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46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome Sequencing.
- Source :
-
The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2015 Jul; Vol. 100 (7), pp. E1022-9. Date of Electronic Publication: 2015 Apr 30. - Publication Year :
- 2015
-
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.<br />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.<br />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.<br />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.<br />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.
- Subjects :
- Adolescent
Adult
Base Sequence
DNA Mutational Analysis methods
Exome
Female
Gonadal Dysgenesis, 46,XY diagnostic imaging
Gonadal Dysgenesis, 46,XY pathology
High-Throughput Nucleotide Sequencing
Humans
Male
Seminoma genetics
Seminoma pathology
Siblings
Testicular Neoplasms genetics
Testicular Neoplasms pathology
Ultrasonography
Gonadal Dysgenesis, 46,XY genetics
Hedgehog Proteins genetics
Homozygote
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7197
- Volume :
- 100
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of clinical endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 25927242
- Full Text :
- https://doi.org/10.1210/jc.2015-1314