What causes congenital primary pediatric adrenal insufficiency (Addison disease)?

Updated: Mar 10, 2020
  • Author: Kimberly Tafuri, DO; Chief Editor: Sasigarn A Bowden, MD  more...
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Congenital Addison disease may occur as a result of adrenal hypoplasia [22, 23, 24] or hyperplasia.

Inherited as an X-linked disorder, adrenal hypoplasia congenita (OMIM 300200)—caused by deletion or mutation of the gene DAX1/NR0B1 (which encodes for the nuclear receptor DAX1) on chromosome Xp21.2—is additionally associated with hypogonadotrophic hypogonadism and primary defects in sperm production. [25] There is often a contiguous gene deletion that also involves the genes for glycerol kinase deficiency and dystrophin, resulting in elevations in serum glycerol (often measured using a triglyceride assay) and Duchenne muscular dystrophy. Deletion or mutation of the gene NR5A1, which encodes for the nuclear receptor steroidogenic factor 1, also results in congenital adrenal hypoplasia and may cause XY gonadal dysgenesis. [20] An alternate form of adrenal hypoplasia congenita, non-X linked, is characterized by intrauterine growth retardation and skeletal and genital anomalies (ie, IMAGe syndrome) (OMIM 614732). Still another type of adrenal hypoplasia congenita, an autosomal recessive form of uncertain etiology, has also been described (OMIM 240200).

Congenital adrenal hyperplasia results from a deficiency of one of several enzymes required for adrenal synthesis of cortisol. Symptoms of adrenal insufficiency (Addison disease) most often develop with combined deficiencies of cortisol and aldosterone. The most prevalent form of congenital adrenal hyperplasia is caused by a deficiency in steroid 21-hydroxylase (OMIM 201910).

Lipoid adrenal hyperplasia is another rare form of adrenal insufficiency (Addison disease) caused by a mutation in the steroid acute regulatory protein (ie, STAR protein) (OMIM 201710) [26] or a mutation in the cholesterol side-chain cleavage gene (at the cytochrome P450 [CYP] 11A locus) (OMIM 118485). [27] This disease causes a defective synthesis of all adrenocortical hormones. In its complete form, the disease is lethal.

Mutations or deletions involving CYP oxidoreductase, a flavoprotein that provides electrons to various enzyme systems, results in combined deficiencies of 17-hydroxylase, 21-hydroxylase, and 17-20 lyase activities. The result is adrenal insufficiency (Addison disease), which is often accompanied by skeletal dysplasia, genital anomalies, and primary hypogonadism (OMIM 613571). [28, 29, 30]

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