Familial glucocorticoid deficiency is a condition that occurs when the adrenal glands, which are hormone-producing glands located on top of each kidney, do not produce certain hormones called glucocorticoids. These hormones, which include cortisol and corticosterone, aid in immune system function, play a role in maintaining normal blood sugar (glucose) levels, help trigger nerve cell signaling in the brain, and serve many other purposes in the body.

A shortage of adrenal hormones (adrenal insufficiency) causes the signs and symptoms of familial glucocorticoid deficiency. These signs and symptoms often begin in infancy or early childhood. Most affected children first develop low blood glucose (hypoglycemia). These hypoglycemic children can fail to grow and gain weight at the expected rate (failure to thrive). If left untreated, hypoglycemia can lead to seizures, learning difficulties, and other neurological problems. Hypoglycemia that is left untreated for prolonged periods can lead to neurological damage and death. Other features of familial glucocorticoid deficiency can include recurrent infections and skin coloring darker than that of other family members (hyperpigmentation).

There are multiple types of familial glucocorticoid deficiency, which are distinguished by their genetic cause.

Mutations in the MC2R, MRAP, and NNT genes account for the majority of cases of familial glucocorticoid deficiency; mutations in other genes, some known and some unidentified, can also cause this condition.

The MC2R gene provides instructions for making a protein called adrenocorticotropic hormone (ACTH) receptor, which is found primarily in the adrenal glands. The protein produced from the MRAP gene transports the ACTH receptor from the interior of the cell to the cell membrane. When the ACTH receptor is embedded within the cell membrane, it is turned on (activated) by the MRAP protein. Activated ACTH receptor can then attach (bind) to ACTH, and this binding triggers the adrenal glands to produce glucocorticoids. MC2R gene mutations lead to the production of a receptor that cannot be transported to the cell membrane or, if it does get to the cell membrane, cannot bind to ACTH. MRAP gene mutations impair the transport of the ACTH receptor to the cell membrane. Without the binding of the ACTH receptor to its hormone, there is no signal to trigger the adrenal glands to produce glucocorticoids.

The NNT gene provides instructions for making an enzyme called nicotinamide nucleotide transhydrogenase. This enzyme is found embedded in the inner membrane of structures called mitochondria, which are the energy-producing centers of cells. This enzyme helps produce a substance called NADPH, which is involved in removing potentially toxic molecules called reactive oxygen species that can damage DNA, proteins, and cell membranes. NNT gene mutations impair the enzyme's ability to produce NADPH, leading to an increase in reactive oxygen species in adrenal gland tissues. Over time, these toxic molecules can impair the function of adrenal gland cells and lead to their death (apoptosis), diminishing the production of glucocorticoids.

Normal Function

The MC2R gene provides instructions for making a protein called adrenocorticotropic hormone (ACTH) receptor. This protein is found primarily in the adrenal glands, which are hormone-producing glands located on top of each kidney.

The ACTH receptor is embedded in the membrane of cells where it attaches (binds) to ACTH. ACTH is a hormone that is released by the pituitary gland, located at the base of the brain. The binding of ACTH to its receptor triggers the adrenal glands to produce a group of hormones called glucocorticoids. These hormones, which include cortisol and corticosterone, aid in immune system function, play a role in maintaining normal blood sugar (glucose) levels, help trigger nerve cell signaling in the brain, and serve many other purposes in the body.

The ACTH receptor also likely plays a role in the development of the adrenal glands before birth.

Health Conditions Related to Genetic Changes

Familial glucocorticoid deficiency

More than 40 mutations in the MC2R gene have been found to cause familial glucocorticoid deficiency. This condition is characterized by potentially life-threatening low blood glucose (hypoglycemia), recurrent infections, and skin coloring darker than that of other family members (hyperpigmentation). MC2R gene mutations account for approximately 25 percent of cases of this condition. Most of these mutations change single protein building blocks (amino acids) in the ACTH receptor. As a result, the receptor cannot be transported to the cell membrane or bind to ACTH. Without the binding of the ACTH receptor to its hormone, there is no signal to trigger the adrenal glands to produce glucocorticoids. A shortage of these hormones impairs blood glucose regulation, immune system function, and other cellular functions, leading to the signs and symptoms of familial glucocorticoid deficiency.

