Novel familial variant of the Desert Hedgehog Gene: clinical findings in two sisters with 46,XY gonadal dysgenesis or 46,XX karyotype and literature review

Background: In humans, Desert Hedgehog (DHH) gene mutations are a very rare cause of 46,XY gonadal dysgenesis (GD), eventually associated with peripheral neuropathy. Patients and Methods: Clinical records of 12 patients with 46,XY GD and unknown genetic background were reviewed and a 46,XY woman with peripheral neuropathy was individuated. Her 46,XX sister affected by similar neuropathy was also investigated. Genomic DNA was extracted and DHH exons sequenced and analyzed. A comparative genomic hybridization array was also performed. Results: In both the 46,XY and 46,XX sisters, a homozygous c.554C>A mutation in exon 2 of the DHH gene was found, determining a premature termination codon (p.Ser 185*). Heterozygous consanguineous carrier parents showed neither reproductive problems nor peripheral neuropathy. In the proband and her sister, a 499-kb duplication in 9p22.1 was also found. Conclusion: A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. Her 46,XX sister, harboring the same mutation, showed normal internal and external female phenotype. Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.