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

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

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Department of Paediatric and Adolescent Medicine, and Division of Experimental Paediatric Endocrinology and Diabetes (R.W., W.B., L.M., O.H.), Departments of Pathology (H.M.), Gynecology (T.S.), Neurology and Institute of Neurogenetics (P.C.), and Paediatric and Adult Movement Disorders and Neuropsychiatry and Institute of Neurogenetics (T.B.), Institute of Integrative and Experimental Genomics (B.R.), University of Luebeck, 23538 Luebeck, Germany; and Department of Biophysics and Biophysical Chemistry (J.M.K.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.



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.


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.


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.


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.


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.

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