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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.