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
Abstract 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)...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-02-01
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| Series: | BMC Endocrine Disorders |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12902-020-0500-2 |
| _version_ | 1818664155557658624 |
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| author | Michelle Cerutti C. Vargas Felipe Scipião Moura Cecília P. Elias Sara R. Carvalho Nelson Rassi Ilda S. Kunii Magnus R. Dias-da-Silva Flavia Amanda Costa-Barbosa |
| author_facet | Michelle Cerutti C. Vargas Felipe Scipião Moura Cecília P. Elias Sara R. Carvalho Nelson Rassi Ilda S. Kunii Magnus R. Dias-da-Silva Flavia Amanda Costa-Barbosa |
| author_sort | Michelle Cerutti C. Vargas |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-17T05:28:15Z |
| format | Article |
| id | doaj.art-82085d1044cc4aaab002f6985a5c818c |
| institution | Directory Open Access Journal |
| issn | 1472-6823 |
| language | English |
| last_indexed | 2024-12-17T05:28:15Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Endocrine Disorders |
| spelling | doaj.art-82085d1044cc4aaab002f6985a5c818c2022-12-21T22:01:48ZengBMCBMC Endocrine Disorders1472-68232020-02-012011710.1186/s12902-020-0500-2Spontaneous fertility and variable spectrum of reproductive phenotype in a family with adult-onset X-linked adrenal insufficiency harboring a novel DAX-1/NR0B1 mutationMichelle Cerutti C. Vargas0Felipe Scipião Moura1Cecília P. Elias2Sara R. Carvalho3Nelson Rassi4Ilda S. Kunii5Magnus R. Dias-da-Silva6Flavia Amanda Costa-Barbosa7Endocrinology Unit, Hospital Geral Alberto RassiDepartment of Medicine, Division of Endocrinology, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, Universidade Federal de São PauloEndocrinology Unit, Hospital Geral Alberto RassiEndocrinology Unit, Hospital Geral Alberto RassiEndocrinology Unit, Hospital Geral Alberto RassiDepartment of Medicine, Division of Endocrinology, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, Universidade Federal de São PauloDepartment of Medicine, Division of Endocrinology, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, Universidade Federal de São PauloDepartment of Medicine, Division of Endocrinology, Escola Paulista de Medicina, Laboratory of Molecular and Translational Endocrinology, Universidade Federal de São PauloAbstract 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.https://doi.org/10.1186/s12902-020-0500-2Adrenal hypoplasia congenita (AHC)Adrenal insufficiencyDAX-1 mutationInfertility |
| spellingShingle | Michelle Cerutti C. Vargas Felipe Scipião Moura Cecília P. Elias Sara R. Carvalho Nelson Rassi Ilda S. Kunii Magnus R. Dias-da-Silva Flavia Amanda Costa-Barbosa 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 BMC Endocrine Disorders Adrenal hypoplasia congenita (AHC) Adrenal insufficiency DAX-1 mutation Infertility |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Adrenal hypoplasia congenita (AHC) Adrenal insufficiency DAX-1 mutation Infertility |
| url | https://doi.org/10.1186/s12902-020-0500-2 |
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