Familial Glucocorticoid Deficiency

Updated: Sep 25, 2013
  • Author: Andrea Haqq, MD; Chief Editor: Stephen Kemp, MD, PhD  more...
  • Print
Overview

Background

In 1959, Familial glucocorticoid deficiency (FGD) was first described by Shepard, Landing, and Mason. [1] They reported 2 sisters with a gradual onset of skin pigmentation, marked muscular weakness, and convulsions in the second year of life. The first sister died at age 30 months; although detailed clinical studies were not conducted postmortem, examination revealed marked adrenocortical atrophy. The second sister had low levels of plasma 11-hydroxycorticosterone that did not respond to adrenocorticotropic hormone (ACTH). Aldosterone secretion was determined to be normal on the basis of reference range serum electrolytes and blood pressure on a salt-restricted diet.

In 1968, Migeon et al described 6 patients with a syndrome of adrenal unresponsiveness to ACTH characterized by hypoglycemia, hyperpigmentation, feeding problems in infancy, low urinary 17-hydroxycorticosteroids, an ability to conserve sodium and increase aldosterone secretion in response to salt deprivation, and a lack of elevation of 17-hydroxycorticosteroid secretion or plasma cortisol concentration with ACTH administration. [2] Two of these patients were brothers. Migeon postulated that the syndrome may be due to an inherited defect within the adrenal gland, causing primary unresponsiveness to ACTH.

In 1972, Kelch et al reported 3 patients with severe isolated glucocorticoid deficiency who did not respond to ACTH stimulation. [3] Analysis of the 3 families supported an autosomal recessive inheritance pattern because both females and males were affected. Researchers described variability in adrenal pathology among these 3 families, suggesting heterogeneity in the condition.

In 1973, Moshang et al studied 5 affected siblings, each of whom demonstrated primary glucocorticoid deficiency and normal mineralocorticoid function. [4] A progressive deterioration of glucocorticoid function was observed in these patients, which suggested an inherited degenerative process involving the adrenal zona fasciculata and reticularis rather than a primary unresponsiveness to ACTH, as initially proposed. The syndrome was beginning to be viewed as a heterogeneous group of disorders.

In 1975, Thistlethwaite et al reported 2 brothers with recurrent hypoglycemia precipitated by an infectious illness at age 21 months and age 19 months. [5] Both brothers were tall and hyperpigmented. Their electrolyte balances were within the reference range even on a sodium-restricted diet, which supported normal aldosterone function. The serum levels of ACTH and deoxycorticosterone in the brothers' blood were markedly elevated; all other plasma corticosteroid levels were within the reference range. Adrenocortical unresponsiveness to ACTH was found to be progressive in the elder brother.

In 1977, Spark and Etzkorn proposed an etiology involving a defect at the ACTH receptor or a postreceptor site. [6]

Next:

Pathophysiology

FGD is a rare autosomal recessive condition. [7, 8] Pathologic evaluation of children affected with this disorder reveals that the zona glomerulosa of the adrenal glands is well preserved. The zona fasciculata and zona reticularis are markedly atrophic. These changes are accompanied by low plasma cortisol concentrations because the zona fasciculata is primarily responsible for glucocorticoid production. Low circulating serum cortisol results in a lack of feedback inhibition to the hypothalamus; markedly increased ACTH levels are often observed. Because the zona glomerulosa is generally well preserved, mineralocorticoid production is usually unaffected. Plasma renin and aldosterone concentrations are usually within the reference range in the baseline state and demonstrate normal variability on salt restriction.

Molecular defects of the ACTH receptor gene, consisting of point mutations, are described in approximately 25-40% of patients with FGD. Mutations in the MC2 receptor accessory protein (MRAP) are responsible for another estimated 15-20% of cases of FGD. [9, 10] The remainder (approximately 50-60%) of patients with FGD have unknown mutations; these mutations may affect ACTH signal transduction, expression of the ACTH receptor, or differentiation of the adrenal cortex. The pathogenesis of Allgrove syndrome (AS), another distinct clinical entity, is due to a defect in a WD-repeat regulatory protein named for alacrima-achalasia-adrenal insufficiency neurologic (ALADIN) disorder.

Previous
Next:

Epidemiology

Frequency

United States

The exact incidence of FGD is unknown; it is a rare disease, and only isolated case reports are documented. From the original descriptions in 1959-1995, more than 50 such cases have been reported. The incidence of FGD may be underestimated because some patients may have episodes of recurring hypoglycemia or convulsions, but FGD may remain undiagnosed for many years.

Mortality/Morbidity

The most frequent cause of FGD death is undiagnosed glucocorticoid insufficiency. Although this disease is easily treatable when recognized, if left untreated it may be fatal or lead to severe mental disability as a result of recurrent hypoglycemia secondary to glucocorticoid insufficiency. Out of more than 50 published cases, 18 patients died as a result of glucocorticoid insufficiency.

In early life, patients have feeding problems characterized by chronic spitting or vomiting and poor appetite. As a result, some patients may also experience poor weight gain. Hypoglycemic seizures secondary to glucocorticoid deficiency are a frequent complication of this disorder when inadequate treatment is provided. Finally, deep hyperpigmentation of the skin is the most common initial presenting sign and is almost always present at diagnosis. The hyperpigmentation is due to the action of ACTH on cutaneous melanocyte-stimulating hormone (MSH) receptors. This hyperpigmentation fades once proper treatment is initiated with glucocorticoids, which reduce ACTH concentrations.

Race

Cases of the condition have been reported in white, black, East Indian, and Middle Eastern populations. FGD is a rare autosomal recessive condition with no racial predilection.

Sex

This disorder occurs with equal frequency in both males and females.

Age

In many case reports in the literature, age of onset of symptoms ranges from birth to 9 years. Patients almost always present with symptoms by age 5 years. Patients usually present with onset of symptoms in the first year of life but may present in early childhood. In an analysis of the current medical literature, approximately 50% of cases occurred in the first year of life.

Previous