AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1959, Familial glucocorticoid deficiency (FGD) was first described by Shepard, Landing, and Mason. 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 when aged 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 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. 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 reported 3 patients with severe isolated glucocorticoid deficiency who did not respond to ACTH stimulation. 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 studied 5 affected siblings, each of whom demonstrated primary glucocorticoid deficiency and normal mineralocorticoid function. 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 reported 2 brothers with recurrent hypoglycemia precipitated by an infectious illness at the ages of 21 and 19 months. 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, while all other plasma corticosteroids 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.

Pathophysiology

FGD is a rare autosomal recessive condition. 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 40% of patients with FGD. The remainder of FGD patients have unknown mutations, which may affect ACTH signal transduction, expression of the ACTH receptor, or differentiation of the adrenal cortex. The pathogenesis of Allgrove syndrome (AS), another distinct subtype of FGD, is due to a defect in a WD-repeat regulatory protein named for alacrima-achalasia-adrenal insufficiency neurologic (ALADIN) disorder.

Frequency

United States

The exact incidence of FGD is not known; 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 Caucasian, African-American, 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Focus the history on symptoms compatible with glucocorticoid deficiency such as hypoglycemia and shock. Children with hypoglycemia can present with pallor, sweating, palpitations, anxiety, shakiness, hunger, abdominal symptoms, vision changes, or changes in mental status such as confusion, mood changes, lethargy, seizures, and coma. In newborns, symptoms of hypoglycemia can be subtle; a high index of suspicion is needed. Newborns can present with irritability, jitteriness, respiratory distress, cyanosis, apnea, hypotonia, or seizures. A history of failure to thrive, poor feeding, absence of weight gain, lethargy, and recurrent or severe infections due to glucocorticoid deficiency suggest FGD. A positive family history of consanguinity or early unexplained infant deaths or other affected family members supports a diagnosis of FGD.

Patients with FGD generally present with signs and symptoms of adrenal insufficiency with the important distinction that mineralocorticoid production is always normal. The most common initial presenting sign is deep hyperpigmentation of the skin, mucous membranes, or both as a result of the action of ACTH on cutaneous MSH receptors. Many patients present with recurrent hypoglycemia or severe infections, although these are not the most common initial presenting signs. In the neonatal period, frequent presenting signs include feeding problems, failure to thrive, regurgitation, and hypoglycemia manifesting as seizures. The hypoglycemia-related seizures may be fatal. Finally, hypoglycemia, lethargy, seizures, shock, or sudden death may be the initial presentation in early childhood. Some children present with tall stature.

Physical

Distinguish FGD from other disorders that cause adrenal insufficiency.

• Positive findings
  • Focus the physical examination of individuals with FGD on eliciting signs of ACTH excess and glucocorticoid deficiency.
  • On physical examination, the most striking finding may be the presence of excess pigmentation of skin, areolae, genitalia, and mucous membranes. The deep pigmentation of the skin is the result of the action of ACTH on cutaneous MSH receptors.
  • Signs of isolated glucocorticoid deficiency may be present on physical examination. These include lethargy, decreased level of consciousness, and muscle weakness.
  • Blood pressure and hemodynamic status may be preserved in these patients because of normal mineralocorticoid function.
  • Tall stature, advanced bone age, or both have been described in some children with FGD. Not all patients with the same ACTH receptor mutation manifest tall stature. To date, growth hormone levels and adrenal androgens have been within the reference range in these children. At this time, the mechanism for this increase in height and advanced bone age in FGD is unknown. Possible explanations for this phenomenon have included an effect of elevated ACTH levels on the MSH receptors in cartilaginous growth plates or an effect of excess ACTH stimulating estradiol synthesis or acting on bone growth factors such as aromatase. For example, a patient with FGD type 2 and an elevated estradiol level that was related to the increase in plasma ACTH has been described. Alternatively, the anabolic properties of growth hormone unopposed by cortisol may result in this increase in height.
• Negative findings
  • Absence of ambiguous genitalia or congenital adrenal hyperplasia
  • Absence of cutaneous candidiasis or polyglandular autoimmune syndrome
  • Absence of alacrima and achalasia or AS
  • Neurologic signs such as observed in AS, adrenoleukodystrophy, and Wolman disease
• An important distinction should be made between FGD and AS (triple A syndrome), another rare autosomal recessive disease. Although both of these syndromes are characterized by glucocorticoid deficiency, AS has the additional features of alacrima (absence of tears), achalasia of the cardia, and a wide spectrum of neurologic abnormalities. AS is discussed in Allgrove (AAA) Syndrome.

