X-linked adrenal hypoplasia congenita

X-linked adrenal hypoplasia congenita is a disorder that is noticeable from birth (congenital) and affects the development of the adrenal glands, which are hormone-producing (endocrine) organs (glands) located on top of each kidney. These glands produce a variety of hormones that regulate many essential functions in the body, such as response to stress.

One of the main signs of this disorder is adrenal insufficiency, which occurs when the adrenal glands do not produce enough hormones. Adrenal insufficiency typically begins in infancy or childhood and can cause vomiting, difficulty with feeding, dehydration, extremely low blood glucose (hypoglycemia), and shock. If untreated, these complications are often life-threatening.

Individuals with X-linked adrenal hypoplasia congenita may also have a shortage of male sex hormones, which leads to underdeveloped reproductive tissues, undescended testicles (cryptorchidism), delayed puberty, and an inability to father children (infertility). Together, these characteristics are known as hypogonadotropic hypogonadism.

The onset and severity of these signs and symptoms can vary, even among affected members of the same family.

X-linked adrenal hypoplasia congenita appears to be an uncommon condition. It has been reported to affect approximately 1 in 12,500 newborns, but this is likely an overestimate. The true prevalence of this condition is unknown.

Variants (also called mutations) in the NR0B1 gene cause X-linked adrenal hypoplasia congenita. The NR0B1 gene provides instructions to make a protein called DAX1. This protein plays an important role in the development and function of several endocrine tissues including the adrenal glands, two hormone-secreting glands in the brain (the hypothalamus and pituitary), and the gonads (ovaries in females and testes in males).  The hormones produced by these glands control many important body functions.

Some NR0B1 variants result in the production of an inactive version of the DAX1 protein, while other variants delete the entire gene. The resulting shortage of DAX1 disrupts the normal development and function of hormone-producing tissues in the body. The signs and symptoms of adrenal insufficiency and hypogonadotropic hypogonadism occur when endocrine glands do not produce the right amounts of certain hormones.

Rarely, the entire NR0B1 gene is deleted along with other neighboring genes, resulting in the development of X-linked adrenal hypoplasia with hypoplasia congenita and other diseases, such as Duchenne and Becker muscular dystrophy and glycerol kinase deficiency.

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a variant must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females.  A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the altered gene, but usually does not experience signs and symptoms of the disorder. In rare cases, however, females who carry an NR0B1 gene variant may experience adrenal insufficiency or signs of hypogonadotropic hypogonadism such as underdeveloped reproductive tissues, delayed puberty, and an absence of menstruation.