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Case Reports
. 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

Ralf Werner  1 , Hartmut Merz  1 , Wiebke Birnbaum  1 , Louise Marshall  1 , Tatjana Schröder  1 , Benedikt Reiz  1 , Jennifer M Kavran  1 , Tobias Bäumer  1 , Philipp Capetian  1 , Olaf Hiort  1
Affiliations
Case Reports

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

Ralf Werner et al. J Clin Endocrinol Metab. 2015 Jul.

Abstract

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.

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Figures

Figure 1.
Figure 1.
Verification of the homozygous R124Q mutation by Sanger sequencing in patient 1.
Figure 2.
Figure 2.
Immunohistological evaluation of the testicular tissue. A, Patient 1, Invasive seminoma/dysgerminoma. No seminiferous tubules could be seen. Testicular tissue was replaced by seminoma cells expressing PLAP (alkaline phosphatase, placental) and CD117 (KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog). A strong expression of Oct3/4 (POU class 5 homeobox 1) and a granular expression of NSE [enolase 2 (gamma, neuronal)] of seminoma cells were seen. B, Patient 2, Seminoma in situ. Seminiferous tubules including Sertoli cells and some germ cells are surrounded by irregular masses of fibrotic tissue. Within the seminiferous tubules, atypical proliferating cells positive for PLAP and CD117 were detected. Periodic acid-Schiff (PAS) staining showed germ cells with granular glycogen-rich cytoplasm. At another site a gonadoblastoma with Call Exner bodies was seen.
Figure 3.
Figure 3.
Expression of CYP17A1 and INSL3 in the gonad of patient 2. A, Nodular Leydig cell-like cells within the unstructured dysgenetic part of the gonad with rare and atrophic tubuli show a strong CYP17A1 expression. B, Only single cells show faint expression of INSL3. C, In contrast, no CYP17A1-expressing Leydig cells could be detected in the interstitium between the seminiferous tubules of areas with seminoma in situ.
Figure 4.
Figure 4.
Cross-sectional ultrasound pictures at the distal third of the lower arm of patient 1 (A) and an age-matched control (B) are shown. The median nerve is marked in yellow in the upper part of the figure. In the lower half of the figure, the median nerves are shown enlarged. The median nerve of patient 1 (and all other investigated nerves at the extremities) showed a loss of the typical fascicular honeycomb-like structure and only very little hypoechogenic dots that may correspond with the formation of minifasciles. Fascicles are marked in yellow.
Figure 5.
Figure 5.
Binding of DHhN to BOC. A, Ribbon diagram of the complex between the DHhN (green) with the third FNIII repeat of BOC (BOCFn3) (gray) (PDB code 3N1G). Represented as spheres are calcium ions (cyan) and zinc ion (pink). R124 of DHhN (yellow) and D758 of BOCFn3 are shown as sticks. B, Close-up view of the binding interface between DHhN (green) and BOCFn3 (white). Residues involved in a hydrogen-bonding network around R124 (yellow) are shown in sticks, with nitrogen atoms colored blue and oxygen atoms red. Potential hydrogen bonds are indicated by dashed lines and the distances between atoms are measured in Ångstroms.
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