Familial Glucocorticoid Deficiency Clinical Presentation

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 familial glucocorticoid deficiency (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, ^[6] mucous membranes, or both as a result of the action of adrenocorticotropic hormone (ACTH) on cutaneous melanocyte-stimulating hormone (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.

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. The most striking physical examination 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

Negative findings include the following:

• Absence of ambiguous genitalia or congenital adrenal hyperplasia

• Absence of cutaneous candidiasis or polyglandular autoimmune syndrome

• Absence of alacrima and achalasia or Allgrove syndrome (AS)

• Neurologic signs such as observed in AS, adrenoleukodystrophy, and Wolman disease

• Absence of adrenarche is a feature typical of children with FGD

An important distinction should be made between FGD and AS (AAA 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.

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 25-40% of these patients have mutations in the ACTH receptor gene. Dividing FGD into the following subcategories has been proposed: type 1 (with ACTH receptor mutations), type 2 (with mutations in the MC2 receptor accessory protein [MRAP] but a normal ACTH receptor), and type 3 and others. ^[7]

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]

Allgrove syndrome is 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 FG

Type 1 FGD is associated with ACTH receptor mutations (approximately 25-40% of FGD cases). Mountjoy et al reported the cloning of the human ACTH receptor in 1992. ^[8] 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 et al were 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. ^[9] 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.

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, C251F), structural disruption (S741, S120R, T159K, P273H, A126S), impairment of disulfide bonds (C251F, T254C), truncated receptor (1052delC, 1272delTA, R201X, 1347insA, L192fs, G217fs, F119fs), or loss of signal transduction (I44M, R128C, R146H, V142L, R137W, G116V) have been described. At least two compound heterozygous mutations in the ACTH receptor have now been reported (S74I and T159K; C21Y and R146H).

A poor correlation between severity of gene defect and clinical phenotype has been observed.

Even with identical mutations of the human MC2R, considerable variation in clinical phenotype is observed. 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 insulin-like growth factor 1 (IGF-1) in these patients have been within the reference range to date.

Type 2 FGD is due to mutations in MRAP (approximately 15-20% of FGD cases). 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 raised the possibility that defects may be located in the regulatory region of the ACTH receptor or that defects occur in other genes, such as cofactors of the ACTH receptor.

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. ^{[10, 11]} A single candidate region emerged at chromosome 21q22.1, with a maximum load score of 2.64. Further analysis identified a gene localized to this interval and expressed in the adrenal cortex. This gene has now been renamed MRAP. The MRAP gene consists of 6 exons and alternative splicing of exon 5 or 6 gives rise to two protein isoforms of 19 kDa and 14.1 kDa, respectively.

Mutations in MRAP have now been identified in families with FGD type 2 (approximately 15-20% of FGD cases). At least 8 different mutations in MRAP have been documented in these patients.

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 and type 4 FGD are due to additional genes.

Other possible candidate genes might include the following:

• Genes involving 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.

• Gene-specific transcription factors or translational regulators affecting ACTH receptor expression. The further characterization of the ACTH receptor promoter will eventually shed light on this possibility.

• Genes coding for differentiation factors of the adrenal cortex.

• Linkage of genes on chromosome 8q to FGD has been described, implicating another gene in this disorder.

AS or AAA syndrome is associated with alacrima and achalasia. First described in 1978 by Allgrove et al, ^[12] AAA 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. ^[13] Other neurologic abnormalities have been associated with AS, including distal motor and sensory neuropathy, dysarthria, ataxia, Parkinsonian disease features, mild dementia, developmental delay, and optic atrophy.

AS is inherited as an autosomal recessive trait. Using genetic linkage analysis, a causative locus was identified on chromosome 12q13. The AAA 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 nervous system and the CNS.

For further details, see Allgrove (AAA) Syndrome.