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). 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.

Effect of Recombinant Gonadotropin on Testicular Function and Testicular Sperm Extraction in Five Cases of NR0B1 (DAX1) Pathogenic Variants

“…However, hormonal levels, BTV, age at diagnosis, and gonadotropin treatment response showed no correlations with the molecular variant. This confirms the absence of any clear genotype–phenotype relation in X-AHC patients and the heterogeneity of the pathology reported elsewhere ( 4 , 10 , 12 , 26 , 27 ).…”

“…Therefore, reduced BTV and low or low-normal inhibin B values for age suggest spermatogenesis failure which can be integrated in the hypogonadotropic hypogonadism profile and in the primary gonadal defect reported in X-AHC patients ( 5 , 9 , 10 , 13 ). As observed here, some authors reported testicular volume ranging from 3 to 6 ml bilaterally in most X-AHC cases ( 6 , 9 , 11 , 25 , 26 , 31 , 32 ). However, testicular volume may be normal in mild forms of X-AHC ( 10 ).…”

“…However, testicular volume may be normal in mild forms of X-AHC ( 10 ). Likewise, inhibin B was reported to be low or in the lowest range of normal at puberty or after ( 6 , 10 , 25 , 26 , 31 , 33 ).…”

The Genetic Backdrop of Hypogonadotropic Hypogonadism

“…Initiation of pubertal development cannot be achieved through the use of pulsatile gonadoliberin (GnRH) owing to the pituitary's unresponsiveness to GnRH caused by genetic mutation. Thus, puberty and virilization are achieved either by the injection of human chorionic gonadotropin (hCG), which stimulates testosterone production, or by initiating testosterone replacement therapy, which is often more patient-friendly and less costly [61,62].…”

The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility—A Unifying Hypothesis?

“…There are also mutations that interfere with the differentiation of the male reproductive system including cytochrome b5 type A ( CYB5A ) which selectively disrupts 17,20-lyase activity leading to disordered sexual development ( 69 ) and deletions on chromosome 21 that also cause defects in male sexual development ( 70 ). Mutations on the X chromosome are also linked with male infertility including: anosmin 1 ( ANOS1 ), a gene linked to Kallmann syndrome ( 71 ), testis expressed 11 ( TEX11 ), linked to meiotic arrest ( 72 ) and nuclear receptor subfamily 0 group B member 1 (NR0B1) associated with adrenal hyperplasia and hypogonadotropic hypogonadism ( 73 ). Mutations in the X-linked androgen receptor gene are also known to induce infertility in around 2% of male patients ( 74 ).…”