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Table 1 Typical causes of primary adrenal insufficiency

From: Hydrocortisone malabsorption due to polyethylene glycols (Macrogol 3350) in a girl with congenital 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
  1. Modified by Charmandari et al., 2014 [16]: 1OMIM: Online Mendelian Inheritance in Man database; 2 ABCD1: atp-binding cassette subfamily D, member 1; 3 ABCD2: atp-binding cassette, subfamily D, member 2; 4 CYP21A2: cytochrome P450, family 21, subfamily A, polypeptide 2; 5 CYP11B1: cytochrome P450, subfamily XIB, polypeptide 1; 6 HSD3B2: 3-beta-hydroxysteroid dehydrogenase 2; 7 CYP17A1: cytochrome P450, family 17, subfamily A, polypeptide 1; 8 POR: cytochrome P450 oxidoreductase; 9 CYP11A1: cytochrome P450, subfamily XIA, polypeptide 1; 10 STAR: steroidogenic acute regulatory protein; 11 DHCR7: 7-dehydrocholesterol reductase; 12 NR0B1: nuclear receptor subfamily 0, group B, member 1; 13 GK: glycerol kinase; 14 DMD: dystrophin; 15 NR5A1: nuclear receptor subfamily 5, group A, member 1; 16 CDKN1C: cyclin-dependent kinase inhibitor 1C; 17 LIPA: lipase A, lysosomal acid; 20 MC2R: melanocortin 2 receptor; 21 MRAP: melanocortin 2 receptor accessory protein; 22 MCM4: minichromosome maintenance, Saccharomyces Cerevisiae, homolog of, 4; 23 GCCR: glucocorticoid receptor; 24 AAAS: AAAS GENE; 25 AIRE: autoimmune regulator.
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Italian Journal of Pediatrics

ISSN: 1824-7288

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