Causes

Patients with FGD present with an isolated defect in glucocorticoid production. Because ACTH levels are in fact elevated, the apparent defect was hypothesized to be signaling either in the ACTH receptor or in post–ACTH receptor mechanisms. Alternatively, an isolated defect in the development of the adrenal zona fasciculata can also result in isolated deficiency of glucocorticoid production.

• DNA analysis of all patients with FGD has demonstrated that only about 40% of these patients have mutations in the ACTH receptor gene. Dividing FGD into 2 categories has been proposed: type 1 (with ACTH receptor mutations) and type 2 (with normal ACTH receptors).
• View AS as a completely separate entity. The presence of mineralocorticoid deficiency in some cases of AS, frequent association with progressive and variable neurologic impairment, and different underlying genetic etiology clearly distinguish AS from FGD.
• Type 1 FGD is associated with ACTH receptor mutations.
  • Mountjoy reported the cloning of the human ACTH receptor in 1992. Defects in the ACTH receptor, a small G protein–coupled receptor, have been described in families and individuals in whom a clinical diagnosis of FGD has been suspected. In 1993, Clark was the first to report a point mutation (S741) in the human ACTH receptor that resulted in a serine substitution for the normal amino acid at site 741 in a male proband of an FGD family. A similar defect was found in an affected sister and a normal sequence in an unaffected brother. Both parents were heterozygous for this defect. This mutation segregated with the disease in an autosomal recessive fashion. Furthermore, this mutation was found to decrease the ability of ACTH to bind to the ACTH receptor in vivo.
  • Recently, several other human ACTH receptor point mutations have been functionally characterized. Several classes of defects were observed. Most of these mutations caused a decrease in the ability of ACTH to bind to the ACTH receptor.
  • Other mutations were found to not only decrease the ability of ACTH to bind to the ACTH receptor (MC2R), but also to lead to defects in downstream signal transduction. For example, several MC2R mutations that cause loss of ligand binding (D103N, D107N, I118fs, T159K, I44M), structural disruption (S741, S120R, T159K, P273H), impairment of disulphide bonds (C251F, T254C), truncated receptor (1052delC, 1272delTA, R201X, 1347insA, L192fs, G217fs, F119fs), or loss of signal transduction (I44M, R128C, R146H, V142L, R137W) have been described. A poor correlation between severity of gene defect and clinical phenotype was observed.
  • Even with identical mutations of the human MC2R, considerable variation in clinical phenotype existed. In general, correlation was poor between the estimated severity of the receptor defect in vitro and the age at clinical presentation and disease severity, as judged by basal and stimulated plasma cortisol levels.
  • When the clinical characteristics of FGD associated with an ACTH receptor mutation were compared with FGD associated with no known mutation, no significant differences were observed in either the age of presentation of the patients or in the symptoms present at diagnosis. In addition, cortisol values were comparable between these two subtypes. The only significant difference found between the two subtypes was a difference in the stature of these patients. All the patients presenting with above-average height standard deviation scores originated from the FGD ACTH receptor mutation–positive group. All measurements of growth hormone and insulinlike growth factor 1 (IGF-1) in these patients have been within the reference range to date.
• Type 2 FGD is associated with normal ACTH receptor.
  • As a result of studying many families with FGD, mutations within the coding region of the ACTH receptor are recognized to account for the underlying defect in only some cases. That raises the possibility that defects may be located in the regulatory region of the ACTH receptor or that defects exist in other genes such as cofactors of the ACTH receptor.
