Addison’s disease (AD) develops when the adrenal glands fail to produce adequate amounts of steroid hormones, specifically cortisol and aldosterone. Cortisol helps the body manage stress and regulate metabolism, while aldosterone controls sodium and potassium balance to maintain blood pressure. This hormonal deficiency is known as primary adrenal insufficiency. The relationship between AD and heredity is complex, involving two distinct mechanisms: a common genetic susceptibility to an autoimmune form, and rare cases of direct inheritance through single-gene disorders.
Autoimmunity and Genetic Predisposition
The majority of Addison’s disease cases, estimated to be about 80%, result from autoimmune adrenalitis (A-AD), where the body’s immune system mistakenly attacks and destroys the adrenal cortex. This common form of AD is considered polygenic, meaning multiple genes combine with environmental factors to create a susceptibility to the disease. The collective effect of these genes raises the risk of developing A-AD, but does not guarantee its inheritance.
Genetic susceptibility is most strongly linked to the human leukocyte antigen (HLA) complex, a gene region on chromosome 6 that manages immune system recognition. Specific HLA Class II variants, such as the haplotypes DRB1\03:01-DQB1\02 and DRB1\04:04-DQB1\03:02, confer a significantly increased risk for A-AD. These HLA molecules are responsible for presenting antigens to T-cells, and certain variants may predispose the immune system to recognize adrenal cells as foreign.
Beyond the HLA complex, other genes involved in immune regulation, such as PTPN22 and CTLA4, also contribute to the overall genetic risk profile. The presence of these multiple genetic risk factors explains why A-AD often occurs alongside other autoimmune conditions, such as Type 1 diabetes and autoimmune thyroid disease. Individuals with A-AD often produce autoantibodies, specifically against the enzyme 21-hydroxylase, which serve as a marker of the ongoing autoimmune destruction of the adrenal glands.
Monogenic Causes and Associated Syndromes
While A-AD is polygenic, a less common subset of cases is caused by a mutation in a single gene, known as monogenic disorders. These single-gene defects often result in AD presenting as part of a broader, more complex syndrome. Understanding these specific syndromes is important because they have clear, predictable inheritance patterns, unlike the complex susceptibility of A-AD.
One example is Autoimmune Polyendocrine Syndrome Type 1 (APECED), which is caused by mutations in the AIRE (Autoimmune Regulator) gene. This syndrome is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the mutated gene, one from each parent, to develop the condition. The AIRE gene is responsible for training the immune system in the thymus, and its malfunction leads to a severe, multi-organ autoimmune attack that almost always includes AD.
Another monogenic cause is X-linked Adrenoleukodystrophy (X-ALD), which is caused by a mutation in the ABCD1 gene located on the X chromosome. X-ALD is an X-linked disorder that primarily affects males and causes the accumulation of very long chain fatty acids, damaging the nervous system and the adrenal glands. The adrenal insufficiency associated with X-ALD typically follows an X-linked inheritance pattern. Genetic testing for the ABCD1 gene is often recommended for males diagnosed with AD, even without neurological symptoms, due to the distinct hereditary risk.
Practical Risk Assessment for Relatives
The familial risk for Addison’s disease varies significantly depending on the underlying cause, making risk assessment a nuanced process for first-degree relatives, such as siblings and children. In cases of A-AD, the overall absolute risk for a first-degree relative to develop the disease remains relatively low, but it is substantially higher than the general population risk.
For first-degree relatives of individuals with A-AD, screening focuses on measuring circulating autoantibodies against 21-hydroxylase, the primary marker of autoimmune attack. The presence of these autoantibodies indicates a heightened risk of progression to overt AD. Relatives who test positive for autoantibodies may undergo periodic monitoring of their adrenal function, often involving an ACTH stimulation test, to detect early signs of adrenal insufficiency.
Genetic counseling is recommended for families affected by either A-AD or the monogenic syndromes. Counseling is particularly valuable for monogenic cases, where the inheritance pattern allows for a clearer calculation of recurrence risk for future children. For A-AD, counseling helps interpret the complex polygenic risk, providing context for the autoantibody screening results and guiding decisions about proactive monitoring and follow-up care.