Practice Essentials
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive condition. [1, 2] 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 adrenocorticotropic hormone (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.
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.
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. [3, 4] 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. [5]
Mutations have also been identified in mini chromosome maintenance-deficient 4 homologue (MCM4), which is involved in DNA replication, and nicotinamide nucleotide transhydrogenase (NNT), which is involved in antioxidant defense. [2]
Clinically judge the adequacy of glucocorticoid treatment by documenting reduced hyperpigmentation, absence of hypoglycemia and weakness, and normal growth at frequent follow-up visits. Administer the lowest dosage of glucocorticoid sufficient to control symptoms of adrenal insufficiency to permit normal growth in these patients.
Patients with FGD have a lifelong loss of adrenal function. They remain at risk of adrenal insufficiency during periods of stress when the adrenal gland normally secretes more hormones. If patients receive adequate glucocorticoid replacement and are properly educated regarding readjustment of medication during times of illness and stress, they should have a normal lifespan and be able to have children of their own.
Epidemiology
Familial glucocorticoid deficiency (FGD) is a rare disease, and only isolated case reports are documented. 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.
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. Of more than 50 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.
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.
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.
Patient Education
Educate patients regarding readjustment of glucocorticoid dosage during intercurrent illness or stress and during minor stress. Regarding fever or upper respiratory tract infections, double or triple the dosage of glucocorticoid until the illness is resolved.
Advise parents and/or caregivers to contact their pediatric endocrinologist if vomiting or diarrhea is present and the child cannot tolerate oral fluids and medication. They may be instructed to administer a prefilled Solu-Cortef syringe intramuscularly in a dose appropriate for the size of the patient. Alternatively, hospitalization may be required in this situation.
In cases of major stress, such as surgery or serious illness, advise parents to contact their pediatric endocrinologist. As a life-saving measure, parents may need to administer a prefilled Solu-Cortef syringe intramuscularly if medical assistance is not immediately available. Following this, advise parents to arrange transfer of their child to the hospital.
In serious illness, the daily requirement of parenteral hydrocortisone is 40-100 mg/m2 (approximately 4-10 times the maintenance dose) in 3 or 4 divided doses. Advise all patients with FGD to wear a MedicAlert bracelet outlining their condition and medical treatment.
Because of the rarity of this condition, provide families with a physician letter outlining FGD and its potential complications and treatments to present to an emergency care facility should a visit to the emergency department be necessary. Counsel patients, families, and/or caregivers regarding the importance of compliance in taking this life-sustaining medication; this medication should never be stopped in any circumstance.
Counsel patients with FGD and their families regarding the autosomal recessive inheritance pattern of FGD.
Monitor siblings and close relatives for potential symptoms of FGD; obtain appropriate laboratory screening to rule out this condition, which is potentially fatal if left untreated.
