Abstract | dc.description.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:Todetermine the phenotypicandgenotypic 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, and10%
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 withGnRHdeficiency, including the novel identification of GnRH-deficientwomenwith
KAL1 variants. The pathogenic mechanism through which KAL1 variants disrupt female reproductive
development requires further investigation. | es_CL |