Mild adrenal insufficiency due to a NROB1 (DAX1) gene mutation in a boy presenting an association of hypogonadotropic hypogonadism, reduced final height and attention deficit disorder

Calliari, Luís Eduardo; Rocha, Mylene Neves; Monte, Osmar; Longui, Carlos Alberto

doi:10.1590/s0004-27302013000700011

Cited by 12 publications

(7 citation statements)

References 8 publications

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“…Although early-onset PAI and pubertal development defects are the most common phenotypic features of Xlinked AHC [1], its diagnosis in adulthood, also called the late-onset form, had been recognized [7-10, 14, 19-21]. AHC phenotypic variability has been described even among patients carrying the same NR0B1 mutations [1,22]. Although the precise PAI onset has been difficult to determine, all affected males (including the deceased ones) in the reported family may have had symptoms during adolescence up to 64 y.…”

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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“…The onset and course of adrenal glomerulosa and fasciculata dysfunction in these patients is variable. The phenotypic spectrum ranges from hypogonadism in the newborn period to delayed pubertal development to normal sexual development; additionally, sexual precocity has been reported . Despite the near complete absence of adrenal glucocorticoid production, this child grew and thrived before hydrocortisone therapy, which is a mysterious phenomenon that remains unexplained.…”

Section: Discussionmentioning

confidence: 92%

“…To date, hundreds of different mutations in NR0B1 have been reported, including deletions, frameshift, and point mutations, with variable onsets of presentation, different degrees of mineralocorticoid and glucocorticoid insufficiency, hypogonadism, and in some instances precocious puberty. A clear genotype–phenotype correlation is yet to be defined …”

Section: Introductionmentioning

confidence: 99%

A novel de novo frameshift mutation in NR0B1 and low prenatal estriol in adrenal hypoplasia congenita

Khattab

Nelson‐Williams

Cabreza

et al. 2018

Annals of the New York Academy of Sciences

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Mutations in the gene NR0B1 have been associated with several clinical phenotypes of X-linked adrenal hypoplasia congenita (AHC). The degree and onset of adrenal insufficiency and involvement of hypogonadotropic hypogonadism is variable and may not be concordant with the identified mutation. We review a patient with AHC in which prenatal estriol levels were low, presenting with early-onset mineralocorticoid deficiency in the newborn period followed by glucocorticoid deficiency 2 years later. The reported child is hemizygous for a novel mutation that is deemed de novo in the ligand-binding site of the protein (DAX1) expressed by NR0B1. The identified frameshift mutation results in a T407N/fs protein change. Low prenatal estriol levels may represent a sensitive marker of potentially fatal disorders associated with adrenal insufficiency and should be utilized more frequently. Additionally, accurate reporting of mutations in NR0B1 and the associated phenotype are important to eventually establish a genotype-phenotype correlation that may help anticipate guidance in AHC.

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“…Calliari and colleagues published a case about a boy with DAX1 mutation and below average adult height. In this case the growth hormone level was not measured and the induction of puberty was started at 12 years of age due to psychological aspects [24]. In two patients published by Rojek the growth hormone deficiency was diagnosed at the age of 13 and 18 years respectively.…”

Section: Discussionmentioning

confidence: 95%

Novel frameshift mutation of the NR0B1(DAX1) in two tall adult brothers

Bertalan

Bencsik²,

Mezei

et al. 2019

Mol Biol Rep

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NR0B1 (nuclear receptor subfamily 0, group B, member 1) is a transcription factor encoded by DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) responsible for the development and maintenance of the steroidogenic tissues. In humans the DAX1 mutations cause congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism (HHG) in boys. Here we report two brothers who were assessed by endocrinologist at the age of 51 and 43 because of their serious osteoporosis. They had been substituted with prednisolone since the age of 4 and 9 years because of their primary adrenal insufficiency (PAI). Due to their late puberty caused by HHG at the age of 16 and 17 years their heights were − 3.1 and − 3.3 SD, but then they had a significant growth during their adulthood and reached the + 1.85 SD and + 3.78 SD respectively. During this period, they received glucocorticoid supplementation, but the treatment of their HHG was inadequate. At the age of 51 and 43 years insulin tolerance test (ITT) and gonadotropin releasing hormone (GnRH) test confirmed their PAI and HHG. Genetic test performed at this time revealed a novel, four nucleotides deletion (del.586-571c.GGGC or 572-575c.GGGC) of DAX1 gene. The two brothers with AHC and HHG caused by a novel DAX1 mutation, reached tall final heights, despite of the disadvantageous prednisolone treatment during their childhood. We assume that the long-term lack of the sexual hormone substitution was a significant reason of their above average height as well as their serious osteoporosis.

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Mild adrenal insufficiency due to a NROB1 (DAX1) gene mutation in a boy presenting an association of hypogonadotropic hypogonadism, reduced final height and attention deficit disorder

Cited by 12 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

A novel de novo frameshift mutation in NR0B1 and low prenatal estriol in adrenal hypoplasia congenita

Novel frameshift mutation of the NR0B1(DAX1) in two tall adult brothers

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