Endocrine Abstracts

Introduction: Variants in the MAP3K1 gene are increasingly recognised as a cause of 46, XY disorders of sexual development (DSD), particularly in individuals with phenotypically female presentation. We report the case of a 15-year-old female who presented with delayed puberty and was ultimately diagnosed with 46, XY DSD due to a gain-of-function variant in MAP3K1.

Case: A 15-year-old girl was referred to the paediatric endocrine service for evaluation of absent pubertal development. There were no concerns regarding her sexual differentiation at birth. Her medical history is significant for recurrent urinary tract infections, chronic kidney disease secondary to reflux nephropathy and bilateral renal scarring. Examination findings: Weight - 25th percentile, height 75th percentile. Blood pressure - normal at 117/71 mmHg. Systemic examination - unremarkable.

Results: FSH (150 IU/l) and LH (61.6 IU/l) were markedly elevated indicating hypergonadotropic hypogonadism, consistent with primary gonadal failure. AMH was undetectable (<1 pmol/l), and both testosterone (0.3 nmol/l) and oestradiol (20 pmol/l) were low, supporting complete gonadal dysgenesis. Pelvic MRI showed a 2 cm hypoplastic uterus with vaginal tissue but no visible gonads. Karyotype was 46, XY with a balanced translocation t (1;4) (p13.3; q31.21), and genetic testing identified a heterozygous likely pathogenic MAP3K1 variant (c.1016G>A; p. Arg339Gln).

Management: She has been started on pubertal induction with transdermal oestradiol. She is awaiting laparoscopic cystoscopy and vaginoscopy. Gonadal localisation and possible gonadectomy will be performed concurrently.

Discussion: MAP3K1 encodes a serine/threonine kinase that plays a critical regulatory role in the MAPK signalling pathway, influencing the balance between pro-testis and pro-ovary pathways during gonadal differentiation. The gain-of-function MAP3K1 variants can lead to upregulation of β-catenin and downregulation of SOX9 expression, thereby disrupting testicular development and favouring ovarian-like differentiation in 46, XY individuals. In individuals with complete gonadal dysgenesis, the risk of developing gonadal malignancies—particularly gonadoblastoma and dysgerminoma—is significantly elevated due to the presence of dysgenetic gonads. Consequently, prophylactic bilateral gonadectomy is recommended.

Conclusion: This case underscores the need to consider 46, XY DSD in adolescents with absent puberty, with MAP3K1 variants as an emerging cause disrupting testicular development via MAPK pathway dysregulation.