What Is Familial Glucocorticoid Deficiency?
Familial glucocorticoid deficiency is a rare genetic disorder yet a serious condition. In this condition, the adrenal glands, hormone-producing glands situated on the uppermost part of each kidney, fail to produce the required amounts of glucocorticoids.
These hormones play an important role in immune system function, help trigger nerve cell signaling in the brain, maintain normal blood sugar levels, and serve many other bodily purposes. A deficiency in adrenal hormones can lead to adrenal insufficiency, giving rise to the signs and symptoms of familial glucocorticoid deficiency. The early onset and chronic nature of this condition make it a life-long battle for affected individuals.
The symptoms of familial glucocorticoid deficiency often begin in early childhood. Generally, the first sign a child with this condition will develop is low blood glucose, known as hypoglycemia. The affected child will not gain the same weight as another normal child. If proper treatment is not provided, this condition can lead to severe other complications such as cognitive inabilities, seizures, and other neurological problems, and even death.
Other symptoms of familial glucocorticoid deficiency can include hyperpigmentation (dark skin coloring) and recurrent infections. Depending on the affected gene, the type and characteristics of the condition vary. Familial glucocorticoid deficiency is a rare condition, affecting less than 1 in 100,000 people worldwide, thus making it an unknown condition to the common population.
What Are the Causes of Familial Glucocorticoid Deficiency?
Familial glucocorticoid deficiency is mainly caused by changes occurring in the MC2R (melanocortin 2 receptor), MRAP (melanocortin 2 receptor accessory protein), and NNT (nicotinamide nucleotide transhydrogenase). However, changes occurring in other genes, some known and some unidentified, can also be responsible for causing this condition.
The MC2R gene directs the production of a protein found in the adrenal gland called adrenocorticotropic hormone (ACTH) receptor. A protein made from the MRAP gene is responsible for moving the ACTH receptor from the inside of the cell to the outer layer. When the ACTH receptor is attached to the outer layer of the cell, it is activated by the MRAP protein. When activated, the ACTH receptor binds to adrenocorticotropic hormone, triggering the adrenal glands to generate glucocorticoids. When any changes occur to the MC2R gene, it can cause the receptor to cannot be moved to the cell membrane or if the ACTH receptor reaches the outer layer of the cell, it may not be able to attach to the adrenocorticotropic hormone. Changes occurring in the MRAP gene mutations can damage the transportation of the ACTH receptor to the outermost cell layer. If the ACTH receptor binds to the adrenocorticotropic hormone, no signal for glucocorticoid production will be made to activate the adrenal glands.
The NNT gene provides directions for the production of an enzyme called nicotinamide nucleotide transhydrogenase, which is attached to the inner membrane of energy-producing centers of cells called mitochondria. This enzyme produces NADPH (nicotinamide adenine dinucleotide phosphate hydrogen). Its role is to remove toxic molecules called reactive oxygen species. These molecules can damage DNA (deoxyribonucleic acid), proteins, and cell membranes. Any abnormal changes to this gene can damage the enzyme's ability to produce NADPH, causing more reactive oxygen species production in adrenal gland tissues. These toxic molecules can slowly damage the function of adrenal gland cells, leading to adrenal gland cell death, which can halt the production of glucocorticoids.
What Are the Symptoms of Familial Glucocorticoid Deficiency?
The symptoms of familial glucocorticoid deficiency vary among affected individuals, depending on the gene affected, the severity of cortisol deficiency, and the age of disease occurrence. Generally, the symptoms occur in early childhood, shortly after birth, but in some individuals, the signs and symptoms can occur in later childhood or adulthood. The more common signs and symptoms of this condition include the following:
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Hypoglycemia: Hypoglycemia means low blood sugar level. In maintaining normal blood sugar levels, cortisol plays a significant role. It stimulates the liver for the release of glucose. So, when there is less cortisol production, the affected individuals may experience hypoglycemia, leading to dizziness, weakness, and confusion.
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Failure to Thrive: The affected individuals will not gain the required weight and the growth will not be at the expected rate despite adequate nutrition. This can be due to the metabolic effects of cortisol deficiency on other body parts.
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Hypotension: Hypotension means low blood pressure. Cortisol regulates blood pressure by providing vasoconstrictive signals. When there is a reduction in cortisol, the affected individuals may experience hypotension, leading to symptoms such as fainting and lightheadedness.
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Fatigue: Cortisol also plays a key role in providing energy to the body, mainly during stressful periods. In the case of less cortisol production, the affected individuals may experience fatigue and weakness due to a lack of energy.
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Salt Craving: Cortisol also takes part in regulating electrolyte balance in the body, including maintaining sodium levels. The affected individual may develop salt cravings due to electrolyte balance disturbances caused by cortisol deficiency.
How Is Familial Glucocorticoid Deficiency Diagnosed?
Familial glucocorticoid deficiency is diagnosed based on an evaluation of various factors, such as patient symptoms, family history, laboratory investigations, and genetic testing. The evaluation starts with checking clinical symptoms and then using some tests to confirm the diagnosis.
Checking Blood Cortisol Levels - Checking the cortisol level in the blood is an important test in diagnosing this condition. It is generally performed by collecting blood samples in the morning when cortisol levels are highest. When the level of cortisol is lower-than-normal it indicates familial glucocorticoid deficiency.
ACTH Levels - Checking for ACTH levels is another key diagnostic evaluation. The role of ACTH is to stimulate the adrenal glands to produce cortisol. ACTH levels will be normally high due to the adrenal glands' lack of response.
What Is the Treatment for Familial Glucocorticoid Deficiency?
The main aim of the treatment is to replace low cortisol levels and improve the quality of life of the affected individuals. Cortisol replacement therapy is the main treatment for this condition and typically involves the administration of synthetic glucocorticoids. These medications include hydrocortisone, Fludrocortisone, Prednisone, and Dexamethasone.
Conclusion
Familial glucocorticoid deficiency is a rare genetic disorder leading to deficient cortisol production. This occurs due to changes in certain genes, mainly the MC2R, MRAP, and NNT genes. Despite its rarity, this condition can have significant implications for affected individuals, leading to serious symptoms such as hypoglycemia, hypotension, failure to thrive, and fatigue. Early diagnosis is crucial to avoid serious complications. Proper medical management can avoid complications and improve the quality of life of the affected individuals.
