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X-linked adrenal hypoplasia congenita: A mutation in DAX1 expands the phenotypic spectrum in males and females

Seminara, SB; Achermann, JC; Genel, M; Jameson, JL; Crowley, WF; (1999) X-linked adrenal hypoplasia congenita: A mutation in DAX1 expands the phenotypic spectrum in males and females. The Journal of Clinical Endocrinology & Metabolism , 84 (12) 4501 - 4509. 10.1210/jc.84.12.4501. Green open access

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Abstract

X-linked adrenal hypoplasia congenita (AHC) is a disorder associated with primary adrenal insufficiency and hypogonadotropic hypogonadism (HH). The gene responsible for X-linked AHC, DAX1, encodes a member of the nuclear hormone receptor superfamily. We studied an extended kindred with AHC and HH in which two males (the proband and his nephew) were affected with a nucleotide deletion (501delA). The proband's mother, sister, and niece were heterozygous for this frameshift mutation. At age 27 yr, after 7 yr of low dose hCG therapy, the proband underwent a testicular biopsy revealing rare spermatogonia and Leydig cell hyperplasia. Despite steadily progressive doses of hCG and Pergonal administered over a 3-yr period, the proband remained azoospermic. The proband's mother, sister (obligate carrier), and niece all had a history of delayed puberty, with menarche occurring at ages 17-18 yr.Baseline patterns of pulsatile gonadotropin secretion and gonad otropin responsiveness to exogenous pulsatile GnRH were examined in the affected males. LH, FSK, and free alpha-subunit were determined during 12.5-24 h of frequent blood sampling (every 10 min). Both patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for 6-7 days. Gonadotropin responses to a single GnRH pulse iv were monitored daily to assess the pituitary responsiveness to exogenous GnRH. In the proband, FSH and LH levels demonstrated a subtle, but significant, response to GnRH over the week of pulsatile GnRH therapy. Free alpha-subunit levels demonstrated an erratic pattern of secretion at baseline and no significant response to pulsatile GnRH.We conclude that 1) affected males with AHC/HH may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; 2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3) although affected individuals display minimal responses to pulsatile GnRH, as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred.

Type: Article
Title: X-linked adrenal hypoplasia congenita: A mutation in DAX1 expands the phenotypic spectrum in males and females
Open access status: An open access version is available from UCL Discovery
DOI: 10.1210/jc.84.12.4501
Publisher version: http://dx.doi.org/10.1210/jc.84.12.4501
Language: English
Additional information: © 1999 by The Endocrine Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: GONADOTROPIN-RELEASING HORMONE, ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPOGONADOTROPIC HYPOGONADISM, HEMOPHILIA-B, CARRIER, GENE, MEN, INACTIVATION, TESTOSTERONE, SECRETION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/154663
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