5.10 Familial glucocorticoid deficiency

Familial glucocorticoid deficiency (FGD), also known as isolated glucocorticoid deficiency or hereditary unresponsiveness to ACTH, is a rare, genetically heterogeneous autosomal recessive disorder. It is characterized by resistance of the adrenal cortex to ACTH, resulting in adrenal failure with isolated glucocorticoid deficiency. Mineralocorticoid production by the adrenal gland remains near normal.

Patients with FGD usually present in early childhood with symptoms relating to cortisol deficiency, including hypoglycaemia, jaundice, recurrent infection, and failure to thrive. Patients are hyperpigmented due to grossly elevated ACTH levels.

FGD was first described in 1959 by Shepard et al. who reported two sisters as having Addison’s disease without hypoaldosteronism (1). Subsequently, a number of patients were reported with an inherited form of adrenal insufficiency also without hypoaldosteronism (2–5). In contrast to Addison’s disease (see Chapter 5.9), FGD is a genetic disorder resulting from mutations in genes encoding essential proteins involved in the early response to ACTH.

ACTH acts by binding to its specific cell-surface receptor, the ACTH receptor or melanocortin 2 receptor (MC2R) to induce adrenal steroidogenesis in all three zones of the adrenal cortex. The MC2R is the smallest member of the melanocortin receptor family, which includes five members, MC1R–MC5R. The melanocortin receptors are seven-transmembrane-domain G-protein-coupled receptors (GPCRs), which are involved in diverse functions including adrenal steroidogenesis, pigmentation, and weight and energy homoeostasis (6). The sole natural ligand for the MC2R is ACTH, in contrast to the other melanocortin receptors which show varying affinity to ACTH and α-, β-, and γ-melanocyte-stimulating hormone.

ACTH binding to the MC2R induces intracellular production of cAMP, one of the major actions of which is to stimulate cAMP-dependent protein kinase (protein kinase A). As a consequence of this stimulus, cholesterol ester is imported into the cell via the scavenger receptor B1 and hydrolysis of the ester by hormone-sensitive lipase occurs. Cholesterol is then taken up into the mitochondrion by a complex including the steroidogenic acute regulatory protein (StAR). Steroidogenic enzyme expression is stimulated via a number of mechanisms including activation of the cAMP response element binding protein, and ultimately results in an increased rate of cortisol synthesis.

FGD is characterized by ACTH resistance due to defects in the early events of ACTH action, leading to failure of cortisol synthesis. The resulting cortisol deficiency causes failure of the negative feedback loop to the pituitary and hypothalamus and grossly elevated ACTH levels. A number of autosomal recessive causes of FGD have been described and include FGD type 1, resulting from mutations in the MC2R, and FGD type 2, resulting from mutations in the melanocortin 2 receptor accessory protein (MRAP). A third subgroup of patients presenting with FGD have recently been shown to have mutations in StAR. A further 50% of patients with FGD have no identifiable mutation in MC2R, MRAP, or StAR.

The MC2R gene (OMIM 607397) was first cloned in 1992 by Mountjoy et al. (7). Researchers were then able to identify point mutations in the MC2R in patients with FGD (8, 9). To date, more than 30 mutations in MC2R have been reported, including both homozygous and compound heterozygous defects. These mutations are distributed throughout the coding region and account for 25% of cases of FGD. A diagram detailing the position of all the known mutations is shown in Fig. 5.10.1. Interestingly, the majority of these are missense mutations. Nonsense mutations are uncommon and are usually compounded with a missense mutation on the other allele. This has led to the suggestion that homozygous nonsense mutations either lead to reduced survival in utero or are associated with a different phenotype (11).

The identification of homozygous mutations in affected individuals is highly suggestive but not definitive evidence of a causative role in the disease. Functional analysis of MC2R mutations has been problematic in view of difficulties expressing the receptor in transfected cells (12). However, since the discovery of MRAP (see below) it has been possible to show convincingly that mutations are associated with loss of receptor function. In the majority of cases the mutation results in a failure of the receptor to traffic to the cell surface, probably because the mutation leads to defective folding of the receptor at the time of its synthesis (13). In a few cases, the mutant receptor is expressed at the cell surface, but the mutation interferes with ACTH binding or signal transduction (12). As is the case in many genetic disorders, there is a poor correlation between in vitro characterization of each mutant and clinical severity.

