Familial glucocorticoid deficiency type 1 (FGD1) is a rare autosomal recessive disease resulting from resistance to the action of adrenocorticotropin (ACTH) on the adrenal cortex. The impairment of the adrenal response to ACTH leads to deficient secretion of cortisol and adrenal C19 androgen precursors. By contrast, mineralocorticoid production, regulated by the renin-angiotensin system, is normal. All the signs and symptoms seen in FGD1 patients are the result of either low levels of plasma cortisol or elevated ACTH levels. They are usually observed during the first year of life and can also appear during infancy or later childhood. These symptoms include, prolonged jaundice, hypoglycemia or hypoglycemic convulsions, failure to thrive, skin hyperpigmentation and sepsis. The symptoms may be lethal in some children. Tall stature has also been reported in a subset of individuals with FGD1, especially prior to glucocorticoid treatment, but the pathogenic basis of this feature is not clear.
Early intervention and constant care are crucial for affected individuals. Treatment consists of replacement therapy with oral hydrocortisone.
Inactivating mutations in the ACTH receptor (melanocortin-2-receptor, MC2R) are well described and account for approximately 25% of cases of FGD1. MC2R encodes a member of the five-member G-protein associated melanocortin receptor family. The interaction of ACTH with its receptor (MC2-R) on the adrenal cortex stimulates glucocorticoid production. Mutations in the MC2R gene affect this interaction, leading to the severe deficiency of glucocorticoids. The combination of low cortisol levels paired with extremely high plasma ACTH levels represent the hallmark features in the pathogenesis of FGD1.
Lin et al. (2007) described a highly consanguineous kindred from Qatar with salt-losing adrenal hypoplasia. Four of 12 children born in three nuclear families had been diagnosed with the condition. The proband (46,XY) presented at 60 days of age with pigmentation and a hypoglycemic convulsion. He had an elevated plasma renin activity (PRA), his aldosterone was inappropriately low, and he had mild hyponatremia/hyperkalemia. Thus, he was diagnosed as having adrenal hypoplasia and treated with hydrocortisone and fludrocortisone. The second child (46,XX) presented at 4 days of age with a hypoglycemic convulsion. She was hyperpigmented and found to be profoundly hypocortisolemic (<14 nmol/l), and was started on hydrocortisone alone. Given the emerging family history, two further children were diagnosed as likely affected on the first day of life on account of marked hyperpigmentation and hypoglycemia, and hydrocortisone was started almost immediately. One child was also commenced on fludrocortisone as it was believed this family had an autosomal recessive form of adrenal hypoplasia, and that treatment should be started before the onset of a salt-losing crisis. Thus, in all three cases, treatment was commenced within the first four days of life before disturbances in PRA or salt balance would likely have become manifest. At molecular level, Lin et al. (2007) identified a novel homozygous three-nucleotide deletion (579-581delTGT leading to a stop codon at 193 (Y193X)) in the MC2R gene in all affected individuals. Their parents are all carriers of this mutation and siblings are either heterozygous or normal. Lin et al. (2007) found that these affected children are likely representing the most severe end of the spectrum of familial glucocorticoid deficiency type 1 (PGD1). Lin et al. (2007) concluded that the diagnosis by MC2R mutations analysis should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis because these children may have been misdiagnosed as having salt-losing adrenal hypoplasia.
Chan et al. (2009) described a Saudi Arabian child, born to first cousin consanguineous parents, and diagnosed with FGD. The child presented with hypoglycemia, apnea, and cyanosis within the first day of his life. At three months of age, he presented with recurrent cough and shortness of breath. Five months later, he presented with collapse, bradycardia, seizures, and hypotension, which required resuscitation. Analysis revealed hypoglycemia and grossly elevated plasma ACTH levels, indicating adrenal insufficiency. He was treated with hydrocortisone replacement. However, he continued to suffer seizures and went on to develop spastic quadriplegia, visual impairment, and neurosensory deafness. Upon examination at 17 months, his height and weight were found to be between the 10th and 25th centile, while his OFC was below the 0.4th centile. He was darkly pigmented, with extremely high plasma ACTH level. He was diagnosed with FGD. Mutation analysis revealed two homozygous mutations in the MC2R genes; one of them activating, while the other was inactivating.