Primary macronodular adrenal hyperplasia

MedlinePlus Genetics provides information about Primary macronodular adrenal hyperplasia

Other Names for This Gene

• ACTH receptor
• ACTHR
• ACTHR_HUMAN
• adrenocorticotropic hormone receptor
• adrenocorticotropin receptor
• corticotropin receptor
• MC2 receptor
• melanocortin 2 receptor (adrenocorticotropic hormone)

Genomic Location

Normal Function

The MRAP gene provides instructions for making a protein called melanocortin-2 receptor accessory protein (MRAP). This protein transports another protein, called the melanocortin-2 receptor (or more commonly the adrenocorticotropic hormone [ACTH] receptor), from the interior of the cell to the cell surface. Specifically, the MRAP protein transports the ACTH receptor from a cell structure called the endoplasmic reticulum (ER), which is involved in protein processing and transport, to the cell membrane so that the receptor can function. The MRAP protein is also needed to turn on (activate) the ACTH receptor.

At the cell membrane, the activated ACTH receptor attaches (binds) to ACTH, which triggers the production of a group of hormones called glucocorticoids. These hormones, which include cortisol and corticosterone, aid in immune system function, play a role in maintaining normal blood sugar (glucose) levels, help trigger nerve cell signaling in the brain, and serve many other purposes in the body.

Health Conditions Related to Genetic Changes

Familial glucocorticoid deficiency

At least 13 mutations in the MRAP gene have been found to cause familial glucocorticoid deficiency. This condition is characterized by potentially life-threatening low blood glucose (hypoglycemia), recurrent infections, and skin coloring darker than that of other family members (hyperpigmentation). MRAP gene mutations account for approximately 20 percent of cases of this condition. Most of these mutations lead to the production of a protein that cannot interact with the ACTH receptor and so is unable to transport it out of the ER to the cell membrane. As a result, the ACTH receptor is not at the cell surface where it is needed to bind to ACTH. Without the binding of the ACTH receptor to its hormone, there is no signal to trigger the adrenal glands to produce glucocorticoids. A shortage of these hormones impairs blood glucose regulation, immune system function, and other cellular functions, leading to the signs and symptoms of familial glucocorticoid deficiency.

Other Names for This Gene

• B27
• C21orf61
• FALP
• fat cell-specific low molecular weight protein
• fat tissue-specific low MW protein
• GCCD2
• melanocortin-2 receptor accessory protein
• MRAP_HUMAN

Genomic Location

Normal Function

The NNT gene provides instructions for making an enzyme called nicotinamide nucleotide transhydrogenase. This enzyme is found embedded in the inner membrane of structures called mitochondria, which are the energy-producing centers of cells. This enzyme helps produce a substance called NADPH, which is involved in removing potentially toxic molecules called reactive oxygen species that can damage DNA, proteins, and cell membranes. Nicotinamide nucleotide transhydrogenase is found throughout the body, but it is particularly abundant in the hormone-producing adrenal and thyroid glands, heart, kidneys, and fatty tissue.

Health Conditions Related to Genetic Changes

Familial glucocorticoid deficiency

At least 25 mutations in the NNT gene have been found to cause familial glucocorticoid deficiency. This condition is characterized by potentially life-threatening low blood glucose (hypoglycemia), recurrent infections, and skin coloring darker than that of other family members (hyperpigmentation). The features of familial glucocorticoid deficiency are caused by an inability of the adrenal glands to produce a group of hormones called glucocorticoids, which play a role in many functions in the body. NNT gene mutations account for approximately 10 percent of cases of this condition.

Most of the mutations that cause familial glucocorticoid deficiency change single protein building blocks (amino acids) in the nicotinamide nucleotide transhydrogenase enzyme. These mutations impair the enzyme's ability to produce NADPH, leading to an increase in reactive oxygen species in the adrenal glands. Over time, these toxic molecules can impair the function of adrenal gland cells and lead to the death of those cells (apoptosis), diminishing the production of glucocorticoids. A shortage of these hormones impairs blood glucose regulation, immune system function, and other cellular functions, leading to the signs and symptoms of familial glucocorticoid deficiency.

It is unclear why NNT gene mutations seem to only affect adrenal gland function. Researchers suggest that individuals with familial glucocorticoid deficiency caused by NNT gene mutations could develop problems in other tissues over time as reactive oxygen species exert their harmful effects.

Other Names for This Gene

• energy-linked transhydrogenase
• GCCD4
• NAD(P) transhydrogenase
• NAD(P) transhydrogenase, mitochondrial
• NADP transhydrogenase
• NADPH transferase
• nicotinamide adenine dinucleotide phosphate + transhydrogenase
• NNTM_HUMAN
• pyridine nucleotide transhydrogenase

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The prevalence of familial glucocorticoid deficiency is unknown.