TY  - JOUR
IS  - 12
TI  - X-linked adrenal hypoplasia congenita: A mutation in DAX1 expands the phenotypic spectrum in males and females
Y1  - 1999/12//
N1  - © 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.
EP  -  4509
SN  - 0021-972X
N2  - 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.
VL  - 84
JF  - The Journal of Clinical Endocrinology & Metabolism
PB  - ENDOCRINE SOC
SP  - 4501 
ID  - discovery154663
AV  - public
A1  - Seminara, SB
A1  - Achermann, JC
A1  - Genel, M
A1  - Jameson, JL
A1  - Crowley, WF
UR  - http://dx.doi.org/10.1210/jc.84.12.4501
KW  - GONADOTROPIN-RELEASING HORMONE
KW  -  ORNITHINE TRANSCARBAMYLASE DEFICIENCY
KW  -  HYPOGONADOTROPIC HYPOGONADISM
KW  -  HEMOPHILIA-B
KW  -  CARRIER
KW  -  GENE
KW  -  MEN
KW  -  INACTIVATION
KW  -  TESTOSTERONE
KW  -  SECRETION
ER  -