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

Author(s)

Vargas, Michelle Cerutti C. ^[1] ; Moura, Felipe Scipiao ^[2] ; Elias, Cecilia P. ^[1] ; Carvalho, Sara R. ^[1] ; Rassi, Nelson ^[1] ; Kunii, Ilda S. ^[2] ; Dias-da-Silva, Magnus R. ^[2] ; Costa-Barbosa, Flavia Amanda ^[2]

Affiliation

^[1] Hosp Geral Alberto Rassi, Endocrinol Unit, Goiania, Go - Brazil

^[2] Univ Fed Sao Paulo, Lab Mol & Translat Endocrinol, Escola Paulista Med, Dept Med, Div Endocrinol, Rua Pedro de Toledo 669, BR-04039032 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: BMC Endocrine Disorders; v. 20, n. 1 FEB 6 2020.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 11/20747-8 - Clinical, biochemical and molecular investigation of Thyrotoxic periodic paralysis
• Grantee: Magnus Régios Dias da Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/06570-6 - Comprehensive whole exome, paired-end RNA and genome sequencing: new insights into genetic bases of thyroid carcinoma in pediatric and adult ages and applications in clinical practice
• Grantee: Janete Maria Cerutti
• Support Opportunities: Research Projects - Thematic Grants