scholarly journals Adrenal hypoplasia congenita: a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism

2015 ◽  
Vol 7 (3) ◽  
Author(s):  
Marta Loureiro ◽  
Filipa Reis ◽  
Brígida Robalo ◽  
Carla Pereira ◽  
Lurdes Sampaio
Keyword(s):  
Adrenal Insufficiency ◽  
Replacement Therapy ◽  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Adrenal Crisis ◽  
Testosterone Replacement Therapy ◽  
Primary Adrenal Insufficiency ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia ◽  
Low Levels

Primary adrenal insufficiency is defined by the impaired synthesis of adrenocortical hormones due to an intrinsic disease of the adrenal cortex. Determining its etiology is crucial to allow adequate long-term management and genetic counseling. We report the case of a male adolescent that presented in the neonatal period with adrenal crisis and received replacement therapy for primary adrenal insufficiency. During follow-up, adrenal hypoplasia congenita (AHC) was suspected given his persistently raised adrenocorticotropic hormone levels, with markedly low 17-OH progesterone and androstenedione levels. DNA sequence analysis revealed a mutation in <em>NR0B1</em> gene (c.1292delG), confirming the diagnosis. Delayed puberty and persistent low levels of gonadotropins led to testosterone replacement therapy. X-linked AHC is a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism, related to mutations in <em>NR0B1</em> gene. Despite its rarity, AHC should be considered in patients who present with primary adrenal failure, low levels of 17-OH progesterone and hypogonadotropic hypogonadism.

scholarly journals A novel stop mutation (p.(Gln22*)) of DAX1 (NR0B1) results in late-onset X-linked adrenal hypoplasia congenita

2017 ◽  
Vol 2017 ◽  
Author(s):  
Judith Gerards ◽  
Michael M Ritter ◽  
Elke Kaminsky ◽  
Andreas Gal ◽  
Wolfgang Hoeppner ◽  
...  
Keyword(s):  
Late Onset ◽  
Direct Sequencing ◽  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Unknown Etiology ◽  
Adrenal Crisis ◽  
List Type ◽  
Orphan Nuclear Receptor ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

Summary DAX1 (NR0B1) is an orphan nuclear receptor, which plays an important role in development and function of the adrenal glands and gonads. Mutations in DAX1 cause X-linked adrenal hypoplasia congenita (X-linked AHC), which is characterized by adrenal insufficiency (AI) and hypogonadotropic hypogonadism (HHG). Affected boys present with adrenal failure usually in childhood and, later in life, with delayed puberty. However, patients with a late-onset form of X-linked AHC have also been described in the past years. We report a male patient who presented with symptoms of an adrenal crisis at the age of 38 years and was later diagnosed with HHG. Family history was positive with several male relatives diagnosed with AI and compatible with the assumed X-chromosomal inheritance of the trait. Direct sequencing of DAX1 of the patient revealed a hemizygous cytosine-to-thymine substitution at nucleotide 64 in exon 1, which creates a novel nonsense mutation (p.(Gln22*)). In order to compare the clinical presentation of the patient to that of other patients with X-linked AHC, we searched the electronic database MEDLINE (PubMed) and found reports of nine other cases with delayed onset of X-linked AHC. In certain cases, genotype–phenotype correlation could be assumed. Learning points: X-linked AHC is a rare disease characterized by primary AI and hypogonadotropic hypogonadism (HHG). The full-blown clinical picture is seen usually only in males with a typical onset in childhood. Patients with a late-onset form of X-linked AHC have also been described recently. Being aware of this late-onset form might help to reach an early diagnosis and prevent life-threatening adrenal crises. Adult men with primary AI of unknown etiology should be investigated for HHG. Detecting a DAX1 mutation may confirm the clinical diagnosis of late-onset X-linked AHC. In relatives of patients with genetically confirmed X-linked AHC, targeted mutation analysis may help to identify family members at risk and asymptomatic carriers, and discuss conscious family planning.

scholarly journals A novel DAX1/NR0B1 mutation in a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism

2012 ◽  
Vol 56 (8) ◽  
pp. 496-500 ◽  
Author(s):  
Claudilene Battistin ◽  
Hamilton Cabral de Menezes Filho ◽  
Sorahia Domenice ◽  
Mirian Yumie Nishi ◽  
Thais Della Manna ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Failure To Thrive ◽  
The Novel ◽  
Site Analysis ◽  
Adrenal Hypoplasia Congenita ◽  
Normal Individuals ◽  
Exon 1 ◽  
Adrenal Hypoplasia ◽  
Low Levels

We report a case of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to a novel DAX1 mutation. A 19-month-old boy with hyperpigmentation and failure to thrive came to our service for investigation. Three brothers of the patient had died due to adrenal failure, and a maternal cousin had adrenal insufficiency. Adrenoleukodystrophy was excluded. MRI showed normal pituitary and hypothalamus. Plasma hormone evaluation revealed high ACTH (up to 2,790 pg/mL), and low levels of androstenedione, DHEA-S, 11-deoxycortisol, and cortisol. At 14 years of age the patient was still prepubescent, his weight was 43.6 kg (SDS: -0.87) and his height was 161 cm (SDS: -0.36), with normal body proportions. In the GnRH test, basal and maximum values of LH and FSH were respectively 0.6/2.1 and < 1.0/< 1.0 U/L. Molecular investigation identified a novel mutation that consists of a deletion of codon 372 (AAC; asparagine) in exon 1 of DAX1. This mutation was not found in a study of 200 alleles from normal individuals. Prediction site analysis indicated that this alteration, located in the DAX1 ligand-binding domain, may damage DAX1 protein. We hypothesize that the novel (p.Asp372del) DAX1 mutation might be able to cause a disruption of DAX1 function, and is probably involved in the development of AHC and HH in this patient. Arq Bras Endocrinol Metab. 2012;56(8):496-500

