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Molecular cytogenetic analysis and genetic counseling: a case report of eight 46,XX males and a literature review.

ABSTRACT: Background:46,XX male syndrome is a rare disorder that usually causes infertility. This study was established to identify the genetic causes of this condition in a series of 46,XX males through the combined application of cytogenetic and molecular genetic techniques. Case presentation:We identified eight azoospermic 46,XX males who underwent infertility-related consultations at our center. They all presented normal male phenotypes. In seven of the eight 46,XX males (87.5%), translocation of the SRY gene to the terminal short arm of the X chromosome was clearly involved in their condition, which illustrated that this translocation is the main mechanism of 46,XX sex reversal, in line with previous reports. However, one patient presented a homozygous DAX1 mutation (c.498G?>?A, p.R166R), which was not previously reported in SRY-negative XX males. Conclusions:We proposed that this synonymous DAX1 mutation in case 8 might not be associated with the activation of the male sex-determining pathway, and the male phenotype in this case might be regulated by some unidentified genetic or environmental factors. Hence, the detection of genetic variations associated with sex reversal in critical sex-determining genes should be recommended for SRY-negative XX males. Only after comprehensive cytogenetic and molecular genetic analyses can genetic counseling be offered to 46,XX males.

SUBMITTER: Yue F

PROVIDER: S-EPMC6827185 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Molecular cytogenetic analysis and genetic counseling: a case report of eight 46,XX males and a literature review.

Yue Fagui F Zhang Hongguo H Xi Qi Q Jiang Yuting Y Li Leilei L Liu Ruizhi R Wang Ruixue R

Molecular cytogenetics 20191104

<h4>Background</h4>46,XX male syndrome is a rare disorder that usually causes infertility. This study was established to identify the genetic causes of this condition in a series of 46,XX males through the combined application of cytogenetic and molecular genetic techniques.<h4>Case presentation</h4>We identified eight azoospermic 46,XX males who underwent infertility-related consultations at our center. They all presented normal male phenotypes. In seven of the eight 46,XX males (87.5%), transl ...[more]

PMID: 31700544

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Project description:Background and objectives: XX male syndrome is part of the disorders of sex development (DSD). The patients generally have normal external genitalia and discover their pathology in adulthood because of infertility. There are no guidelines regarding XX male syndrome, so the aim of our study was to evaluate the literature evidence in order to guide the physicians in the management of these type of patients. Materials and Methods: We performed a systematic review of the available literature in September 2018, using MEDLINE, Web of Science, Embase and Google Scholar database to search for all published studies regarding XX male syndrome according to PRISMA guidelines. The following search terms were used: "46 XX male", "DSD", "infertility", "hypogonadism". Results: After appropriate screening we selected 37 papers. Mean (SD) age was 33.14 (11.4) years. Hair distribution was normal in 29/39 patients (74.3%), gynecomastia was absent in 22/39 cases (56.4%), normal testes volume was reported in 0/14, penis size was normal in 26/32 cases (81.2%), pubic hair had a normal development in 6/7 patients (85.7%), normal erectile function was present in 27/30 cases (90%) and libido was preserved in 20/20 patients (100%). The data revealed the common presence of hypergonadotropic hypogonadism. All patients had a 46,XX karyotype. The sex-determining region Y (SRY) gene was detected in 51/57 cases. The position of the SRY was on the Xp in the 97% of the cases. Conclusions: An appropriate physical examination should include the evaluation of genitalia to detect cryptorchidism, hypospadias, penis size, and gynecomastia; it is important to use a validated questionnaire to evaluate erectile dysfunction, such as the International Index of Erectile Function (IIEF). Semen analysis is mandatory and so is the karyotype test. Abdominal ultrasound is useful in order to exclude residual Müllerian structures. Genetic and endocrine consultations are necessary to assess a possible hypergonadotropic hypogonadism. Testicular sperm extraction is not recommended, and adoption or in vitro fertilization with a sperm donor are fertility options.

Project description:Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309-320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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Molecular cytogenetic analysis and genetic counseling: a case report of eight 46,XX males and a literature review.

Publications

Molecular cytogenetic analysis and genetic counseling: a case report of eight 46,XX males and a literature review.

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