Inborn Defects of Steroidogenesis

The most common causes of adrenocortical insufficiency in infancy are the salt-losing forms of congenital adrenal hyperplasia (Chapter 570). Approximately 75% of infants with 21-hydroxylase deficiency, almost all infants with lipoid adrenal hyperplasia, and most infants with a deficiency of 3β-hydroxysteroid dehydrogenase manifest salt-losing symptoms in the newborn period because they are unable to synthesize either cortisol or aldosterone.

Adrenal Hypoplasia Congenita

Adrenal hypoplasia congenita (AHC) represents approximately half of cases of adrenal failure in boys that are not caused by congenital adrenal hyperplasia, autoimmune disease, or adrenoleukodystrophy. Hypoadrenalism usually occurs acutely in the neonatal period but may be delayed until later childhood or even adulthood with a more insidious onset. Histologic examination of the hypoplastic adrenal cortex reveals disorganization and cytomegaly. The disorder is caused by mutation of the DAX1 (NR0B1) gene, a member of the nuclear hormone receptor family, located on Xp21. Boys with AHC often do not undergo puberty owing to hypogonadotropic hypogonadism; both AHC and hypogonadotropic hypogonadism are caused by the same mutated DAX1 gene. Cryptorchidism, often noted in these boys, is probably an early manifestation of hypogonadotropic hypogonadism.

AHC also occurs as part of a contiguous gene deletion syndrome together with Duchenne muscular dystrophy, glycerol kinase deficiency, mental retardation, or a combination of these conditions.

Other Genetic Causes of Adrenal Hypoplasia

The transcription factor SF-1 is required for adrenal and gonadal development (Chapter 568). Males with a heterozygous mutation in SF-1 (NR5A1) have impaired development of the testes despite the presence of a normal copy of the gene on the other chromosome and can appear to be female, similar to patients with lipoid adrenal hyperplasia (Chapter 570). Rarely, such patients have adrenal insufficiency as well.

Adrenal hypoplasia is also occasionally seen in patients with Palister-Hall syndrome caused by mutations in the GLI3 oncogene (Chapter 568).

Adrenoleukodystrophy

In adrenoleukodystrophy (ALD), adrenocortical deficiency is associated with demyelination in the central nervous system (Chapters 80 and 592.3). High levels of very long chain fatty acids are found in tissues and body fluids, resulting from their impaired β-oxidation in the peroxisomes.

The most common form of ALD is an X-linked disorder with various presentations. The most common clinical picture is of a degenerative neurologic disorder appearing in childhood or adolescence and progressing to severe dementia and deterioration of vision, hearing, speech, and gait, with death occurring within a few years. A milder form of X-linked ALD is adrenomyeloneuropathy (ALM), which begins in later adolescence or early adulthood. Many patients have evidence of adrenal insufficiency at the time of neurologic presentation, but Addison disease may be present without neurologic symptoms or can precede them by many years. X-linked adrenal leukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene located on Xq28. The gene encodes a transmembrane transporter involved in the importation of very long chain fatty acids into peroxisomes. More than 400 mutations have been described in patients with X-ALD; the majority of X-ALD families have a unique mutation. Clinical phenotypes can vary even within families, perhaps owing to modifier genes or other unknown factors. There is no correlation between the degree of neurologic impairment and severity of adrenal insufficiency. Prenatal diagnosis by DNA analysis and family screening by very long chain fatty acid assays and mutation analysis are available. Women who are heterozygous carriers of the X-ALD gene can develop symptoms in midlife or later; adrenal insufficiency is rare.

Neonatal ALD is a rare autosomal recessive disorder. Infants have neurologic deterioration and have or acquire evidence of adrenocortical dysfunction. Most patients have severe mental retardation and die before 5 yr of age. This disorder is a subset of Zellweger (cerebrohepatorenal) syndrome, in which peroxisomes do not develop at all owing to mutations in any of several genes controlling the development of this organelle.

Familial Glucocorticoid Deficiency

Familial glucocorticoid deficiency is a form of chronic adrenal insufficiency characterized by isolated deficiency of glucocorticoids, elevated levels of ACTH, and generally normal aldosterone production, although salt-losing manifestations as are present in most other forms of adrenal insufficiency occasionally occur. Patients mainly have hypoglycemia, seizures, and increased pigmentation during the 1st decade of life. The disorder affects both sexes equally and is inherited in an autosomal recessive manner. There is marked adrenocortical atrophy with relative sparing of the zona glomerulosa. Mutations in the gene for the ACTH receptor (MCR2) have been described in approximately 25% of these patients, most of which affect trafficking of receptor molecules from the endoplasmic reticulum to the cell surface. Another 20% of cases are caused by mutations in MRAP, which encodes a melanocyte receptor accessory protein required for this trafficking.

Another syndrome of ACTH resistance occurs in association with achalasia of the gastric cardia and alacrima (triple A or Allgrove syndrome). These patients often have a progressive neurologic disorder that includes autonomic dysfunction, mental retardation, deafness, and motor neuropathy. This syndrome is also inherited in an autosomal recessive fashion, and the AAAS gene has been mapped to chromosome 12q13. The encoded protein, aladin, might help regulate nucleocytoplasmic transport of other proteins.

Type I Autoimmune Polyendocrinopathy

Although autoimmune Addison disease most often occurs sporadically (see later), it can occur as a component of 2 syndromes, each consisting of a constellation of autoimmune disorders (Chapter 560). Type I autoimmune polyendocrinopathy (APS-1), also known as autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome, is inherited in mendelian autosomal recessive manner, whereas APS-2 (described later) has complex inheritance. Chronic mucocutaneous candidiasis