ESPE Abstracts

The proband is a Caucasian girl with primary amenorrhea and no breast development at the age of 16 11/12 yrs. Unrelated parents; an older brother in good health and a twin brother (GA 31 days; BW 1450g) with reported agenesis of the corpus callosum and socio-emotional behavioral problems. The mother (menarche 14 yrs. and bicornuate uterus) presented four early spontaneous abortions and one stillborn fetus (46, XX) in the 6th month of pregnancy; remaining negative family history. The patient (BW 859g) presented with typical female external genitalia (EGS = 2), scarce pubic and axillary hair, and absence of telarche. After endocrinological and genetic counseling, in the suspicion of DSD, the determination of the karyotype (2017) was normal 46, XY with positive FISH SRY. Pelvic ultrasound and subsequent magnetic resonance imaging (MRI) of the pelvis showed a hypoplastic uterus (STAP 40x13x8 mm) and no identifiable gonadal tissue. Laboratory evaluation revealed elevated gonadotropins, with undetectable gonadal sex steroids and AMH consistent with gonadal insufficiency. Therefore, the clinical-instrumental and laboratory data were compatible with a complete gonadal dysgenesis. In 2018 the following were negative: molecular analysis of the NR5A1 (SF1) and SRY genes, and MLPA of the NROB1 (DAX1), WNT4, SOX9, NR5A1, SRY genes. The CGH array has identified two microduplications with no clear pathological significance transmitted by the mother. Finally (04/2020), the analysis of an NGS panel with 33 DSD causative genes showed the presence in heterozygosity of the variant c.556A> G, (P.Arg186Gly) in MAP3K1, not described in the literature and classified as "probably pathogenetic ". With the consent of the patient, a feminizing hormone replacement therapy was started (07/2019) at moderately progressive doses of only natural estrogens in patch (18 months) and then sequential estrogen-progestogens (03/2021); the first cycle occurred 23 days after the therapeutic change. Laparoscopy performed on 03/2022 showed a normal-sized uterus and gonadal strips (streaks) that were removed for cancer prophylaxis. This report adds a new pathogenetic alteration in the MAP3K1 gene, and highlights the clinical importance of considering defects in MAP3K1 in the differential diagnosis for complete or partial gonadal dysgenesis.