Expanding the phenotype and genotype of female GnRH deficiency.

Details

Serval ID
serval:BIB_23E5B52EC611
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Expanding the phenotype and genotype of female GnRH deficiency.
Journal
Journal of Clinical Endocrinology and Metabolism
Author(s)
Shaw N.D., Seminara S.B., Welt C.K., Au M.G., Plummer L., Hughes V.A., Dwyer A.A., Martin K.A., Quinton R., Mericq V., Merino P.M., Gusella J.F., Crowley W.F., Pitteloud N., Hall J.E.
ISSN
1945-7197[electronic], 0021-972X[linking]
Publication state
Published
Issued date
2011
Volume
96
Number
3
Pages
E566-E576
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Context: GnRH deficiency is a rare genetic disorder of absent or partial pubertal development. The clinical and genetic characteristics of GnRH-deficient women have not been well-described. Objective: To determine the phenotypic and genotypic spectrum of a large series of GnRH-deficient women. Design, Setting, and Subjects: Retrospective study of 248 females with GnRH deficiency evaluated at an academic medical center between 1980 and 2010. Main Outcome Measures: Clinical presentation, baseline endogenous GnRH secretory activity, and DNA sequence variants in 11 genes associated with GnRH deficiency. Results: Eighty-eight percent had undergone pubarche, 51% had spontaneous thelarche, and 10% had 1-2 menses. Women with spontaneous thelarche were more likely to demonstrate normal pubarche (P = 0.04). In 27% of women, neuroendocrine studies demonstrated evidence of some endogenous GnRH secretory activity. Thirty-six percent (a large excess relative to controls) harbored a rare sequence variant in a gene associated with GnRH deficiency (87% heterozygous and 13% biallelic), with variants in FGFR1 (15%), GNRHR (6.6%), and PROKR2 (6.6%) being most prevalent. One woman had a biallelic variant in the X-linked gene, KAL1, and nine women had heterozygous variants. Conclusions: The clinical presentation of female GnRH deficiency varies from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this cohort, rare sequence variants were present in all of the known genes associated with GnRH deficiency, including the novel identification of GnRH-deficient women with KAL1 variants. The pathogenic mechanism through which KAL1 variants disrupt female reproductive development requires further investigation.
Pubmed
Web of science
Open Access
Yes
Create date
09/03/2011 11:19
Last modification date
20/08/2019 14:01
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