Autoimmune polyglandular syndrome type I (APS1) is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (Neufeld et al., 1981). However, variable APS1 phenotypes have been observed, even among sibs. In addition, some patients may exhibit apparent isolated hypoparathyroidism, an early manifestation of APS1 with peak incidence at around age 5 years; over long-term follow-up, the development of additional features of APS1 may be observed (Cranston et al., 2022).

Liddle syndrome is an inherited form of high blood pressure (hypertension). This condition is characterized by severe hypertension that begins unusually early in life, often in childhood, although some affected individuals are not diagnosed until adulthood. Some people with Liddle syndrome have no additional signs or symptoms, especially in childhood. Over time, however, untreated hypertension can lead to heart disease or stroke, which may be fatal.\n\nIn addition to hypertension, affected individuals can have low levels of potassium in the blood (hypokalemia). Signs and symptoms of hypokalemia include muscle weakness or pain, fatigue, constipation, or heart palpitations. The shortage of potassium can also raise the pH of the blood, a condition known as metabolic alkalosis.

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess, virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursors 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension (White et al., 1991). CAH due to 11-beta-hydroxylase deficiency accounts for approximately 5 to 8% of all CAH cases; approximately 90% of cases are caused by 21-hydroxylase deficiency (201910) (White et al., 1991).

CMO type I deficiency is an autosomal recessive disorder caused by a defect in the penultimate biochemical step of aldosterone biosynthesis, the 18-hydroxylation of corticosterone (B) to 18-hydroxycorticosterone (18-OHB). This enzymatic defect results in decreased aldosterone and salt-wasting. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal. These patients have an increased ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998). The CYP11B2 gene product also catalyzes the final step in aldosterone biosynthesis: the 18-oxidation of 18-OHB to aldosterone. A defect in that enzymatic step results in CMO type II deficiency (610600), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).

Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood glucose (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two.\n\nMany of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).\n\nPeople with this condition may have other neurological abnormalities, such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time.\n\nPeople with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.\n\nAlacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. They develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.

NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD.

Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone (review by Ferrari, 2010).

Familial isolated glucocorticoid deficiency (GCCD) is an adrenocortical failure characterized by very low levels of plasma cortisol despite high levels of plasma adrenocorticotropin (ACTH). Moreover, the adrenal response to ACTH is severely impaired. There is no mineralocorticoid deficiency and the renin-angiotensin system is not affected (summary by Genin et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of familial glucocorticoid deficiency, see GCCD1 (202200).

Hypertension due to gain-of-function mutations in the mineralocorticoid receptor is a rare genetic hypertension characterized by a familial severe hypertension with an onset before age 20 years, associated with suppressed plasma renin and low aldosterone levels in the presence of low or normal levels of the mineralocorticoid aldosterone, that is highly resistant to antihypertensive medication. During pregnancy, there is a marked exacerbation of hypertension, accompanied by low serum potassium levels and undetectable aldosterone levels, but without signs of preeclampsia, requiring early delivery.

CMO type II deficiency is an autosomal recessive disorder caused by a defect in the final biochemical step of aldosterone biosynthesis, the 18-hydroxylation of 18-hydroxycorticosterone (18-OHB) to aldosterone. This enzymatic defect results in decreased aldosterone and salt-wasting associated with an increased serum ratio of 18-OHB to aldosterone. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998). The CYP11B2 gene product also catalyzes an earlier step in aldosterone biosynthesis: the 18-hydroxylation of corticosterone to 18-OHB. A defect in that enzymatic step results in CMO type I deficiency (204300), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal (Portrat-Doyen et al., 1998).

Liddle syndrome is an autosomal dominant form of hypertension characterized by early onset of hypertension associated with hypokalemia, suppressed plasma renin activity, and suppressed secretion of the mineralocorticoid hormone aldosterone (summary by Hansson et al., 1995). For a general phenotypic description and a discussion of genetic heterogeneity of Liddle syndrome, see 177200.

Liddle syndrome, or pseudoaldosteronism, is an autosomal dominant form of salt-sensitive hypertension characterized by suppressed plasma renin and aldosterone, hypokalemia, and metabolic alkalosis (summary by Salih et al., 2017). For a discussion of genetic heterogeneity of Liddle syndrome, see 177200.