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Disease Profile

Familial glucocorticoid deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

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ICD-10

E27.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

ACTH resistance

Categories

Congenital and Genetic Diseases; Endocrine Diseases

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 361

Definition
Familial glucocorticoid deficiency (FGD) is a group of primary adrenal insufficiencies characterized clinically by neonatal hyperpigmentation, hypoglycemia, failure to thrive, and recurrent infections, and biochemically by glucocorticoid deficiency without mineralocorticoid deficiency.

Epidemiology
The prevalence is unknown. In Ireland there is a prevalence of around 1/200,000, but this is likely to be skewed by a high prevalence in the Irish Traveler sub-population.

Clinical description
FGD usually presents in infancy or early childhood with hyperpigmentation of the skin and gums (present at birth or that develops over time), hypoglycemic seizures and failure to thrive. Recurrent infections are also a common finding (and may be the presenting sign in older children). Weakness, fatigue, weight loss, anorexia, vomiting, flank or abdominal pain, constipation and diarrhea are additional symptoms seen in some patients due to hypocortisolemia. Hypoglycemic crises resulting in convulsions can lead to coma or death if untreated and recurrent hypolglycemia may lead to neurological sequelae (i.e. learning disabilities, intellectual deficit, and sometimes severe, neuronal damage leading to major sensory and motor defects such as quadriplegia). Tall stature has been reported in some patients with FGD, typically those with MC2R gene defects. MRAP defects have been associated with a more severe disease and an earlier age of onset while a milder phenotype is seen in those with defects in the MCM4 gene (Irish Traveler FGD).

Etiology
FGD is due, in most cases, to defects in the adrenocorticotropin (ACTH) receptor, or its signaling pathway, resulting in a failure of the cells of zona fasciculata in the adrenal cortex to respond appropriately to adrenocorticotrophic hormone (ACTH), leading to a glucocorticoid deficiency. These defects are most commonly caused by mutations in MC2R (18p11.2), accounting for 25% of cases, and MRAP (21q22.1), accounting for 20% of cases. Other mutations reported in patients with FGD include MCM4 (8q12-q13), probably uniquely in the Irish Traveler population; NNT (5p12), accounting for around 15% of cases; and TXNRD2 (22q11.21). Certain partially inactivating mutations of STAR (8p11.2) or CYP11A1 (15q23-q24) can cause a phenotype that masquerades as FGD.

Diagnostic methods
Diagnosis is based on clinical and laboratory findings. Patients have high plasma ACTH and low serum morning cortisol levels that do not respond to exogenous ACTH stimulation. Mineralocorticoid function is normal. Molecular genetic testing revealing a mutation in one of the disease causing genes confirms diagnosis of FGD.

Differential diagnosis
The main differential diagnosis of FGD is Addison's disease (usually of autoimmune origin), in which case a mineralocorticoid deficiency is present. Other differential diagnoses include triple A syndrome, congenital adrenal hyperplasia and other acquired causes of primary adrenal insufficiency (see these terms).

Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation but is rarely performed.

Genetic counseling
FDG is inherited in an autosomal recessive manner. Genetic counseling is possible.

Management and treatment
Treatment consists of a replacement therapy with oral hydrocortisone. A dosage of 10-12 mg/m2/day (usually divided into three doses) normalizes cortisol and reduces, but rarely normalizes, ACTH. Dose modification is necessary during stresses such as surgery or intercurrent illness, and patients should have injectable hydrocortisone available for emergencies and carry a medical alert type bracelet or card. Prompt and adequate treatment of a hypoglycemic crisis is essential. Treatment is life-long.

Prognosis
The prognosis is good for patients who are diagnosed and treated early. Only when left untreated is FGD a disease with high morbidity (neurological sequelae) and mortality.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
100% of people have these symptoms
Decreased circulating cortisol level
Low blood cortisol level
0008163
80%-99% of people have these symptoms
Abnormality of circulating adrenocorticotropin level
0011043
Decreased circulating dehydroepiandrosterone level
0031214
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Generalized hyperpigmentation
0007440
Hypotension
Low blood pressure
0002615
Impaired cortisol response to insulin stimulation test
0031076
Ketotic hypoglycemia
0012734
30%-79% of people have these symptoms
Anorexia
0002039
Chronic fatigue
Chronic extreme exhaustion
0012432
Constipation
0002019
Diarrhea
Watery stool
0002014
Episodic abdominal pain
0002574
Hyperkalemia
Elevated serum potassium levels
0002153
Hypernatriuria
0012605
Hypoglycemic seizures
0002173
Hyponatremia
Low blood sodium levels
0002902
Renal salt wasting
Loss of salt in urine
0000127
Vomiting
Throwing up
0002013
Weight loss
0001824
5%-29% of people have these symptoms
Cryptorchidism
Undescended testes
Undescended testis

[ more ]

0000028
Decreased circulating aldosterone level
Low blood aldosterone level
0004319
Precocious puberty
Early onset of puberty
Early puberty

[ more ]

0000826
Tall stature
Increased body height
0000098
Testicular adrenal rest tumor
0025451
1%-4% of people have these symptoms
Azoospermia
Absent sperm in semen
0000027
Congenital hypothyroidism
Underactive thyroid gland from birth
0000851
Hypertrophic cardiomyopathy
Enlarged and thickened heart muscle
0001639
Hypoglycemic coma
Coma caused by low blood sugar
0001325
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Leydig cell neoplasia
0100618
Recurrent urinary tract infections
Frequent urinary tract infections
Repeated bladder infections
Repeated urinary tract infections
Urinary tract infections
Urinary tract infections, recurrent

[ more ]

0000010
Tetraplegia
Paralysis of all four limbs
0002445
Percent of people who have these symptoms is not available through HPO
Accelerated skeletal maturation
Advanced bone age
Early bone maturation

[ more ]

0005616
Autosomal recessive inheritance
0000007
Coma
0001259
Hyperpigmentation of the skin
Patchy darkened skin
0000953
Increased circulating ACTH level
High blood corticotropin levels
0003154
Recurrent hypoglycemia
Recurrent low blood sugar levels
0001988
Recurrent infections
Frequent infections
Frequent, severe infections
Increased frequency of infection
infections, recurrent
Predisposition to infections
Susceptibility to infection

[ more ]

0002719
Seizure
0001250

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Familial glucocorticoid deficiency. This website is maintained by the National Library of Medicine.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.