Active hypothalamic-pituitary-gonadal axis in an infant with X-linked adrenal hypoplasia congenita

Takahashi, Tsutomu; Shoji, Yutaka; Shoji, Yasuko; Haraguchi, Naoki; Takahashi, Ikuko; Takada, Goro

doi:10.1016/s0022-3476(97)70217-8

Cited by 79 publications

(53 citation statements)

References 8 publications

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“…Although the hypogonadotropic hypogonadism associated with AHC is conventionally perceived as a congenital disorder, recent data have demonstrated transient postnatal activation of the HPG axis in AHC patients. Normal serum gonadotropin and testosterone levels have been demonstrated in a newborn male with AHC and a confirmed DAX1 mutation (A300V) (25). Hormonal data from four boys with AHC (aged 1-3 months) have also suggested an active HPG axis (26).…”

Section: Discussionmentioning

confidence: 92%

X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females

Seminara¹

1999

Journal of Clinical Endocrinology & Metabolism

106

124

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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 gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the affected males. LH, FSH, and free ␣-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 ␣-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. (J Clin Endocrinol Metab 84: [4501][4502][4503][4504][4505][4506][4507][4508][4509] 1999) A DRENAL hypoplasia congenita is a rare developmental disorder of the adrenal gland. In the X-linked cytomegalic form, the adrenal glands lack the permanent adult zone of the adrenal cortex (1). Affected boys typically present with adrenal insufficiency in early infancy or childhood and hypogonadotropic hypogonadism (HH) at the time of puberty (2). The gene responsible for adrenal hypoplasia congenita (AHC) is DAX1 (dosage-sensitive, sex reversal, adrenal hypoplasia congenita, critical region on the X-chromosome, gene 1), which encodes for a protein that is a member of the orphan nuclear hormone receptor superfamily (3, 4). Although the carboxyl-terminus of DAX-1 (putative ligand-binding domain) displays sequence homology with several other transcription factors, the amino-terminus of DAX-1 has a novel amino acid tandem repeat structure that lacks the zinc finger motif typically...

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Section: Discussionmentioning

confidence: 92%

X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females

Seminara¹

1999

Journal of Clinical Endocrinology & Metabolism

106

124

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“…Remarkably, all mutations associated with AHC reported to date alter the structure of the carboxy terminus of the DAX-1 protein (1,11,13,26,27,29,32,33,35,(48)(49)(50)(51)(52)(53)(54)(55)(56). The majority of these are frameshift or nonsense (stop codon) mutations that result in a truncated protein.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism

Tabarin¹,

Achermann²,

Récan³

et al. 2000

J. Clin. Invest.

176

131

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IntroductionThe DAX1 gene encodes an orphan member of the nuclear receptor superfamily that lacks the typical zinc finger DNA-binding motif, but retains the ligand-binding domain characteristic of other family members (1). DAX-1 is expressed in the adrenal cortex, gonads, hypothalamus and anterior pituitary (2). It interacts with another orphan nuclear receptor, steroidogenic factor-1 (SF-1) (3), which plays a pivotal role in the development and function of these tissues (4-9). In vitro studies suggest that DAX-1 represses SF-1-mediated transcription, but the roles of SF-1 and DAX-1 in the development and function of these tissues remain unclear (5-7). Recent results obtained in Ahch (the mouse Dax1 homologue) knockout mice suggest that DAX-1 may also play a direct role in spermatogenesis (10).Mutations in the DAX1 gene in humans cause the Xlinked cytomegalic form of adrenal hypoplasia congenita (AHC), a rare disorder characterized by impaired development of the permanent zone of the adrenal cortex and hypogonadotropic hypogonadism (HHG) (1, 11). Affected boys develop adrenal failure shortly after birth or during early childhood, whereas HHG, a universal feature of the syndrome, is usually recognized at the expected time of puberty (9, 12, 13). Whether or not DAX1 mutations affect spermatogenesis in humans, independent of the effects of gonadotropin deficiency, remains unknown (9).In this report, we describe the clinical features of a patient with a mild phenotypic presentation of AHC and examine the functional properties of the mutant DAX-1 protein. In addition, we describe the results of exogenous gonadotropin therapy on spermatogenesis. Recognition of this unique phenotype is of practical importance because it extends the clinical spectrum of the disease to include mild forms of HHG and delayed onset of adrenal insufficiency. Studies in this patient also suggest that DAX-1 function is required for spermatogenesis in humans, independent of gonadotropin and testosterone production. Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). In affected boys, primary adrenal insufficiency occurs soon after birth or during early childhood; HHG is recognized at the expected time of puberty. In this report, we describe the novel phenotype of a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development and undiagnosed incomplete HHG. Gonadotropin therapy did not improve his marked oligospermia, suggesting a concomitant primary testicular abnormality. Genomic analysis revealed a novel missense mutation, I439S, in DAX1. The mutant DAX-1 protein was studied for its ability to function as a transcriptional repressor of target genes. Consistent with the patient's mild clinical phenotype, the I439S mutation conferred intermediate levels of repressor activity of DAX-1 when compared with mutations associated with classic AHC. This unique case extends the clinical spectrum of AHC to include de...

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“…1 All patients described to date have been male, and female carriers have had no clinical symptoms. [1][2][3][4][5][6][7][8][9][10] Although most patients present with adrenal crisis in the neonatal period, the onset of adrenal insufficiency varies, even within a family, from the neonatal period to 10 years of age. 1,3,4,9 The gene responsible for this disorder, DAX1, is on the short arm of the X chromosome 11 and encodes a 470-amino-acid member of the nuclear hormone receptor superfamily.…”

mentioning

confidence: 99%

“…The few reported missense mutations of the DAX1 gene are in the presumptive ligand-binding domain. 1,7,9,10 No relation between the onset of adrenal insufficiency and the site of the mutation has been demonstrated.…”

mentioning

confidence: 99%

Hypogonadotropic Hypogonadism in a Female Caused by an X-Linked Recessive Mutation in theDAX1Gene

et al. 1999

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Active hypothalamic-pituitary-gonadal axis in an infant with X-linked adrenal hypoplasia congenita

Cited by 79 publications

References 8 publications

X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females

X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females

A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism

Hypogonadotropic Hypogonadism in a Female Caused by an X-Linked Recessive Mutation in theDAX1Gene

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