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

Abstract

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.

Genetic testing of XY newborns with a suspected disorder of sex development

“…SOX9 variants were detected in patients with gonadal dysgenesis and concomitant bone abnormalities due to the lack of chondrocyte-specific enhancer activity [78]. Although a small number of individuals were found to be carriers of variants in DHH, gonadal cancer was evident in almost 30% of them [60] and it was commonly associated with peripheral minifascicular neuropathy [61,79,80]. 46, XY PGD and CGD due to missense variants in WT1 were recognised in Denys Drash syndrome [81] and concurrent renal abnormalities [82].…”

Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh

“…The Hedgehog pathway plays a critical role in developmental processes, embryogenesis, cell proliferation and tissue regeneration 33 – 36 . DHH is important in gonadal differentiation 37 – 39 as it is produced by Sertoli cells and is important for fetal Leydig cell differentiation 40 . Once cleaved, DHh -N domain functions as a signaling molecule while the DHh -C participates in autoprocessing regulation 34 .…”

Convergent pathological and ultrasound features in hereditary syndromic and non‐syndromic minifascicular neuropathy related to DHH

“…Methodological details about our diagnostic workup were reported elsewhere. 7 In brief, right sural nerve sections underwent microscopic analysis after hematoxylin/eosin and toluidine blue staining. Epithelial membrane antigen (EMA) and S-100 protein (S-100) reactivities were assessed in paraffin sections, using the EMA clone E29 (1:400, Dako-Agilent, Santa Clara, California) and S-100 antibodies (1:3000, Dako-Agilent, Santa Clara, California), respectively.…”

“…However, molecular screening for the most frequent genes associated with CMT and hereditary sensory autonomic neuropathies (HSAN) was inconclusive in both sisters. 7 The proband also underwent sural nerve biopsy ( Figure 1 and slightly enlarged on more proximal scans in patient II-4, whereas sciatic nerves' size was invariably increased, reaching maximal CSA in the older sister ( Figure S2; Table S2).…”