Autoimmune adrenalitis (AA)

Isolated AA

AI

Associations with HLA-DR3, CTLA-4

AA as part of autoimmune polyendocrine syndromes (APS)

APS 1 (= APECED)

APS 2

AI + hypoparathyroidism + chronic mucocutaneous candidiasis ± other autoimmune disorders

AI + thyroid disease (= Schmidt’s syndrome) + type 1 diabetes mellitus (= Carpenter’s syndrome) ± other autoimmune diseases

AIRE gene mutations (21q22.3)

Associations with HLA-DR3, CTLA-4

Infectious adrenalitis

Tuberculous adrenalitis

AI + other organ manifestations of tuberculosis

Tuberculosis

AIDS

AI +other AIDS-associated diseases

HIV, CMV

Fungal adrenalitis

AI + mostly immunosupppressed patients

Cryptococcosis, histoplasmosis, coccidioidomycosis

Genetic disorders leading to AI

Adrenoleucodystrophy (ALD)

Adrenomeyloneuropathy (AMN)

AI + demyelination of CNS (cerebral ALD) or spinal cord/peripheral nerves (AMN)

Mutation of the X-ALD gene encoding for the peroxisomal adrenoleucodystrophy protein (ALDP)

Congenital adrenal hyperplasia (CAH)

21-hydroxylase deficiency

11β-hydroxylase deficiency

3β-HSD type 2 deficiency

17α-hydroxylase deficiency

P450 oxidoreductase deficiency

AI + ambiguous genitalia in females

AI + ambiguous genitalia in females + hypertension

AI + ambiguous genitalia in males + postnatal virilization in females

AI + ambiguous genitalia in males + lack of puberty in both sexes + hypertension

AI + ambiguous genitalia in both sexes + skeletal malformations

CYP21A2 mutation

CYP11B1 mutation

HSD3B2 mutation

CYP17A1 mutation

POR mutation

Congenital lipoid adrenal hypoplasia (lipoid CAH)

AI + XY sex reversal

Mutations in the steroidogenic acute regulatory protein (STAR) gene

Mutations in CYP11A1 (encoding P450scc)

Smith–Lemli–Opitz syndrome (SLOS)

AI, mental retardation, craniofacial malformations, growth failure

Sterol delta-7-reductase gene (DHCR7) mutations

Adrenal hypoplasia congenita (AHC)

X-linked AHC

Xp21 contiguous gene syndrome

SF-1 linked AHC

AI + hypogonadotropic hypogonadism

AI + Duchenne muscular dystrophy + glycerol kinase deficiency (psychomotor retardation)

AI + XY sex reversal

Mutation in NROB1 (encoding DAX1)

Deletion of the Duchenne muscular dystrophy, glycerol kinase, and DAX1 genes

Mutation in NR5A1 (encoding SF-1)

IMAGe syndrome

Intrauterine growth retardation + metaphyseal dysplasia + AI + genital anomalies

?

Kearns–Sayre syndrome

Progressive external ophthalmoplegia, pigmentary retinal degeneration and cardiac conduction defects; endocrinopathies include gonadal failure, hypoparathyroidism, type 1 diabetes, only rarely AI

Mitochondrial DNA deletions

ACTH insensitivity syndromes = familial glucocorticoid deficiency (FGD)

Glucocorticoid deficiency, excess plasma ACTH; no (or only very mild) impairment of mineralocorticoid synthesis; lack of adrenarche

FGD 1

FGD 2

FGD 3

Triple A syndrome

(= Allgrove’s syndrome)

AI, tall stature

AI

AI

AI + alacrimia + achalasia; additional symptoms (neurological impairment, deafness, mental retardation, hyperkeratosis)

Mutations in melanocortin-2-receptor (MC2R) encoding the ACTH receptor

Mutations in MC2R accessory protein (MRAP)

?

Mutations in the triple A gene (AAAS) encoding a WD repeat protein

Bilateral adrenal haemorrhage

AI + symptoms of underlying disease

Septic shock, specifically meningococcal sepsis (Waterhouse–Friderichsen syndrome)

Primary antiphospholipid syndrome

Adrenal infiltration

AI + symptoms of underlying disease

Adrenal metastases

primary adrenal lymphoma

sarcoidosis, amyloidosis, haemochromatosis

Bilateral adrenalectomy

AI + symptoms of underlying disease

e.g. in the management of Cushing’s due to ectopic ACTH secretion of unknown source or following tumour nephrectomy

Drug-induced AI

AI

Treatment with mitotane, aminoglutethimide, arbiraterone, trilostane, etomidate, ketoconazole, suramin, RU486