46,XY gonadal dysgenesis due to a homozygous mutation in desert hedgehog (DHH) identified by exome sequencing

Ralf Werner, Hartmut Merz, Wiebke Birnbaum, Louise Marshall, Tatjana Schröder, Benedikt Reiz, Jennifer M. Kavran, Tobias Bäumer, Philipp Capetian, Olaf Hiort

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34 Scopus citations


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.Thegonads ofonepatientshowedpartial gonadal dysgenesis with loss of Leydig cells in tubular areas withseminomain situandahyperplasia of Leydig cell-like cells expressingCYP17A1 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 casesmaybe due to impairment of Sertoli cell-Leydig cell interaction during gonadal development.

Original languageEnglish (US)
Pages (from-to)E1022-E1029
JournalJournal of Clinical Endocrinology and Metabolism
Issue number7
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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