  • Mutations in genes responsible for zona fasciculata development may cause an identical clinical syndrome. In 1994, Weber and colleagues used a genomic marker (D18S40) closely linked to the ACTH receptor locus to confirm that some cases of FGD result from mutations in genes other than the ACTH receptor. No recombination was found between this marker (D18S40) and the ACTH receptor locus in 5 families with known ACTH mutations, supporting the fact that the D18S40 marker is linked closely to the ACTH receptor (logarithm of odds [lod] score = 4.8 at ø=0). No linkage was reported in an analysis with this same marker on a further analysis of 3 FGD families. The lack of linkage found in these 3 families with unknown gene mutations suggests that the disease is not caused by ACTH receptor mutations in these families. These studies support the hypothesis that FGD has more than a single genetic cause.
  • Because FGD now seems likely to be caused by multiple genetic defects, speculating on other possible candidate genes is possible.
  • A first class of gene defects to consider involves ACTH signal transduction. Because many of these genes are fundamental mediators of signal transduction in multiple tissues, a mutation that would cause a disorder restricted to only the adrenal gland seems unlikely.
  • A second class of genetic defects to consider includes gene-specific transcription factors or translational regulators affecting ACTH receptor expression. The further characterization of the ACTH-R promoter will eventually shed light on this possibility.
  • Finally, a third set of genes that could be responsible for FGD may include differentiation factors of the adrenal cortex. As yet, these factors are not well-characterized. However, one might postulate that failure of differentiation of fasciculata/reticularis cells only with normal glomerulosa cell differentiation may result in FGD.
  • Recently, Metherall and colleagues conducted a whole-genome scan by microarray analysis of single nucleotide polymorphisms (SNPs) using genomic DNA from parents, affected children, and unaffected siblings who manifest FGD type 2. A single candidate region emerged at chromosome 21q22.1, with a maximum lod score of 2.64. Further analysis identified a gene localized to this interval and expressed in the adrenal cortex. This gene encodes a 19-kDA single-transmembrane domain protein which has now been renamed the melanocortin 2 receptor accessory protein (MRAP).
  • Mutations in MRAP have now been identified in other families with FGD type 2. In vitro analysis further shows that MRAP and MC2R interact physically and are both colocalized in the endoplasmic reticulum and plasma membrane. Furthermore, MRAP is required for MC2R expression in certain cell types, suggesting that MRAP plays a role in processing, trafficking, or function of the MC2R.
• Type 3 FGD is associated with alacrima and achalasia (triple A syndrome or AS).
  • First described in 1978 by Allgrove, triple A syndrome is characterized by glucocorticoid deficiency, alacrima, achalasia of the cardia, and a wide spectrum of neurologic abnormalities. Alacrima is often manifest at birth, and patients may present with conjunctival injection and irritation. If alacrima is unrecognized, it may lead to severe keratopathy and corneal melting (dehydration-induced ulceration). Achalasia is a neuromuscular disorder of the esophagus resulting in elevated lower esophageal sphincter (LES) pressure, incomplete relaxation of the LES, and aperistalsis of the body of the esophagus. In childhood, achalasia may result in complications of severe lung disease, growth retardation, and respiratory death. However, not all children with achalasia have AS.
  • In one study, 1 out of the 35 children with achalasia had AS. Other neurologic abnormalities have been associated with AS, including distal motor and sensory neuropathy, dysarthria, ataxia, parkinsonian features, mild dementia, developmental delay, and optic atrophy.
  • AS is inherited as an autosomal recessive trait. Utilizing genetic linkage analysis, a causative locus was identified on chromosome 12q13. The triple A gene identified at this locus is called ALADIN and belongs to the WD-repeat family of regulatory proteins. The expression of this gene in neuroendocrine and neuronal structures suggests its role in normal development of the peripheral and central nervous systems.
  • For further details, see Allgrove (AAA) Syndrome.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Adrenoleukodystrophy
Autoimmune polyglandular syndrome type 1

