Table 1.
Selected monogenic causes of adrenal insufficiency in children.
| Condition | Gene (PROTEIN if different) | Inheritance | Associated features |
|---|---|---|---|
| Secondary adrenal insufficiency | |||
| CPHD | GLI1, HESX1, LHX3, LHX4, SOX3, SOX2, OTX2 and others; also PROP1, GH1 (delayed) | Variable | Many variable associated features including holoprosencephaly, tooth abnormalities (GLI1); septo-optic dysplasia (esp. HESX1); short rigid neck, hearing loss (LHX3); anophthalmia (SOX2, OTX2) |
| Isolated ACTH deficiency | TBX19 (TPIT) | AR | |
| POMC deficiency | POMC (Pro-opio-melanocortin) | AR | Obesity, red hair |
| Prohormone convertase deficiency | PCSK1 (PC-1) | AR | Obesity, hypoglycemia, hypogonadotropic hypogonadism |
| Primary adrenal insufficiency | |||
| Disorders of steroidogenesis | |||
| Smith–Lemli–Opitz syndrome | DHC7R (7-dehydrocholesterol reductase) | AR | Syndactyly, polydactyly, facial features, microcephaly, cardiac defects, gastrointestinal features, hypospadias/undescended testes |
| Congenital lipoid adrenal hyperplasiaa | STAR | AR | 46,XY DSD, impaired gonadal steroidogenesis |
| P450 side chain cleavage def.a | CYP11A1 (P450scc) | AR | 46,XY DSD, impaired gonadal steroidogenesis |
| 21-hydroxylase def. (CAH) | CYP21A2 (P450c21) | AR | 46,XX DSD, virilization, early puberty |
| 11β-hydroxylase def. (CAH) | CYP11B1 (P450c11) | AR | 46,XX DSD, virilization, early puberty, hypertension |
| 3β-hydroxysteroid dehydrogenase type 2 def. (CAH) | HSD3B2 (3β-HSD2) | AR | 46,XY DSD, impaired gonadal steroidogenesis; 46,XX DSD, clitoromegaly |
| 17α-hydroxylase/17,20-lyase def. (CAH) | CYP17A1 (P450c17) | AR | 46,XY DSD, impaired gonadal steroidogenesis, hypertension |
| P450 oxidoreductase def. (CAH) | POR (P450 oxidoreductase) | AR | Antley-Bixler syndrome (craniosynostosis, skeletal features, choanal atresia), atypical genitalia (46,XY and 46,XX), impaired gonadal steroidogenesis at puberty |
| Adrenal hypoplasia | |||
| X-linked AHC | NR0B1 (DAX-1) | X-linked | Hypogonadotropic hypogonadism, impaired spermatogenesis |
| Steroidogenic factor-1 | NR5A1 (SF-1) | AD, AR, SLD | 46,XY DSD, asplenia |
| IMAGe syndrome | CDKN1C | Imprinted | IUGR, metaphyseal dysplasia, genital anomalies |
| IMAGe-like syndrome with immunodeficiency | POLE1 | AR | IUGR, skeletal changes, adrenal hypoplasia, genital anomalies, infections/immunodeficiency, developmental dysplasia of the hip, post-natal growth restriction/facial features |
| MIRAGE syndrome | SAMD9 | AD (de novo) | Infections, IUGR/preterm, gonadal dysfunction, enteropathy, anemia, thrombocytopenia; risk of monosomy 7 and myelodysplastic syndrome |
| SERKAL syndrome | WNT4 | AR | 46,XX DSD, renal dysgenesis, pulmonary hypoplasia |
| ACTH-resistance and related conditions | |||
| FGD1 | MC2R (ACTH receptor) | AR | Tall stature (pre-treatment) |
| FGD2 | MRAP (MC2R-accessory protein) | AR | |
| Nicotinamide nucleotide transhydrogenase | NNT | AR | Early puberty |
| Thioredoxin reductase 2 | TXNRD2 | AR | Heart defects |
| Triple A syndrome (Allgrove syndrome) | AAAS (Aladin) | AR | Achalasia, alacrima, ataxia/neurological involvement, hyperkeratosis |
| Minichromosome maintenance-4 | MCM4 | AR | Natural killer cell defects, microcephaly, post-natal growth failure |
| Metabolic conditions | |||
| Sphingosine-1-phosphate lyase 1 insufficiency | SGPL1 | AR | Steroid-resistant nephrotic syndrome, ichthyosis, neurological involvement, hypothyroidism, cryptorchidism |
| X-linked adrenoleukodystrophy | ABCD1 | X-linked | Neurological dysfunction |
| Zellweger spectrum disorders (incl. neonatal adrenoleukodystrophy) | PEX genes; related genes (Peroxins) | AR | Neurological, facial features, hepatic dysfunction |
| Mitochondrial disorders (Kearne-Sayre syndrome; Pearson syndrome; others) | Mitochondrial DNA, MRPS7, NDUFAF5, GFER | Maternal or AR | Variable multisystem features |
| Wolman disease | LIPA (Cholesterol ester) | AR | Failure to thrive, hepatosplenomegaly, adrenal calcification |
| Autoimmune conditions | |||
| APS1 (APECED) | AIRE (Autoimmune regulator) | AD, AR | Hypoparathyroidism, mucocutaneous candidiasis, alopecia, pernicious anemia, other autoimmune features |
CPHD, combined (multiple) pituitary hormone deficiency; AD, autosomal dominant; AR, autosomal recessive; CAH, congenital adrenal hyperplasia, DSD, differences (disorders) in sex development; SLD, sex-limited dominant; IUGR, intrauterine growth restriction; FGD, familial glucocorticoid deficiency.
a
Partial defects in STAR and P450scc can present with predominant glucocorticoid insufficiency in childhood and mimic FGD.
Modified with permission from Lin and Achermann (7). Copyright 2004 Blackwell Publishing Ltd.