MC2R is unable to form a functional ACTH-responsive receptor in nonadrenal cell lines due to lack of cell surface localization. This observation led to the hypothesis that a specific accessory factor, present in adrenal cells types, is required to facilitate trafficking of MC2R to the cell surface. Genetic studies were carried out using homozygosity mapping in consanguineous families affected with FGD. This identified a locus on chromosome 21q22.1. Further studies identified mutations in a candidate gene in this region, which showed high adrenal expression, and this gene was subsequently named the MRAP (OMIM 609196) (14).

MRAP is a small, single-transmembrane-domain protein. Alternative splicing gives rise to two protein isoforms—MRAPα of 19 kDa and MRAPβ of 11.5 kDa. Functional analysis of MRAP revealed that it was essential for normal MC2R function (15). MRAP forms a unique antiparallel homodimer, which directly interacts with the MC2R at the endoplasmic reticulum and is required for correct folding or trafficking of the receptor to the cell surface. Current evidence suggests that MRAP is also required at the plasma membrane for ACTH binding and signal transduction (15). These possible modes of action are summarized in Fig. 5.10.2. To date, nine MRAP mutations causing FGD have been reported, all of which result in either an absent or severely truncated protein (Fig. 5.10.3).

It was reported in 2002 (16) that in a small subset of patients with FGD the disease mapped to a locus on chromosome 8. This gene has recently been identified as the STAR gene (OMIM 600617) (17). StAR is a mitochondrial phosphoprotein that mediates the acute response to steroidogenic stimuli by increasing cholesterol transport from the outer to the inner mitochondrial membrane. Defects in StAR usually result in congenital lipoid adrenal hyperplasia (OMIM 201710) (CLAH), a severe form of congenital adrenal hyperplasia. Review of history, examination, and biochemical data in the individuals diagnosed with FGD confirmed they had isolated glucocorticoid deficiency with normal or near normal renin and aldosterone levels. However, some patients did have mild reproductive anomalies, including hypospadias and cryptorchidism which had not previously been connected to their adrenal failure. The mutations found in StAR in FGD appear to lead to only partial impairment of the cholesterol uptake function of this protein. Thus classical CLAH is caused by mutations that completely abolish any functioning StAR while mutations that allow the protein to retain some function are associated with a nonclassical CLAH or FGD (17).

There remain many FGD patients (c. 50%) without mutations in MC2R, MRAP, or STAR and who show no linkage to these loci. Ongoing research in this area is aimed at identifying new genes responsible for FGD.

Patients with FGD usually present during the neonatal period or early childhood with symptoms related to cortisol deficiency and ACTH excess. The most common presenting feature is hypoglycaemia. This may be overlooked in the postnatal period as it may respond to routine treatment, e.g. decreasing the time interval between feeds, and transient asymptomatic hypoglycaemia in healthy infants is relatively common. Symptoms secondary to hypoglycaemia include jitteriness, tremors, hypotonia, lethargy, apnoea, poor feeding, and hypoglycaemic seizures. In a small number of patients, undiagnosed hypoglycaemia in infancy may have been sufficiently severe to cause serious long-term neurological sequelae.

Neonates may also present with jaundice, failure to thrive, and collapse. Transient neonatal hepatitis has been described in one case (18). There may be a history of unexplained neonatal or childhood death and as this is an autosomal recessive disorder there is frequently a history of consanguinity. Hyperpigmentation will usually develop by a few months of age due to the over-stimulation of MC1R by high circulating ACTH levels, and in some cases this is the presenting complaint. Older children may present with a variety of features including recurrent hypoglycaemia and lethargy, recurrent infections, and shock.