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Baseline 9 am serum cortisol and ACTH stimulation test
• FGD is characterized in laboratory testing by a low or low-normal first morning serum cortisol and markedly elevated ACTH levels in contrast to a normal renin-aldosterone axis. Cortisol levels are typically in the range of less than 10 to 75 ng/mL (reference range is 50-150 ng/mL), while ACTH values are typically in the range of greater than 300 to 7000 ng/L (reference range is 10-80 ng/L).
• The cortisol levels are unresponsive to exogenous ACTH stimulation (Cortrosyn stimulation test).
• Plasma tests: Plasma results show normal very long chain fatty acids (VLCFAs), thus ruling out adrenoleukodystrophy.
• Serum tests
• • Test sodium, potassium, aldosterone, and renin levels.
  • Supine and standing renin and aldosterone concentrations are within the reference range in FGD, demonstrating normal variability in response to salt restriction.
  • The electrolyte abnormalities, including hyponatremia and hyperkalemia, are not usually present. These abnormalities typically characterize other adrenal diseases.
  • FGD is often characterized by low levels of serum dihydroxyepiandrosterone sulphate (DHEAS).
  • Consider a diagnosis of congenital adrenal hyperplasia (CAH) in any infant with signs of glucocorticoid deficiency. The most common form, 21-hydroxylase deficiency, can be ruled out by reference range 17-OH progesterone levels. Virilized genitalia may be present in some female infants with CAH, although this does not occur in FGD.
• Steroid deficiencies
• • Patients with adrenoleukodystrophy also present with multiple adrenal hormone deficiencies.
  • VLCFAs are elevated in adrenoleukodystrophy.
• Antiadrenal antibodies: Antiadrenal antibodies can usually be detected in patients with Addison disease (AD), an autoimmune form of adrenal insufficiency, and may be useful in ruling out AD as a diagnostic possibility.
• Ophthalmologic examination: Ophthalmologic examination is indicated when the diagnosis of AS is being considered. AS is characterized by glucocorticoid deficiency, alacrima (absence of tears), achalasia of the cardia, and a wide spectrum of neurologic abnormalities.
• • Alacrima is determined by a Schirmer test that provides a semiquantitative measure of tearing. In this test, a standardized test strip is placed in the conjunctival sac and wetting of the strip over a 5-minutes interval is determined. Alacrima is defined as less than 10 mm of wetting.
  • Slit lamp examination and fluorescein staining may be helpful in illustrating corneal pathology secondary to decreased tear production.
  • Should these tests indicate a diagnostic possibility of AS, other investigations are warranted and include barium esophagraphy, esophageal manometry, endoscopy, neurologic evaluation, brainstem auditory evoked response (BAER), and autonomic testing.
  • These tests are outlined in Allgrove (AAA) Syndrome.
• Hypoglycemia tests
• • Obtain a complete blood cell count, serum glucose level, and a comprehensive metabolic panel with and without CSF studies for protein, glucose, cell count, and culture.
  • In any patient presenting with seizures, ruling out hypoglycemia as the inciting cause is imperative. In some cases, a lumbar puncture may also be indicated. These investigations are not specific in making a diagnosis of FGD, but they can provide important clues to the etiology of the seizure.
• Pituitary hormone evaluation: Hypopituitarism can also lead to adrenal insufficiency. If ACTH levels are low in the setting of adrenal insufficiency, clinically evaluate other pituitary hormones with specific laboratory testing.

