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A rare cause of primary amenorrhoea, the XY female with gonadal dysgenesis.

ABSTRACT: Disorders of sexual development are conditions where sexual phenotype and genotype are discordant. Genetic sex is determined at conception as the ovum is fertilised by a spermatozoon that contains either an X or Y chromosome. A complex pathway determined by genes and hormones leads to gonadal differentiation into testis or ovary and promotes the development of internal and external genitalia. We present a case of an 18-year-old woman who presented with primary amenorrhoea. She was a virgin, and apart from hirsutism and overweight, had no complaints. Her family history was insignificant. The patient was tall and had underdeveloped breasts. Her blood results showed hypergonadotropic hypogonadism. A 46, XY genotype was detected with karyotype analysis. Ultrasound and MRI demonstrated the presence of a uterus, but no overt gonads. Laparoscopy was performed, with bilateral removal of streak ovaries.

SUBMITTER: Mannaerts D

PROVIDER: S-EPMC4330456 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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A rare cause of primary amenorrhoea, the XY female with gonadal dysgenesis.

Mannaerts Dominique D Muys Joke J Blaumeiser Bettina B Jacquemyn Yves Y

BMJ case reports 20150209

Disorders of sexual development are conditions where sexual phenotype and genotype are discordant. Genetic sex is determined at conception as the ovum is fertilised by a spermatozoon that contains either an X or Y chromosome. A complex pathway determined by genes and hormones leads to gonadal differentiation into testis or ovary and promotes the development of internal and external genitalia. We present a case of an 18-year-old woman who presented with primary amenorrhoea. She was a virgin, and ...[more]

PMID: 25666240

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Project description:Partial and mixed gonadal dysgenesis (PGD and MGD) are characterized by genital ambiguity and the finding of either a streak gonad and a dysgenetic testis or two dysgenetic testes. The karyotype in PGD is 46,XY, whereas a 45,X/46,XY mosaicism or its variants (more than two lineages and/or structural abnormalities of the Y chromosome) is generally found in MGD. Such mosaics are also compatible with female phenotype and Turner syndrome, ovotesticular disorder of sex development, and infertility in men with normal external genitalia. During the last few years, evidences of a linkage between Y microdeletions and 45,X mosaicism have been reported. There are also indications that the instability caused by such deletions might be more significant in germ cells. The aim of this work was to investigate the presence of Y chromosome microdeletions in individuals with PGD and in those with 45,X/46,XY mosaicism or its variants and variable phenotypes.Our sample comprised 13 individuals with PGD and 15 with mosaicism, most of them with a MGD phenotype (n?=?11). Thirty-six sequence tagged sites (STS) spanning the male specific region (MSY) on the Y chromosome (Yp, centromere and Yq) were analyzed by multiplex PCR and some individual reactions.All STS showed positive amplifications in the PGD group. Conversely, in the group with mosaicism, six individuals with MGD had been identified with Yq microdeletions, two of them without structural abnormalities of the Y chromosome by routine cytogenetic analysis. The deleted STSs were located within AZFb and AZFc (Azoospermia Factor) regions, which harbor several genes responsible for spermatogenesis.Absence of deletions in individuals with PGD does not confirm the hypothesis that instability of the Y chromosome in the gonads could be one of the causes of such condition. However, deletions identified in the second group indicate that mosaicism may be associated with Y chromosome abnormalities detectable only at the molecular level. If patients with mosaicism and Y microdeletions reared as males decide to undergo in vitro fertilization, Y chromosomes which tend to be unstable during cell division may be transmitted to offspring.

Project description:Purpose: Patients with syndromic 46, XY disorders/differences of sex development (DSD) are characterized by gonadal and phenotypic genders inconsistent with their chromosomal sexes as well as abnormalities of multiple extragonadal organs. They are caused by mutations in specific genes, which are expressed in the affected organs and regulate their development, and over fourteen genes have been identified. In this study, we aimed to determine the underlying cause of a patient with syndromic 46, XY DSD and review the clinical presentations and genetic findings of all reported similar cases. Methods: Whole-exome sequencing (WES) was performed to find a molecular cause of the patient. In silico tools were used to analyze the pathogenicity of the variants. Reports of cases with similar clinical features and involved genes were summarized by searching through PubMed/MEDLINE using keywords "PPP2R3C" or "G5PR" and "46,XY disorders of sex development". Results: Compound heterozygous variants (p.F229del/p.G417E) in PPP2R3C were identified in the 24-year-old female by WES and verified by Sanger sequencing. The patient presents complete testicular dysgenesis, low birth weight, facial deformity, cubitus valgus, and decreasing number of CD19+ B lymphocytes and CD4+ T lymphocytes. A total of thirteen 46, XY DSD cases with four homozygous PPP2R3C mutations (p.Leu103Pro, p.Leu193Ser, p.Phe350Ser, and p.Ser216_Tyr218dup) have been reported previously, and their clinical manifestations are roughly similar to those of our patient. Conclusion: Novel compound heterozygous variants in PPP2R3C cause specific syndromic 46, XY gonadal dysgenesis, which broadened the pathogenic variants spectrum of PPP2R3C. The typical phenotype of PPP2R3C mutation is complete 46, XY gonadal dysgenesis with multiple extragonadal anomalies, including facial deformities, skeletal system abnormalities, muscle abnormalities, impaired nervous system, impaired hearing and vision, heart and kidney anomalies, and gastrointestinal dysfunction.

Dataset Information

A rare cause of primary amenorrhoea, the XY female with gonadal dysgenesis.

Publications

A rare cause of primary amenorrhoea, the XY female with gonadal dysgenesis.

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