46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome Sequencing

J Clin Endocrinol Metab. 2015 Jul;100(7):E1022-9. doi: 10.1210/jc.2015-1314. Epub 2015 Apr 30.


Background: 46,XY disorders of sex development (DSD) comprise a heterogeneous group of congenital conditions. Mutations in a variety of genes can affect gonadal development or androgen biosynthesis/action and thereby influence the development of the internal and external genital organs.

Objective: The objective of the study was to identify the genetic cause in two 46,XY sisters of a consanguineous family with DSD and gonadal tumor formation.

Methods: We used a next-generation sequencing approach by exome sequencing. Electrophysiological and high-resolution ultrasound examination of peripheral nerves as well as histopathological examination of the gonads were performed.

Results: We identified a novel homozygous R124Q mutation in the desert hedgehog gene (DHH), which alters a conserved residue among the three mammalian Hedgehog ligands sonic hedgehog, Indian hedgehog, and desert hedgehog. No other relevant mutations in DSD-related genes were encountered. The gonads of one patient showed partial gonadal dysgenesis with loss of Leydig cells in tubular areas with seminoma in situ and a hyperplasia of Leydig cell-like cells expressing CYP17A1 in more dysgenetic parts of the gonad. In addition, both patients suffer from a polyneuropathy. High-resolution ultrasound revealed a structural change of peripheral nerve structure that fits well to a minifascicle formation of peripheral nerves.

Conclusion: Mutations in DHH play a role in 46,XY gonadal dysgenesis and are associated with seminoma formation and a neuropathy with minifascicle formation. Gonadal dysgenesis in these cases may be due to impairment of Sertoli cell-Leydig cell interaction during gonadal development.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Base Sequence
  • DNA Mutational Analysis / methods
  • Exome
  • Female
  • Gonadal Dysgenesis, 46,XY / diagnostic imaging
  • Gonadal Dysgenesis, 46,XY / genetics*
  • Gonadal Dysgenesis, 46,XY / pathology
  • Hedgehog Proteins / genetics*
  • High-Throughput Nucleotide Sequencing
  • Homozygote*
  • Humans
  • Male
  • Mutation*
  • Seminoma / genetics
  • Seminoma / pathology
  • Siblings
  • Testicular Neoplasms / genetics
  • Testicular Neoplasms / pathology
  • Ultrasonography


  • DHH protein, human
  • Hedgehog Proteins