Histologic Findings

Histologic examinations of the adrenal glands of children with FGD have characteristically demonstrated a well-preserved zona glomerulosa but a markedly atrophic zona fasciculata and zona reticularis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Hypoglycemia
  • Immediate diagnosis and treatment of hypoglycemia is essential. Children with seizures or prolonged recurrent episodes of hypoglycemia are more likely to experience brain damage.
  • When the cause of hypoglycemia is unknown, start an intravenous line and collect 5-10 mL of blood in a heparinized tube.
  • When hypoglycemia is suspected, start treatment without waiting for the results of the blood or plasma glucose tests.
  • In neonates, administer intravenous 10% dextrose 2.5 mL/kg as a rapid IV bolus followed by a continuous IV infusion of 3-5 mL/kg/h (5-8 mg glucose per kg/min).
  • In children, administer 50% dextrose diluted to 25% in water at an initial dose of 1 mL/kg IV followed by an IV infusion of 10% dextrose at 2-3 mL/kg/h (3-5 mg glucose per kg/min).
  • If any difficulty in establishing IV access occurs, administer glucagon 0.03 mg/kg IM (not to exceed 1 mg). Glucagon therapy has a transient effect and must be followed by an intravenous dextrose infusion as above.
• Glucocorticoid deficiency
• • Treatment for FGD includes the replacement of glucocorticoids in order to avoid not only adrenal crisis but to allow normal growth in these children. Glucocorticoid replacement is achieved with hydrocortisone 12-16 mg/m²/24h PO divided into 3 doses. An equivalent dose of prednisone or dexamethasone may be administered to adults and the occasional patient who has difficulty with compliance. However, the potential for growth suppression with either prednisone or dexamethasone is greater than hydrocortisone, and, therefore, these agents should be used with caution. Administer the lowest dosage necessary to prevent symptoms of adrenal failure in order to avoid suppression of growth.
  • The adequacy of a treatment regimen may be clinically judged by noting decreased hyperpigmentation, absence of weakness, and normalization of blood sugar values. Adequate glucocorticoid replacement should not cause any adverse effects.
  • Overtreatment may result in poor linear growth, hypertension, edema, euphoria, insomnia, headache, steroid-induced acne, hyperglycemia, Cushing syndrome, peptic ulcers, and cataract formation.
  • Intercurrent illness or stress necessitates a readjustment of glucocorticoid dosage. For minor stress, such as a fever or upper respiratory tract infection, double or triple the glucocorticoid dosage until the illness has resolved. If the patient is ill with vomiting or diarrhea and cannot tolerate oral fluids and medication, hospitalization may be necessary. In individuals with severe stress, such as surgery or serious illness, the daily requirement for parenteral hydrocortisone is 40-100 mg/m²/24h (approximately 3-10 times the maintenance dose) in 3-4 divided doses.
  • With a major decline in the clinical condition of the patient (eg, development of hypotension, fever, decreasing mental status, acute intercurrent illness), promptly initiate treatment for possible adrenal crisis even before the diagnosis is confirmed.
  • The treatment of an adrenal crisis includes fluid, dextrose, and glucocorticoid replacement in order to restore fluid volume and prevent hypoglycemia and death. Adequately treat any precipitating event such as an infection.
  • Fluids administered (eg, 0.9% NaCl with 5% dextrose) should be administered at 1.5-2 times the maintenance rate (2250-3000 mL/m²/d). If the patient presents in shock, administer 0.9% NaCl (10-20 mL/kg) during the first hour of treatment. In addition, cortisol as a soluble ester (21-hemisuccinate or 21-phosphate) must be administered as an immediate IV bolus and every 6 hours (25 mg for infants; 50 mg for small children; 100-150 mg for larger children or adolescents).
  • Once the clinical condition improves, gradually taper down the steroid dosage by one third every day until the patient is back to maintenance dose.
  • All patients with FGD on replacement glucocorticoid therapy must be instructed on appropriate sick day management to adjust steroid dosage and taught how to administer parenteral hydrocortisone at home in cases of severe stress or when oral intake is compromised, and they should be provided a 24-hour physician contact number in case of emergency.
  • All patients with FGD should 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 if a visit to the emergency department becomes necessary.
• Achalasia and alacrima
• • In those cases of FGD associated with achalasia and alacrima, these conditions should be monitored and managed carefully.
  • See Allgrove (AAA) Syndrome for full details.

