Hereditary unresponsiveness to ACTH (familial glucocorticoid
deficiency, FGD) can present as an acute adrenal crisis precipitated
by an intercurrent illness in an infant or with the signs and symptoms
of chronic adrenal insufficiency in childhood. Several autosomal
recessive causes of FGD have been identified.20 Patients
with FGD usually produce mineralocorticoids, because production
of aldosterone by the adrenal zona glomerulosa is regulated principally
by the renin angiotensin system. Thus, the presenting picture consists
of failure to thrive, lethargy, pallor, hyperpigmentation, and hypoglycemia,
often associated with seizures. Familial glucocorticoid
deficiency type 1 (FGD1) results from recessive mutations
in the ACTH receptor,20-22 accounting for ~25% of
cases of FGD. Patients with FGD1 have the typical findings of glucocorticoid
deficiency; hypoglycemia is common, and ACTH can be markedly elevated.
Tall stature and increased head circumference have been reported.22,23 Replacement
doses of glucocorticoids usually prevent adrenal crises but may
not suppress elevated ACTH levels completely.20Familial
glucocorticoid deficiency type2 (FGD2), which is clinically
indistinguishable from FGD1, is caused by mutations in the melanocortin
2 receptor accessory protein, MRAP,20,24 accounting for
about 20% of cases of FGD. MRAP appears to play a role
in trafficking the ACTH receptor from the endoplasmic reticulum
to the cell membrane. Triple A (Allgrove) Syndrome consists
of ACTH-resistant adrenal insufficiency (80% of individuals),
achalasia of the cardia (85%), and alacrima (90%).25 Mineralocorticoid
insufficiency is reported in only about 15% of cases, but
many patients also have progressive neurological symptoms (intellectual
impairment, sensorineural deafness, peripheral and cranial neuropathies,
optic atrophy, Parkinsonism, and autonomic dysfunction).21,26,27 Triple
A syndrome is caused by mutations in the gene for a WD-repeat protein
termed ALADIN.28,29 Clinical findings can vary even within
the same family. Adrenal insufficiency is rarely the presenting
feature. Thus, a detailed family history of achalasia, alacrima,
or neurological disorders is important when evaluating a patient
with primary adrenal failure.