Table 1 Typical causes of primary adrenal insufficiency
1) Genetic disorders | OMIM1(gene map) | Etiologic mechanisms | Other signs and symptoms |
|---|---|---|---|
Adrenoleukodystrophy | 300100 (Xq28) | Mutations of ABCD1 2, ABCD2 3 | Weakness, diminished visual acuity, deafness, cerebellar ataxia, hemiplegia, convulsions, dementia |
Congenital adrenal hyperplasia | |||
21-hydroxylase deficiency | 201910 (6p21.33) | Mutations of CYP21A2 4 | Hyperandrogenism, ambiguous genitalia in females |
11β-hydroxylase deficiency | 202010 (8q24.3) | Mutations of CYP11B1 5 | Hyperandrogenism, hypertension |
3β-hydroxysteroid dehydrogenase type 2 deficiency | 201810 (1p12) | Mutations of HSD3B2 6 | Ambiguous genitalia in boys, postnatal virilisation in girls |
17α-hydroxylase deficiency | 202110 (10q24.32) | Mutations of CYP17A1 7 | Pubertal delay in both sexes, primary amenorrhea, lack of secondary sexual characteristics, hypertension |
P450 oxidoreductase deficiency | 201750 (7q11.23) | Mutations of POR 8 | Skeletal malformations, especially craniofacial; severe abnormal genitalia |
P450 side-chain cleavage deficiency | 613743 (15q24.1) | Mutations of CYP11A1 9 | XY sex reversal |
Congenital lipoid adrenal hyperplasia | 201710 (8p11.23) | Mutations of STAR 10 | XY sex reversal |
Smith-Lemli-Opitz syndrome | 270400 (11q13.4) | Mutations of DHCR7 11 | Mental retardation, craniofacial malformations, growth failure, cholesterol deficiency |
Adrenal hypoplasia congenita | |||
X-linked | 300200 (Xp21.2) | Mutations of NR0B1 12 | Hypogonadotropic hypogonadism in boys (occasionally in carrier females for skewed X-chromosome inactivation) |
Xp21 deletion syndrome | 300679 (Xp21) | Deletion of GK 13, DMD 14, and NR0B1 | Duchenne muscular dystrophy, glycerol kinase deficiency psychomotor retardation |
SF1-linked | 612965 (9q33.3) | Mutations of NR5A1 15 | XY sex reversal |
IMAGe syndrome | 614732 (11p15.4) | Mutations of CDKN1C 16 | Intrauterine growth retardation, metaphyseal dysplasia, genital abnormalities |
Kearns-Sayre syndrome | Deletions of mitochondrial DNA | Deafness; heart, ocular and cerebral involvement; skeletal muscle myopathy; intestinal disorders; hormonal deficits | |
Wolman disease | 278000 (10q23.31) | Mutations of LIPA 17 | Bilateral adrenal calcification, hepatosplenomegaly |
Sitosterolaemia | Mutations of ABCG5 18 and ABCG8 19 | Xanthomata, arthritis, premature coronary artery disease, short stature, gonadal failure | |
Familial glucocorticoid deficiency or corticotropin insensitivity syndromes | |||
Type 1 | 202200 (18p11.21) | Mutations of MC2R 20 | Hyperpigmentation, tall stature, typical facial features, lethargy and muscle weakness with normal blood pressure |
Type 2 | 607398 (21q22.11) | Mutations of MRAP 21 | Hyperpigmentation, normal height, hypoglycaemia, lethargy, and muscle weakness with normal blood pressure |
Variant of familial glucocorticoid deficiency | 609981 (8q11.21) | Mutations of MCM4 22 | Growth failure, increased chromosomal breakage, natural killer cell deficiency |
Primary generalised glucocorticoid resistance | (5q31.3) | Mutations of GCCR 23 | Fatigue, hypoglycaemia, hypertension, hyperandrogenism |
Triple A syndrome (Allgrove's syndrome) | 231550 (12q13.13) | Mutations of AAAS 24 | Achalasia, alacrima, deafness, mental retardation, hyperkeratosis |
2) Acquired diseases | |||
Bilateral adrenal haemorrhage | - | Meningococcal sepsis, antiphospholipid syndrome | Symptoms and signs of underlying disease |
Bilateral adrenal metastases | - | Lung, stomach, breast, and colon cancers | Disease-associated clinical manifestations |
Bilateral adrenalectomy | - | Adrenal masses, phaeochromocytoma unresolved Cushing's syndrome | Symptoms and signs of underlying disease |
Bilateral adrenal infiltration | - | Adrenal lymphoma, amyloidosis, haemochromatosis | Disease-associated clinical manifestations |
Drug-induced adrenal insufficiency | - | Anticoagulants, ketoconazole, fluconazole, etomidate, phenobarbital, phenytoin, rifampicin, troglitazone | None, unless related to drug |
Infectious adrenalitis | - | Tuberculosis, HIV-1, histoplasmosis, cryptococcosis, coccidioidomycosis, syphilis, trypanosomiasis | Disease-associated manifestations in other organs |
Autoimmune adrenalitis | - | ||
Isolated | None | ||
APS type 1 (APECED) | 240300 (21q22.3) | Mutations of AIRE 25 | Chronic mucocutaneous candidosis, hypoparathyroidism, other autoimmune diseases |
APS type 2 | 269200 | Thyroid autoimmune disease, type 1 diabetes, other autoimmune diseases | |
APS type 4 | Autoimmune gastritis, vitiligo, coeliac disease, alopecia, excluding thyroid disease and type 1 diabetes |