Analysis of DAX1 (NR0B1) and Steroidogenic Factor-1 (NR5A1) in Children and Adults with Primary Adrenal Failure: Ten Years’ Experience

Lin, Lin; Gu, Wen; Özışık, Gökhan; To, Wing S.; Owen, Catherine J.; Jameson, J. Larry; Achermann, John C.

doi:10.1210/jc.2006-0603

Cited by 179 publications

(167 citation statements)

References 54 publications

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“…Interestingly, young DAX1-knockout mice initially exhibited a hyperfunction adrenal state consistent with the loss of DAX1-dependant inhibition of steroidogenesis (97) but was followed by the attenuation of steroidogenic capacity when they aged, with profound loss of the subcapsular region, and concomitant adrenal dysplasia was observed (97,98). This model is in keeping with a number of patients with DAX1 mutations demonstrating enhancement of steroidogenic function state prior to the development of adrenal failure in later childhood (99,100). Overall, there is compelling evidence to support the presence of ACSCs and we will discuss our experience attempting to restore adrenal steroidogenesis by manipulating adrenal plasticity using various therapeutic approaches.…”

Section: Adrenal Biology and Adrenocortical Stem/ Progenitor Cells (Asupporting

confidence: 59%

MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addison’s disease

Gan

Pearce

2017

European Journal of Endocrinology

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The treatment for autoimmune Addison's disease (AAD) has remained virtually unchanged in the last 60 years. Most patients have symptoms that are relatively well controlled with exogenous steroid replacement, but there may be persistent symptoms, recurrent adrenal crisis and poor quality of life, despite good compliance with optimal current treatments. Treatment with conventional exogenous steroid therapy is also associated with premature mortality, increased cardiovascular risk and complications related to excessive steroid replacement. Hence, novel therapeutic approaches have emerged in the last decade attempting to improve the long-term outcome and quality of life of patients with AAD. This review discusses the recent developments in treatment innovations for AAD, including the novel exogenous steroid formulations with the intention of mimicking the physiological biorhythm of cortisol secretion. Our group has also carried out a few studies attempting to restore endogenous glucocorticoid production via immunomodulatory and regenerative medicine approaches. The recent advances in the understanding of adrenocortical stem cell biology, and adrenal plasticity will also be discussed to help comprehend the science behind the therapeutic approaches adopted.

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Section: Adrenal Biology and Adrenocortical Stem/ Progenitor Cells (Asupporting

confidence: 59%

MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addison’s disease

Gan

Pearce

2017

European Journal of Endocrinology

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“…After this first report, the study of several cohorts of individuals with 46,XY DSD has shown that adrenal insufficiency is a rare finding in patients with NR5A1 defects (Lin et al, 2006; Guran et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

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Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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“…The clinical presentation of patients affected by NR5A1 mutations is very diverse, ranging in 46,XY individuals from phenotypically females with complete gonadal dysgenesis with or without adrenal failure (5)(6)(7)(8)(9)(10) to males with penoscrotal hypospadias (8,11,12) or bilateral anorchia (13). In 46,XX women, NR5A1 mutations have been associated with premature ovarian failure (3).…”

Section: Introductionmentioning

confidence: 99%

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

Cools

Hoebeke

Wolffenbuttel

et al. 2012

European Journal of Endocrinology

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Objective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth. Design and methods: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c.9TOA, p.Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9:g.(126306276-126307705)_(126303229-126302828)del) of NR5A1, both predicted to fully disrupt gene function. Results: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen. Conclusions: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.

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Analysis of DAX1 (NR0B1) and Steroidogenic Factor-1 (NR5A1) in Children and Adults with Primary Adrenal Failure: Ten Years’ Experience

Abstract: DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys. SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.

Cited by 179 publications

References 54 publications

MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addison’s disease

MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addison’s disease

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

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