There was no history of miscarriages, neonatal deaths, infertility, developmental delay, or endocrine or sex reversal disorders. Those siblings were born to a non-consanguineous couple (Figure 1). Molecular characterization of the aetiology was made possible after one of the siblings referred for genetic evaluation before proceeding with surgical correction. Three siblings with ambiguous genitalia, were evaluated by the Genetic and Endocrine teams at Tawam Hospital, Al Ain, United Arab Emirates. This study was approved by our regional research ethical committee.
2 PATIENTS AND METHODS 2.1 Ethical compliance Here, we report three siblings with a heterozygous missense MAP3K1 variant causing variable degrees of 46, XY partial gonadal dysgenesis. Most individuals with DSD lack a known specific genetic aetiology however, exome sequencing has been used to identify a likely genetic aetiology in up to 43% of patients with 46, XY DSD (Baxter et al., 2015 Eggers et al., 2016). The 46, XY DSDs comprise disorders of gonadal development, disorders of androgen synthesis and action, persistent Müllerian duct syndrome, and other unclassified disorders (León et al., 2019). Sertoli cells in the developing testis produce Anti-Müllerian Hormone (AMH), leading to regression of the Müllerian ducts, while production of testosterone by the Leydig cells promotes differentiation of Wolffian duct structures into male internal genitalia.ĭSDs are classified into three subclasses: sex chromosome DSDs, 46, XY DSDs and 46, XX DSDs. The third stage is sex differentiation where the gonads produce hormones that differentiate the internal and external genitalia (León et al., 2019). Whereas in the absence of a Y chromosome and expression of SRY, the undifferentiated gonad develops as an ovary and the Wolffian ducts regress (Ono & Harley, 2013).
The expression of the SRY gene on the Y chromosome causes the undifferentiated gonad to develop into a testis. These genes comprise two signaling pathways, SRY (NM_003140.2) and its downstream target SOX9 (NM_000346.3) in the testis determination and WNT4- CTNNB1 (β-catenin, NM_001098209.1) signaling pathway in the ovary determination (León et al., 2019 Xue et al., 2019). This stage is controlled by several determining genes. This is followed by sex determination stage where the bipotential gonads form testes or ovaries. The indifferent stage, from fertilization to 6 weeks gestation, is where both XY and XX embryos are morphologically indistinguishable. The process of sex development in human embryo composed of three stages.
The incidence rate among subjects with 46, XY to have a DSD has been estimated to be 1 in 20,000 births (Lee et al., 2016). There are no clear estimates of the incidence rate of subjects presenting with ambiguous genitalia at birth, however, it has been estimated to be approximately 1 in 4500–5500 birth. This report adds to the genotype-phenotype correlation, highlighting the clinical importance of considering MAP3K1 gene defects as part of the differential diagnosis for complete or partial gonadal dysgenesis especially with multiple affected family members.ĭisorders of sex development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical (Granados et al., 2017). The identified mutation (p.Thr657Arg) was previously classified as a pathogenic variant, although apparently there are no reported humans with this mutation. Clinical and genetic assessments were performed for the three siblings, while endocrine evaluation was done for two of them. We report three siblings with same novel variant in MAP3K1 gene presenting with variable degrees of partial gonadal dysgenesis. Few mutations in this gene have previously been identified in a high proportion of individuals with 46, XY gonadal dysgenesis. It can present as complete or partial gonadal dysgenesis even within the same kindred. Mitogen-activated protein kinase kinase kinase 1 ( MAP3K1) is one of the commonest genes that has been identified to cause 46, XY DSD. Disorders of sex development (DSD) can result from congenital defect in sex determining pathway.
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