X-linked adrenal hypoplasia congenita

Other Names: X-linked congenital adrenal hypoplasia; X-linked AHC; Adrenal hypoplasia congenita; Congenital adrenal hypoplasia

X-linked adrenal hypoplasia congenita is a disorder that mainly affects males. It involves many hormone-producing (endocrine) tissues in the body, particularly a pair of small glands on top of each kidney called the adrenal glands. These glands produce a variety of hormones that regulate many essential functions in the body.

Epidemiology

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.

Cause

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 hormone-producing (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 mutations result in the production of an inactive version of the DAX1 protein, while other mutations 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.

Inheritance

X-linked recessive inheritance

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated 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 mutation 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 mutated 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 a NR0B1 mutation may experience adrenal insufficiency or signs of hypogonadotropic hypogonadism such as underdeveloped reproductive tissues, delayed puberty, and an absence of menstruation.

Signs and symptoms

X-linked adrenal hypoplasia congenita is a disorder that mainly affects males. 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 sugar (hypoglycemia), and shock. If untreated, these complications may be life-threatening

Affected males may also have a shortage of male sex hormones, which leads to underdeveloped reproductive tissues, undescended testicles, delayed puberty, and an inability to father children. 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.

Diagnosis

Clinical Findings

• Acute primary adrenal insufficiency in the first (or second) month of life
• Primary adrenal insufficiency later in childhood
• Primary adrenal insufficiency and/or hypogonadotropic hypogonadism in young adulthood

Laboratory Findings

• Primary adrenal insufficiency
• A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test.
• In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time.
• Rarely, boys may have a predominant cortisol insufficiency and normal salt balance.
• Hypogonadotropic hypogonadism
• Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism)
• Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test
• Low inhibin B

Imaging Studies Abdominal CT, MRI, or ultrasound examination may reveal small adrenal glands.

The diagnosis of NR0B1-related adrenal hypoplasia congenita is established in a male proband by detection of either a hemizygous pathogenic variant in NR0B1.

Treatment

Adrenal Insufficiency Some guidance on the treatment of adrenal insufficiency in children and adults is provided by recent Endocrine Society clinical practice guidelines.

Acute episodes. Episodes of acute adrenal insufficiency are usually treated in an intensive care unit with close monitoring of blood pressure, hydration, clinical status, and serum concentration of glucose and electrolytes. Correction of hyperkalemia may be needed. Individuals are treated by the IV administration of saline, glucose, and hydrocortisone (e.g., Solu-Cortef®). If the serum concentration of electrolytes does not improve, a mineralocorticoid (fludrocortisone) is added or the dose of Solu-Cortef® is increased. Adequate sodium must be provided as well as monitoring for hypoglycemia.

Chronic treatment. Once the initial acute episode has been treated, affected individuals are started on replacement doses of glucocorticoids and mineralocorticoids and – in younger children – oral supplements of sodium chloride (NaCl). Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis. Maintenance hormone treatment is best managed in growing children by a pediatric endocrinologist.

Treatment during stress. Steroid dosage must be increased during periods of stress (e.g., intercurrent illness, surgery, trauma); glucose and sodium may be needed. Local hospitals should provide parents with a plan for emergency treatment and instruction regarding when extra oral or injected hydrocortisone is needed. Correction of hypoglycemia may also be needed. Parents should have access to rapid medical advice; guidelines for hospital admission should be clear. Children should carry appropriate documentation indicating that they are steroid deficient. Death from acute adrenal insufficiency in individuals known to have NR0B1-related adrenal hypoplasia congenita may still occur if steroid replacement therapy is not adequate, particularly during times of stress or fluid imbalance (e.g., severe gastroenteritis).

Other. Steroid replacement therapy is monitored clinically and hormonally by an endocrinologist. ACTH levels should normalize when replacement therapy is adequate. A sudden rise in ACTH despite steroid treatment has revealed the presence of a pituitary adenoma in one case .

The wearing of a Medic Alert® bracelet is strongly recommended.

Ongoing education and support, as well as access to appropriate resources, is important for families and young people.

Hypogonadotropic Hypogonadism Hormone replacement therapy. If there is evidence of HH, treatment with increasing doses of testosterone to induce age-appropriate puberty may be necessary and should be monitored by a pediatric endocrinologist. Treatment is usually initiated at around or just after the time puberty would be expected (age 12 years in boys). Testosterone doses are increased gradually over a two- to three-year period until adult replacement doses are reached. Lifelong hormone replacement is needed.

Testosterone supplementation is also needed to support growth and bone mineralization.

Fertility has been achieved in a man with classic early-onset X-linked AHC using testicular sperm extraction-intracytoplasmic sperm injection following fairly extensive prior gonadotropin treatment . It is not yet known whether this success will be possible in general or whether this represents an isolated case.

Psychological counseling is indicated as needed for families and young people to discuss the issues related to hormone replacement therapy and future issues with fertility.

Other. Developmental delay is evaluated and managed in the routine manner.

NIH genetic and rare disease info

• NIH info on X-linked adrenal hypoplasia congenita

X-linked adrenal hypoplasia congenita is a rare disease.

X-linked adrenal hypoplasia congenita Resources
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