Adrenal hypoplasia congenita – an uncommon reason of primary adrenal insufficiency

2010 ◽  
Vol 71 (4) ◽  
pp. 309-313 ◽  
Author(s):  
M. Fichna ◽  
M. Żurawek ◽  
P. Gut ◽  
J. Sowiński ◽  
J. Nowak
Keyword(s):  
Adrenal Insufficiency ◽  
Primary Adrenal Insufficiency ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

Clinical and molecular characterization of five Spanish kindreds with X-linked adrenal hypoplasia congenita: atypical findings and a novel mutation in NR0B1

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Amaia Rodríguez Estévez ◽  
Gustavo Pérez-Nanclares ◽  
Joaquin Fernández-Toral ◽  
Francisco Rivas-Crespo ◽  
Juan P. López-Siguero ◽  
...  
Keyword(s):  
Molecular Level ◽  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Delayed Puberty ◽  
Salt Wasting ◽  
Adrenal Hypoplasia Congenita ◽  
Intrafamilial Variability ◽  
Adrenal Hypoplasia

AbstractX-linked adrenal hypoplasia congenita (AHC) is caused byTo characterize clinically and at the molecular level a cohort of Spanish patients with AHC.Nine boys (from five families) with AHC were screened forgene mutations were found in all analyzed patients, one of them being novel (p.Gln305*). One patient presented with preserved hypothalamic-pituitary-gonadal axis. Salt-wasting episodes, delayed puberty, and hypogonadotropic hypogonadism were common, although no association was observed between AHC phenotype and genetic mutations. None of the patients has had descendants.AHC phenotype cannot be predicted based on genetic results as there is no definite genotype-phenotype relationship, including intrafamilial variability. Nevertheless, genetic testing for

scholarly journals Identification and Analysis of a Novel NR0B1 Mutation in Late-Onset Adrenal Hypoplasia Congenita and Hypogonadism

2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Yutaka Hasegawa ◽  
Yoshihiko Takahashi ◽  
Yuichiro Kezuka ◽  
Wataru Obara ◽  
Yoichiro Kato ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Missense Mutation ◽  
Target Genes ◽  
Late Onset ◽  
Hypogonadotropic Hypogonadism ◽  
Skin Pigmentation ◽  
Hydrophobic Core ◽  
Testicular Microlithiasis ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

Abstract Objective X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadotropic hypogonadism (HHG) caused by mutations of the NR0B1/DAX1 gene. We aimed to search for the presence of any NR0B1/DAX1 gene mutations in a referred patient and to further characterize the phenotypes of the identified mutation. Case Presentation Herein, we report a Japanese patient with a novel missense mutation of the NR0B1/DAX1 gene resulting in adult-onset AHC and HHG. The patient was referred with diffuse skin pigmentation at 28 years of age, presented partial adrenal insufficiency and had undiagnosed incomplete HHG. Urological examination revealed severe oligospermia and testicular microlithiasis. Results The NR0B1/DAX1 gene mutation was identified by exome sequencing as a novel missense mutation (c.884A&gt;T, p.Leu295His). We conducted in silico modeling of this mutant NR0B1/DAX1 protein (p.Leu295His) which affected the conserved hydrophobic core of the putative ligand-binding domain (LBD). In addition, functional analysis revealed that this mutant showed a decreased ability as a transcriptional repressor to suppress target genes, such as STAR and LHB. Furthermore, this mutant showed functionally impaired repression of steroidogenesis in human adrenocortical H295R cells. Conclusions We identified a novel missense mutation of the NR0B1/DAX1 gene in a patient suffering from late-onset AHC and HHG, who presented with oligospermia and testicular microlithiasis. This mutant NR0B1/DAX1 protein was found to have reduced repressor activity, according to in vitro studies, clinically consistent with the patient’s phenotypic features.

scholarly journals Clinical polymorphism of congenital X-linked adrenal hypoplasia

2009 ◽  
Vol 55 (2) ◽  
pp. 15-18
Author(s):  
E M Orlova ◽  
M A Kareva
Keyword(s):  
Adrenal Insufficiency ◽  
Autosomal Recessive ◽  
Intrauterine Growth Retardation ◽  
Hypogonadotropic Hypogonadism ◽  
Primary Adrenal Insufficiency ◽  
Intrauterine Growth ◽  
Congenital Adrenal Hypoplasia ◽  
Genital Structure ◽  
Adrenal Hypoplasia ◽  
Autosomal Recessive Manner

Congenital adrenal hypoplasia is a rare clinical variant of primary adrenal insufficiency. Two forms of this disease are known, one of which is inherited in an autosomal recessive manner (including IMAGe syndrome - a combination of adrenal hypoplasia with intrauterine growth retardation, metaphysical dysplasia and abnormal genital structure, OMIM 300290), and the other has X-linked nature of inheritance (DAX-1 gene defect). X-linked adrenal hypoplasia is relatively more common and studied in more detail.Congenital X-linked adrenal hypoplasia is manifested by a combination of primary adrenal insufficiency and hypogonadotropic hypogonadism and is caused by defects in the DAX-1 gene (measurement-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene-1).

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