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Identification and Functional Analysis of Six DAX1 Mutations in Patients With X-Linked Adrenal Hypoplasia Congenita.

ABSTRACT: Context:DAX1 (NR0B1) mutations cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) in affected male patients. Affected individuals typically present with early-onset adrenal insufficiency and develop HH during puberty. Rare cases can present with late-onset adrenal insufficiency or other unusual phenotypes. Objectives:We sought to identify and functionally characterize DAX1 mutations in seven Thai male subjects in six families with X-linked AHC. Patients and Methods:Six patients had classic phenotypes with early-onset adrenal failure. One patient presented with late-onset Addison disease at 17 years. In the early-onset group, one patient had GnRH-independent sexual precocity at 3 years of age, and another patient had growth hormone deficiency. The DAX1 gene was sequenced from all patients, and the transcriptional activities of the identified mutations were assessed in vitro using luciferase assays. Results:DAX1 mutations were identified in all patients, including three novel mutations [c.363delG (p.Gly122Valfs*142), c.1062delC (p.Ala355Profs*17), and c.1156C>T (p.Leu386Phe)] and three known mutations [c.1148_1149delGG (p.Gly383Aspfs*5), c.501_502insG (p.Ala170Argfs*15), and c.805_807delGTC (p.Val269del)]. Functional studies showed that the DAX1 mutants had lower levels of repressor activity on the StAR gene promoter compared with the wild-type DAX-1 protein. Conclusions:This study describes unusual phenotypes and three novel mutations, extending the phenotypic and mutational spectra of DAX1 mutations.

SUBMITTER: Suthiworachai C

PROVIDER: S-EPMC6316980 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Identification and Functional Analysis of Six <i>DAX1</i> Mutations in Patients With X-Linked Adrenal Hypoplasia Congenita.

Suthiworachai Chanisara C Tammachote Rachaneekorn R Srichomthong Chalurmpon C Ittiwut Rungnapa R Suphapeetiporn Kanya K Sahakitrungruang Taninee T Shotelersuk Vorasuk V

Journal of the Endocrine Society 20181212 1

<h4>Context</h4><i>DAX1</i> (<i>NR0B1</i>) mutations cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) in affected male patients. Affected individuals typically present with early-onset adrenal insufficiency and develop HH during puberty. Rare cases can present with late-onset adrenal insufficiency or other unusual phenotypes.<h4>Objectives</h4>We sought to identify and functionally characterize <i>DAX1</i> mutations in seven Thai male subjects in six famil ...[more]

PMID: 30620004

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Project description:BackgroundX-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization.MethodsThe clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed.ResultsHyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy (P < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year.ConclusionsThis study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.

Dataset Information

Identification and Functional Analysis of Six DAX1 Mutations in Patients With X-Linked Adrenal Hypoplasia Congenita.

Publications

Identification and Functional Analysis of Six <i>DAX1</i> Mutations in Patients With X-Linked Adrenal Hypoplasia Congenita.

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