ESPE Abstracts

Introduction: Desert hedgehog (DHH) is mainly involved in testicular development and peripheral nerve sheath formation. DHH protein is produced by Sertoli cells and promotes Leydig cell development. It regulates androgen synthesis through Sertoli-Leydig cell interaction and is also involved in sex differentiation. Biallelic DHH (MIM*605423) variants are an extremely rare cause of 46,XY gonadal dysgenesis (GD). Patients may present with abnormal genitalia in the neonatal/infant period, primary amenorrhoea or lack of breast development in adolescence. Peripheral neuropathy has also been described in few patients.

Case report: A 12-year-old girl presented with absence of breast development, genital abnormality which had been noticed since the age of 6 years and had recently become prominent. She was born at term with a birth weight of 2800g. Past medical history was unremarkable. Parents were first cousins and her uncle and paternal aunt had the history of infertility treatment. Physical examination revealed deep voice, Tanner stage 1 and 4 breast and pubic hair development, respectively. Phallus size was 5.5x2.4 cm, bilateral inguinal gonads were palpable. Systemic examinations were otherwise normal. Laboratory tests showed FSH: 32.5 IU/L (N:3.5-12.5), LH: 17.7 IU/L (N:2.4-12.6), E2: <5 ng/L (N:30.9-90.4), T. Testosterone: 361 ng/dL (0-75), AMH: 2.5 ng/mL (0.49-6.9), Creatine kinase: 110 U/L (N:0-190), adrenal functions were normal. Pelvic US showed punctate calcifications in both testes at inguinal region, seminal vesicles were hypoplasic. Uterus and ovaries were absent. Karyotype was 46,XY. Targeted next generation sequencing (NGS) analysis revealed a novel homozygous c.1159C>A p.(Leu387Ile) variant in the DHH gene (NM_021044.4). This variant was predicted as likely pathogenic according to ACMG criteria and parents were heterozygous. The patient was evaluated by multidisciplinary DSD team. Gender identity was described as female by the child and adolescent psychiatrist. Laparoscopy, gonadal malignancy surveillance EMG and genetic counselling were planned.

Conclusion: The DHH variants reported in only 26 patients with 46,XY GD, so far. Partial gonadal dysgenesis caused by DHH mutations should be considered as a rare cause of 46,XY DSD leading to pubertal virilization. Neuropathy, gonadoblastoma, seminoma and dysgerminoma have also been reported in these cases and should be monitored closely.