5% with likely pathogenic findings, and 15% with variants of unknown clinical significance. CONCLUSIONS:Early identification of the genetic cause of a DSD will in many cases streamline and direct the clinical management of the patient, with more focused endocrine and imaging studies and better-informed surgical decisions. Exome sequencing proved an efficient method toward such a goal in 46,XY DSD patients.
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Project description:Background:Ovotesticular disorder is characterized by the presence of testicular and ovarian tissues in the same individual. Single gene mutations in SRY, SOX9, DMRT1 and DAX1 can lead to ovotesticular disorder of sexual development. Case Report:Herein, we report a 3-month-old phenotypically female baby in whom differentiated tissues of both Müllerian and Wolffian ducts were detected on pathological analysis of laparoscopic biopsy material. Chromosomal analysis observed 46,XY, der(9)t(3;9)(p25;p24) with deletion of 9p24.3p23 including the DMRT gene cluster and duplication of 3p26.3p24.3 on array comparative genomic hybridisation. Conclusion:In support of previous literature, we found that haploinsufficiency of the DMRT gene cluster leads to ovotesticular disorder of sexual development. In addition, we emphasize that array comparative genomic hybridisation is an important technique in the molecular diagnosis of ovotesticular disorder of sexual.
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Project description:Background46,XY disorders of sex development (DSD) comprise a heterogeneous group of congenital conditions. Mutations in a variety of genes can affect gonadal development or androgen biosynthesis/action and thereby influence the development of the internal and external genital organs.ObjectiveThe objective of the study was to identify the genetic cause in two 46,XY sisters of a consanguineous family with DSD and gonadal tumor formation.MethodsWe used a next-generation sequencing approach by exome sequencing. Electrophysiological and high-resolution ultrasound examination of peripheral nerves as well as histopathological examination of the gonads were performed.ResultsWe identified a novel homozygous R124Q mutation in the desert hedgehog gene (DHH), which alters a conserved residue among the three mammalian Hedgehog ligands sonic hedgehog, Indian hedgehog, and desert hedgehog. No other relevant mutations in DSD-related genes were encountered. The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more dysgenetic parts of the gonad. In addition, both patients suffer from a polyneuropathy. High-resolution ultrasound revealed a structural change of peripheral nerve structure that fits well to a minifascicle formation of peripheral nerves.ConclusionMutations in DHH play a role in 46,XY gonadal dysgenesis and are associated with seminoma formation and a neuropathy with minifascicle formation. Gonadal dysgenesis in these cases may be due to impairment of Sertoli cell-Leydig cell interaction during gonadal development.
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Project description:Sex-chromosome discordant chimerism (XX/XY chimerism) is a rare chromosomal disorder in humans. We report a boy with ambiguous genitalia and hypospadias, showing 46,XY[26]/46,XX[4] in peripheral blood cells. To clarify the mechanism of how this chimerism took place, we carried out whole-genome genotyping using a SNP array and microsatellite analysis. The B-allele frequency of the SNP array showed a mixture of three and five allele combinations, which excluded mosaicism but not chimerism, and suggested the fusion of two embryos or a shared parental haplotype between the two parental cells. All microsatellite markers showed a single maternal allele. From these results, we concluded that this XX/XY chimera is composed of two different paternal alleles and a single duplicated maternal genome. This XX/XY chimera likely arose from a diploid maternal cell that was formed via endoduplication of the maternal genome just before fertilization, being fertilized with both X and Y sperm.
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Project description:Male breast cancer (MBC) is rare and accounts for approximately 1% of all breast cancer cases worldwide. Previous studies have suggested that several factors significantly increase the risk of MBC. Prolactinoma has the highest incidence rate among patients with functional pituitary tumors. However, whether prolactinoma is involved in the onset and progression of breast cancer remains unclear. To date, there are only five case reports globally on MBC with concurrent prolactinoma. We hereby describe the first case of MBC with prolactinoma in China. We also explored the patient's genetic profile using whole exome sequencing. Our findings may help advance our understanding of the molecular pathogenesis of MBC. Further molecular analyses of such cases are warranted to improve auxiliary molecular diagnostic methods and targeted therapy for MBC.
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Project description:IntroductionOvotestis is a rare cause of sexual ambiguity characterized by the presence in a patient of both testicular and ovarian tissue, leading to the development of both male and female structures. We report a case of ovotestis diagnosed in an adolescent, with a review of the literature.Case reportA 15-year-old patient presented with a right scrotal swelling associated with gynecomastia. Histology showed a juxtaposition of ovarian stroma with ovarian follicle and seminiferous tubules. Karyotype revealed a male subject (XY). We have therefore retained the diagnosis of ovotesticular disorders of sex development.ConclusionOvotestis is a rare finding, heterogeneous in its genetic etiology and clinical presentation. While many patients are diagnosed during infancy or childhood, we presented a case diagnosed in a 15-year-old adolescent.
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Project description:Disorders of sex development (DSD) are congenital conditions characterized by atypical development of chromosomal, gonadal, and phenotypic sex. 46, XY DSD can result from disorders of testicular development or disorders of androgen synthesis/action. Prophylactic gonadectomy should be considered in patients with 46, XY DSD because of the increased risk of gonadal malignancy. We report two rare cases of 46, XY DSD, including XY pure gonadal dysgenesis and complete androgen insensitivity syndrome, who underwent a prophylactic gonadectomy.
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Project description:Inactivating mutations of the 5?-steroid reductase type-2 (SRD5A2) gene result in a broad spectrum of masculinization defects, ranging from a male phenotype with hypospadias to a female phenotype with Wolffian structures. Molecular studies of the SRD5A2 revealed a new heterozygous gene variant within the coding region that results in phenotypic expression. A c.92C>T transition changing serine to phenylalanine at codon 31 of exon 1 (p.Ser31Phe) was identified in a patient with 46,XY disorder of sexual development who displayed glandular hypospadias with micropenis and bilateral cryptorchidism. The restoration of the p.Ser31Phe mutation by site-directed mutagenesis and transient expression assays using cultured HEK-293 cells showed that this novel substitution does not abolish but does deregulate the catalytic efficiency of the enzyme. Thus, the maximum velocity (V max) value was higher for the mutant enzyme (22.5 ± 6.9 nmol DHT mg protein(-1) h(-1)) than for the wild-type enzyme (9.8 ± 2.0 nmol DHT mg protein(-1) h(-1)). Increased in vitro activity of the p.Ser31Phe mutant suggested an activating effect. This case provides evidence that heterozygous missense mutations in SRD5A2 may induce the abnormal development of male external genitalia.
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