Background: Desert Hedgehog (DHH) gene acts on early testicu-lar development, testis cord formation and differentiation of fetal Leydig cells. It also has a role in nerve sheath formation. DHH gene mu-tations is a very rare cause of 46,XY gonadal dysgenesis (GD). Gonadal tumors and peripheral neuropathy have been associated with DHH mutations.
Aim: To present three patients with 46,XY GD due to novel homozygous DHH mutations.
Patients and methods: Targeted next-generation sequencing of three patients by in-house designed DSD gene-panel.
Results: First patient (one of the siblings) presented at age 1 year with penoscrotal hypospadias [external masculinization score (EMS) 5], bilateral inguinal testes, Müllerian structure evident on biopsy, no response to HCG, raised as female initially and converted to male at 5 years of age. Second patient (the other siblings) presented at age 14 days with severe micropenis, bilateral inguinal testes (EMS 2), no Müllerian structure. Testosterone response was normal to HCG and the patient was raised as female. Gonadectomy revealed gonadal dysgenesis with loss of Leydig cells with intratubuler germ cell neoplasia. Third patient presented at age 19 days with penoscrotal hypospadias, bilateral inguinal testes (EMS 6), penile size 2 cm, and basal testosterone at 4 months of age was 1.48 ng/ml, no Müllerian structure, low AMH and raised as male. Consanguinity was present in all. In two siblings, a novel homozygous c.114G>A mutation in exon 3 of the DHH gene was predicted to cause nonsense type alteration (p.Trp382*). In other patient two missense variants in homozygous form were shown (c.71G>C in exon 1 and c.1063C>T in exon 3). None of patients had any clinical signs of neuropathy but detailed neurophysiologic evaluation has not been performed.
Conclusion: DHH gene mutation should be analyzed in patients with 46,XY gonadal dysgenesis for diagnosis and the presence of potential neuropathy and gonadal tumors. In vivo studies are needed to further delineate the phenotype genotype relation.