MAP3K1‐related gonadal dysgenesis: Six new cases and review of the literature

Abstract

Investigation of disorders of sex development (DSD) has resulted in the discovery of multiple sex-determining genes. MAP3K1 encodes a signal transduction regulator in the sex determination pathway and is emerging as one of the more common genes responsible for 46,XY DSD presenting as complete or partial gonadal dysgenesis. Clinical assessment, endocrine evaluation and genetic analysis were performed in six individuals from four unrelated families with 46,XY DSD. All six individuals were found to have likely pathogenic MAP3K1 variants. Three of these individuals presented with complete gonadal dysgenesis, characterized by bilateral streak gonads with typical internal and external female genitalia, while the other three presented with partial gonadal dysgenesis, characterized by incomplete testicular development, resulting in clitoral hypertrophy with otherwise typical female external genitalia. Testing for MAP3K1 variants should be considered in patients with 46,XY complete or partial gonadal dysgenesis, particularly in families with multiple members affected with 46,XY DSD. Identification of a MAP3K1 variant should prompt an evaluation for DSD in female siblings of the proband.

Metachronous Synovial Sarcoma After Treatment of Mixed Germ Cell Tumor in a Child with Complete Gonadal Dysgenesis

“…Rarely mutations in the CBX2 gene and also dublication of DAX1 gene have been considered responsible for the development of 46, XY CGD( 5 , 6 , 7 ). Mutations in the MAP3K1 gene (located on chromosome 5q) that cause downstream alterations in the MAP kinase signaling pathway have been identified ( 8 ).…”

The molecular pathways underlying early gonadal development

“…Coelomic epithelium, expression domain expands in an anteriorposterior direction, precedes expression of Sf1 (Hu et al 2013) Absent gonads No expansion of the coelomic epithelium (Hu et al 2013) Following sex determination, roles in ovarian and testicular development (Efimenko et al 2013) Testicular abnormalities, ambiguous genitalia (Lourenco et al 2011) Frequent mutation in ovarian cancers (Cai et al 2009) MAP3K1 Coelomic epithelium and gonad mesenchyme (Warr et al 2011) Minor testis abnormalities (Warr et al 2011) Ambiguous genitalia streak gonads (Pearlman et al 2010, Granados et al 2017 development, from formation of the bi-potential gonad of both sexes, to sex-specific roles following gonadal sex determination. Currently, we are lacking a detailed gene network integrating both the roles of these transcription factors, along with the signalling pathways that regulate them, to gain a broader picture of how these components together regulate cellular processes like differentiation and proliferation to control formation of the bi-potential gonad.…”

“…While these genes are also critical for mouse gonadal development, largely supporting the use of the mouse as a model for human gonad development, there are several exceptions. For example, sequencing screens have found gain-of-function mutations in the mitogen-activated protein kinase kinase kinase 1 (MAP3K1) gene, including patients with streak gonads and female genitalia (Pearlman et al 2010, Loke et al 2014, Baxter et al 2015, Eggers et al 2016, Granados et al 2017), suggesting a requirement for MAP3K1 function in gonad development for both sexes. However, although the mouse orthologue, Map3k1, is expressed in Figure 5 Histology sections through human embryos 36-44 days (Carnegie stages 14-18).…”

Fertility and pregnancy issues in a 46, XY (Swyer syndrome) patient in the face of ovarian cancer

“…Mutations in SRY and SOX9 account for approximately 20% of 46,XY complete gonadal dysgenesis patients. Genes such as CBX, DHH, WNT4, WT1, MAP3K1, NR5A1, NR0B1, FGFR2, DMRT, DHH are crucial in the stages of normal gonadal differentiation [5,6,7,8,9]. Mutations affecting DAX1 (NR0B1), SF1 (NR5A1), WNT4, DHH, and MAP3K1 are responsible for not more than 30% of cases.…”