Table 1

Congenital causes of adrenal insufficiency

ConditionAffected geneClinical phenotype
Primary
CAH
 21-α-hydroxylase deficiency CYP21A2 46,XX DSD/androgen excess; salt-wasting
 3-β-hydroxysteroid dehydrogenase deficiency HSD3B2 Ambiguous genitalia/salt-wasting
 11-β-hydroxylase deficiency CYP11B2 46,XX DSD/androgen excess; hypertension (not infants)
 P450 side-chain cleavage syndrome CYP11A 46,XY DSD; salt-wasting, hypogonadism
 Lipoid hyperplasia StAR 46,XY DSD; salt-wasting; hypogonadism
 P450 oxidoreductase deficiency (PORD) POR 46,XY DSD, salt-wasting, hypogonadism, Antley-Bixler malformation; altered drug metabolism
Congenital adrenal hypoplasia SF-1
(NR5A1)
46,XY DSD, gonadal insufficiency
DAX-1 (NROB1) Hypogonadotropic hypogonadism
CDKN1C IMAGe syndrome (intrauterine growth retardation, metaphyseal dysplasia, genital anomalies)
Triple A or Allgrove AAAS Achalasia, alacrima
Isolated familial glucocorticoid deficiency (FGD) MC2R,
MRAP
Tall stature, normal mineralocorticoid production
FGD–DNA repair defect MCM4 NK-cell defect, short stature, recurrent viral infections, microcephaly, chromosomal breakage
Glucocorticoid resistance GCCR Mineralocorticoid/androgen excess
Metabolic diseases
 Adrenoleukodystrophy ABCD1 Neurologic deterioration
 Zellweger PEX Cerebrohepatorenal syndrome
 Smith-Lemli-Opitz DHCR7 46,XY sex reversal, polydactyly, mental retardation
 Wolman LIPA Hepatomegaly
Mitochondrial disease
 Kearns-SayreOphthalmoplegia, myopathy
Secondary: hypothalamus
Holoprosencephaly GLI2,
FGF8
CRH deficiency
Maternal hypercortisolemia
Secondary: pituitary/hypothalamus
Isolated ACTH deficiency TPIT
Multiple anterior pituitary hormone deficiencies due to pituitary aplasia/hypoplasia HESX1 Septo-optic dysplasia (optic nerve hypoplasia), nystagmus
PROP1
LHX4
OTX2 Anophthalmia, developmental delay
SOX3 X linked, mental retardation, ectopic posterior pituitary
Isolated ACTH deficiency TPIT (TBX19)
Proopiomelanocortin deficiency POMC Severe early-onset hyperphagic obesity, red hair
Proprotein convertase 1 mutation PCSK1 Hypoglycemia, malabsorption, gonadotropin deficiency
  • ACTH, adrenocorticotropic hormone; CAH, congenital adrenal hyperplasia; CRH, corticotropin-releasing hormone; DSD, disorder of sex development; NK, natural killer.