Surgical Care

Those cases of FGD associated with achalasia and AS require surgical intervention (see Allgrove (AAA) Syndrome).

Consultations

• Geneticist
  • Counsel patients with FGD and their families regarding the inheritance pattern of FGD, which is autosomal recessive.
  • Observe siblings and other close relatives for potential symptoms of FGD.
  • Screen family members with a Cortrosyn stimulation test to exclude this condition, which is potentially fatal if unrecognized and untreated.
  • Some cases of FGD have been associated with mutations in the MC2-R gene. Confirming this diagnosis by DNA analysis may be possible in some cases.
• Other consultations: In individuals with FGD associated with alacrima, achalasia, or AS, other consultations are warranted, including an ophthalmologist to assess alacrima and a neurologist to assess development and to address the neurologic manifestations of AS (see Allgrove (AAA) Syndrome).

Diet

In individuals with FGD, the renin-aldosterone axis is normal and no dietary manipulation, such as salt replacement, is needed.

Activity

No restriction of physical activity is necessary in adequately treated cases of FGD. In a small subset of patients with AS and autonomic disturbance, some activities may need to be limited because of problems of recurring postural hypotension and decreased heart rate variability.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Glucocorticoids

These are used for physiologic replacement of glucocorticoid deficiency. They elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Glucocorticoid replacement: Focus FGD inpatient care on providing adequate replacement of glucocorticoids. Administer an initial maintenance dose of 12-16 mg/m²/d of oral hydrocortisone divided in 3 doses.

Further Outpatient Care

• Glucocorticoid replacement
• • 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.

In/Out Patient Meds

• Glucocorticoids are previously discussed.

Complications

• FGD, if left untreated or inadequately treated, may lead to death from adrenal crisis or to severe mental disability as a result of recurrent hypoglycemia. Alternatively, overtreatment with glucocorticoids may result in growth failure and features of Cushing syndrome, which include weight gain, hypertension, obesity, skin changes, osteoporosis, glucose intolerance, and muscle weakness.

Prognosis

• 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.

Patient Education

• Glucocorticoid therapy
• • 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.
• Genetics
• • 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize hypoglycemia and provide appropriate treatment
• Failure to provide appropriate treatment and to reassess glucocorticoid deficiency: Glucocorticoid replacement is needed for prevention of adrenal crisis and to ensure normal growth in these children. The lowest dosage sufficient to control symptoms of adrenal insufficiency should be administered to permit normal growth in these patients. The adequacy of treatment should be judged clinically by documenting reduced hyperpigmentation, absence of hypoglycemia and weakness, and normal growth at frequent follow-up visits.
• Failure to educate the family and patients: Appropriate education of the family and patient(s) regarding readjustment of glucocorticoid dosage during intercurrent illness or stress is mandatory and should be documented in the medical record.

Special Concerns

• Pregnancy
• • Counsel patients regarding maintaining adequate caloric intake throughout pregnancy to prevent hypoglycemia. Adequate glucocorticoid replacement must be ensured throughout pregnancy. Counsel patients with FGD regarding the inheritance pattern of FGD, which is a rare autosomal recessive disorder. Thus, the chances of having a child similarly affected with FGD would be negligible unless parents were consanguineous.
  • In the newborn, symptoms may be subtle and a high degree of suspicion is needed. In an individual whose hypoglycemia is indeed documented, an appropriate endocrine workup must be performed, including an evaluation of adrenal status. While awaiting diagnostic studies, prompt treatment of hypoglycemia is mandatory to prevent irreversible neurologic damage. Consider hospital admission for investigation and treatment in any child presenting with hypoglycemia of unknown etiology.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Allgrove J, Clayden GS, Grant DB, Macaulay JC. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. Jun 17 1978;1(8077):1284-6. [Medline].
• Allolio B, Reincke M. Adrenocorticotropin receptor and adrenal disorders. Horm Res. 1997;47(4-6):273-8. [Medline].
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Article Last Updated: Jun 26, 2006