Case Report: Minipuberty hormonal profile in PPP1R12A-related persistent Müllerian duct syndrome

Persistent Müllerian duct syndrome (PMDS) is a rare difference/disorder of sex development and maturation characterized by the retention of Müllerian structures during fetal development in individuals with a 46,XY karyotype. It is typically due to mutations in anti-Müllerian hormone (AMH) or its receptor, anti-Müllerian hormone receptor type 2 (AMHR2). Here, we report a novel de novo heterozygous loss-of-function frameshift variant in protein phosphatase 1 regulatory subunit 12A (PPP1R12A; p.Lys197IlefsTer13) identified in a 46,XY neonate presenting with bilateral cryptorchidism and a Müllerian remnant detected on pelvic ultrasound. Hormonal evaluation during the first days of life and minipuberty revealed the expected activation of the hypothalamic-pituitary-gonadal axis and preserved gonadal function: serum inhibin B, 108 pg/mL; AMH, 174.4 pmol/L; and testosterone, 1.4 nmol/L at birth; and inhibin B, 259 pg/mL; AMH, 342 pmol/L; testosterone, 9.2 nmol/L; LH, 19.1 IU/L; and FSH, 10.4 IU/L, respectively. At 10 months, AMH (149.8 pmol/L) and inhibin B (76 pg/mL) concentrations were below the reported age-specific reference intervals, raising the possibility of evolving Sertoli cell dysfunction. In silico analyses predict a truncated protein and/or nonsense-mediated mRNA decay. The endocrine profile supports the hypothesis that the PPP1R12A variant may contribute to PMDS through abnormal duct development rather than primary gonadal failure. These findings broaden the endocrine phenotype associated with this syndrome and suggest a role for PPP1R12A in Müllerian duct regression and differentiation rather than in gonadal development.