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

Estévez, Amaia Rodríguez; Pérez-Nanclares, Gustavo; Fernández-Toral, Joaquín; Rivas-Crespo, Francisco; López-Siguero, Juan Pedro; Díez, Ignacio; Grau, Gema; Castaño, Luís

doi:10.1515/jpem-2014-0472

Cited by 7 publications

(2 citation statements)

References 8 publications

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“…HH is the most common finding [1,24]. However, delayed or incomplete puberty associated with partial gonadotropin deficiency [1,26,27] or phenotypes with normal gonadotropin function have also been described [12,14,[28][29][30][31]. More puzzling, some have suggested that chronic ACTH stimulus to Leydig cells may be related to gonadotropin-independent precocious puberty phenotype in X-linked AHC boys [28].…”

Section: Discussionmentioning

confidence: 99%

Spontaneous fertility and variable spectrum of reproductive phenotype in a family with adult-onset X-linked adrenal insufficiency harboring a novel DAX-1/NR0B1 mutation

Vargas¹,

Moura

Elias³

et al. 2020

BMC Endocr Disord

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Background: Adrenal hypoplasia congenita (AHC) is an X-linked disorder that affects the adrenal cortex and hypothalamus-pituitary-gonadal axis (HPG), leading to primary adrenocortical insufficiency (PAI) and hypogonadotropic hypogonadism. AHC is caused by a mutation in the DAX-1 gene (NR0B1). More commonly, this disease is characterized by early-onset PAI, with symptoms in the first months of life. However, a less severe phenotype termed late-onset AHC has been described, as PAI signs and symptoms may begin in adolescence and adulthood. Here we describe a family report of a novel mutation within NR0B1 gene and variable reproductive phenotypes, including spontaneous fertility, in a very late-onset X-linked AHC kindred. Case presentation: Three affected maternal male relatives had confirmed PAI diagnosis between 30 y and at late 64 y. The X-linked pattern has made the endocrinology team to AHC suspicion. Regarding the HPG axis, all males presented a distinct degree of testosterone deficiency and fertility phenotypes, varying from a variable degree of hypogonadism, oligoasthenoteratozoospermia to spontaneous fertility. Interestingly, the other five maternal male relatives unexpectedly died during early adulthood, most likely due to undiagnosed PAI/adrenal crisis as the probable cause of their premature deaths. Sequencing analysis of the NR0B1 gene has shown a novel NR0B1 mutation (p.Tyr378Cys) that segregated in three AHC family members. Conclusions: NR0B1 p.Tyr378Cys segregates in an AHC family with a variable degree of adrenal and gonadal phenotypes, and its hemizygous trait explains the disease in affected family members. We recommend that NR0B1 mutation carriers, even those that are allegedly asymptomatic, be carefully monitored while reinforcing education to prevent PAI and consider early sperm banking when spermatogenesis still viable.

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Section: Discussionmentioning

confidence: 99%

Spontaneous fertility and variable spectrum of reproductive phenotype in a family with adult-onset X-linked adrenal insufficiency harboring a novel DAX-1/NR0B1 mutation

Vargas¹,

Moura

Elias³

et al. 2020

BMC Endocr Disord

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“…Frameshift and non-sense mutations may occur within the entire open reading frame, while missense mutations are found mainly in the region encoding the C-terminus of the DAX1 protein (22,25). Other pathogenic alterations comprise copy-number variations (CNVs) of different sizes (26). In patient 6, AHC was caused by a pathogenic deletion encompassing the entire exon 2 of DAX1, which has not been reported before.…”

Section: Genetic Causes For Pai Case Seriesmentioning

confidence: 87%

Primary Adrenocortical Insufficiency Case Series in the Neonatal Period: Genetic Etiologies Are More Common Than Expected

Gao

Chen

2020

Front. Pediatr.

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Primary adrenocortical insufficiency (PAI) is an important cause of morbidity in neonates. The most common cause of PAI in neonates is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). Other rarer monogenic cases, for example, adrenal hypoplasia congenita (AHC) or familial glucocorticoid deficiency, also simulate clinical manifestation of 21-OHD, leading to misdiagnosis. The therapies and prognosis of these monogenic cases of PAI are entirely different. This study aimed to compare the differences of clinical data and identify genetic etiologies of PAI cases in the neonatal period. All 7 neonates initially presented with hyperpigmentation, hyponatremia, hyperkalemia, and high serum adrenocorticotropic hormone levels. Only CAH patients showed hyperandrogenism and remarkably elevated serum 17-hydroxyprogesterone levels. All the pathogenic mutations found in CYP21A2 were well known, except c.1069C>T (exon 8). The male patient with AHC had a novel hemizygous deletion of exon 2 in DAX1. The other one with familial glucocorticoid deficiency type 1 had two novel heterozygous mutations in the gene coding melanocortin 2 receptor, c.701C>T (exon 2) and c.119delT (exon 2). Glucocorticoid and/or mineralocorticoid replacement therapy depends on the cause of PAI. Genetic testing can be performed as a alternative diagnostic approach to provide information about therapy, prognosis, and genetic counseling.

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Hipoplasia adrenal congénita ligada al cromosoma X: mutación missense de novo en el gen DAX-1

García¹,

Rodriguez²,

Guedes

2019

Medicina Clínica

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

Cited by 7 publications

References 8 publications

Spontaneous fertility and variable spectrum of reproductive phenotype in a family with adult-onset X-linked adrenal insufficiency harboring a novel DAX-1/NR0B1 mutation

Spontaneous fertility and variable spectrum of reproductive phenotype in a family with adult-onset X-linked adrenal insufficiency harboring a novel DAX-1/NR0B1 mutation

Primary Adrenocortical Insufficiency Case Series in the Neonatal Period: Genetic Etiologies Are More Common Than Expected

Hipoplasia adrenal congénita ligada al cromosoma X: mutación missense de novo en el gen DAX-1

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