A feature that has been observed in patients with FGD type 1 is tall stature and discordant ossification (19, 20). The underlying mechanism is not clear and the limited data available suggests that the growth hormone–insulin-like growth factor (IGF-1) axis is normal. Hydrocortisone replacement appears to stop this excessive growth and bring the height back towards the midparental height (19). This suggests that either the cortisol deficiency itself or excessively high ACTH levels may have a causative role. Studies have shown a number of melanocortin receptors are expressed in bone and the cartilaginous growth plate and therefore ACTH at high concentrations may activate these receptors and stimulate growth (21). Alternatively, it has been reported that glucocorticoid inhibits the synthesis of IGF binding protein 5 (IGFBP-5) in the osteoblast (22). As bone growth is stimulated by IGFBP-5 it is conceivable that cortisol deficiency could result in a lack of inhibition and hence increased growth. Tall stature is not a recognized feature of FGD type 2 or other causes of adrenal failure, and it may be that the chronic exposure to high ACTH/low cortisol from birth is important. There is evidence that FGD type 2 presents at an earlier age than FGD type 1 (23) and thus the length of high ACTH/low cortisol exposure may be less.

ACTH is required for adrenal androgen synthesis and hence for adrenarche to occur normally in children. Children with FGD can have an absent adrenarche with delayed or absent pubic hair development associated with low or undetectable adrenal androgen levels. Normal pubertal development controlled by the hypothalamic–pituitary–gonadal axis is unaffected and fertility is normal.

The hallmark of FGD is low or undetectable cortisol paired with high ACTH levels and normal electrolytes, renin, and aldosterone levels. ACTH levels are often extremely high—levels of above 200 pmol/l (normal range <18 pmol/l) are commonly found. A short ACTH stimulation test showing an impaired cortisol response (<550 nmol/l) may be necessary to confirm adrenal insufficiency.

The most important feature to distinguish FGD from other causes of adrenal insufficiency is the absence of mineralocorticoid deficiency. However, this is not always simple to ascertain for various reasons. Firstly, at presentation, children with FGD may be hypovolaemic, or pyrexial, and are usually stressed. Alternatively, they may be relatively water overloaded as a result of intravenous fluid replacement and because of reduced free water clearance associated with glucocorticoid deficiency. ACTH is normally an effective stimulus to aldosterone production and this action will be deficient in FGD. As a result, FGD patients frequently present with minor abnormalities of the renin–aldosterone axis. Furthermore, there is evidence that those rare patients with nonsense mutations of the MC2R in whom no MC2R function is possible often do have mild hyperreninaemia and/or partial aldosterone deficiency (24, 25). These investigations should nevertheless distinguish those patients with adrenal failure from other causes in whom there is overt aldosterone deficiency and compensatory elevated renin values. Usually, after introduction of appropriate hydrocortisone replacement renin and aldosterone normalize and fludrocortisone replacement is not required.

MRI/CT scanning of the adrenal gland are not usually necessary to establish the diagnosis of FGD. In FGD the gland is usually small in size (26) in contrast to congenital adrenal hyperplasia or infiltrative disorders in which the adrenal is enlarged.

Some histopathology studies of adrenal glands are available from patients who died prior to diagnosis. These report the absence of fasciculata and/or reticularis cells with disorganization of granulosa cells (4, 5).

Alternative diagnoses and their most likely distinguishing clinical and biochemical features that should be considered in patients potentially presenting with FGD are:

The treatment is with physiological glucocorticoid replacement. This is usually given in the form of oral hydrocortisone 10–12 mg/m² per day in children and 20 mg/day in adults. The total daily dose is given in three divided doses throughout the day.

Glucocorticoid dosing must be increased during times of stress to two to three times the maintenance dose. It is vital to ensure the patient and their family have adequate education to understand when and how to increase hydrocortisone doses and emergency management with intramuscular hydrocortisone or hydrocortisone suppositories. Patients should also be given a Medic alert bracelet and ‘steroid card’.

Patients should be monitored for symptoms and signs of excessive glucocorticoid replacement and the dose titrated to prevent overtreatment. In individuals with adequate replacement therapy, ACTH levels often remain elevated and therefore cutaneous pigmentation can persist. Attempting to suppress the ACTH levels must be avoided as it will lead to over treatment, iatrogenic Cushing’s syndrome, and growth failure in children.

Primary adrenal failure in a child with a normal renin–angiotensin–aldosterone axis is highly suggestive of a diagnosis of FGD. Confirming the diagnosis with genetic analysis is now possible in approximately 50% of patients, this is important both in providing reassurance that mineralocorticoid replacement is unnecessary and for genetic counselling.