Endocrine Abstracts

Introduction: We present a case of 46,XX sex-determining region Y (SRY)-negative difference in sex development (DSD) where a heterozygous paternally inherited pathogenic RSPO1 gene variant has been identified. Further work is needed to uncover a second variant.

Case presentation: A term infant, born to non-consanguineous parents, presented at birth with atypical genitalia. There was no history of maternal androgen exposure or family history of DSD/infertility. Examination revealed an enlarged genital tubercle (2 cm), perineal opening at its base, mild labioscrotal rugosity, and no palpable gonads; a mobile left inguinal lump was noted (external genitalia score 1.5/12). Ultrasound showed an anteverted uterus (33x11x8mm), an echogenic structure (7x11x5mm) consistent with a testis in left inguinal canal, with associated hernia. Standard evaluations for congenital adrenal hyperplasia were normal. Quantitative fluorescent PCR and peripheral blood karyotype confirmed 46,XX SRY-negative pattern. Hormonal assessment (day 9) revealed LH 11.4 IU.L^-1, FSH 15.8 IU.L^-1, testosterone 1.4 nmol.L^-1 and oestradiol <100 pmol.L^-1. Laparoscopic hernia repair allowed visualisation of healthy urethra, uterus, and vagina. Gonadal biopsy confirmed testicular tissue (46,XX karyotype). Human chorionic gonadotropin stimulation test showed robust testosterone response (basal/stimulated): DHEAS 0.8/<0.4 µmol.L^-1 (NR 1.6–7.8), androstenedione 1.9/3.6 nmol.L^-1 (2.0–5.4), testosterone 4.4/8.4 nmol.L^-1, dihydrotestosterone 1.2/2.09 nmol.L^-1 (0.32–1.64). Genetic analysis identified a paternally inherited heterozygous pathogenic RSPO1 variant. Female sex assignment was agreed through multidisciplinary team discussions with the family. Follow-up ultrasound at 3 months showed bilateral gonadal structures (2.2x0.9x1.3 cm and 1.1x0.7x0.8 cm) with cysts, and previously biopsied testis. Eye examination was normal, and no skin changes. Further genetic analysis is underway to identify a second RSPO1 variant.

Discussion: Pathogenic biallelic RSPO1 variants typically cause an extremely rare autosomal recessive 46,XX DSD associated with palmoplantar keratoderma and predisposition to squamous cell carcinoma; thus attribution of this infant’s phenotype to a single heterozygous RSPO1 variant would be premature. The presence of histologically confirmed testicular tissue in a 46,XX context, bilateral evolving gonadal structures, and robust Leydig responsiveness suggest broader gonadal developmental complexity, potentially within the ovotesticular/complex DSD spectrum. Our case underscores the value of staged phenotyping, longitudinal imaging, and multidisciplinary counselling when genotype-phenotype correlation is incomplete.