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Familial glucocorticoid deficiency
FGD is a genetic condition primarily affecting children, causing the body to be unable to make sufficient cortisol. This can lead to serious health issues if not diagnosed and managed early through lifelong hormone replacement therapy.
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Overview
Familial glucocorticoid deficiency (FGD) is a rare genetic disorder characterised by the adrenal glands' inability to produce cortisol, a vital steroid hormone. These glands, located on top of each kidney, usually increase cortisol production during stress, illness, or injury. In people with FGD, however, the adrenal glands do not respond correctly to the signals from the pituitary gland that tell them to make cortisol. This leads to a persistent shortage of cortisol in the body, which can have significant health consequences if left untreated [PMID:24077221].
Symptoms & clinical features
The symptoms of familial glucocorticoid deficiency often appear in early childhood, typically between birth and two years of age. They can include episodes of low blood sugar (hypoglycaemia), fitting, weakness, poor feeding, and recurrent infections. Infants may fail to thrive, meaning they don't gain weight or grow as expected. Rashes or darkening of the skin (hyperpigmentation) can also be present due to the body attempting to stimulate the adrenal glands to produce cortisol [PMID:22037703]. If the condition is not diagnosed and treated, an adrenal crisis can occur, which is a life-threatening emergency caused by extremely low cortisol levels.
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Affected organs
The primary organs affected in familial glucocorticoid deficiency are the adrenal glands. These small glands are responsible for producing several important hormones, including cortisol. In FGD, the problem lies specifically in the adrenal glands' ability to respond to the adrenocorticotropic hormone (ACTH) signal from the pituitary gland. While other hormones such as aldosterone (which regulates salt and water balance) and adrenal androgens (sex hormones) are typically produced normally, the lack of cortisol affects many bodily functions, impacting metabolism, immune response, and blood pressure regulation.
Risks & severity
Familial glucocorticoid deficiency typically presents in infancy or early childhood. If not diagnosed and managed, the condition can lead to severe health complications, including recurrent hypoglycaemic episodes, developmental delays, and life-threatening adrenal crises. An adrenal crisis is a medical emergency that can cause confusion, severe weakness, vomiting, dehydration, and a drop in blood pressure. With appropriate and lifelong treatment, individuals with FGD can generally lead full and healthy lives, though careful monitoring and adherence to medication are essential to prevent crises [PMID:22037703].
Genetic causes
Familial glucocorticoid deficiency is caused by changes (pathogenic variants) in specific genes. The most common genetic causes currently identified are variants in the MC2R gene and the MRAP gene. The MC2R gene provides instructions for making the melanocortin 2 receptor, which is found on the surface of adrenal gland cells. This receptor is essential for the adrenal glands to recognise and respond to ACTH, prompting them to produce cortisol. Pathogenic variants in MC2R can prevent the receptor from functioning correctly, meaning the adrenal glands cannot receive the 'signal' to make cortisol. Similarly, the MRAP gene produces a protein called melanocortin 2 receptor accessory protein. This protein acts as a chaperone, helping the MC2R receptor to reach the cell surface and function properly [PMID:24077221]. Variants in MRAP can therefore also disrupt the adrenal glands' ability to produce cortisol.
- MC2R melanocortin 2 receptor
- MRAP melanocortin 2 receptor accessory protein
Inheritance pattern
Familial glucocorticoid deficiency is inherited in an autosomal recessive pattern. This means that a person must inherit two altered copies of the same gene - one from each parent - to develop the condition. Individuals who inherit only one altered copy are called carriers. Carriers typically do not show symptoms of FGD themselves because their unaffected gene copy can still produce enough functional protein. When two carriers have a child, there is a 25% chance with each pregnancy that the child will inherit two altered gene copies and develop FGD, a 50% chance the child will be a carrier, and a 25% chance the child will inherit two unaffected gene copies.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of familial glucocorticoid deficiency typically begins with clinical suspicion based on a child's symptoms, such as recurrent hypoglycaemia, fitting, or developmental delays. Blood tests measuring cortisol, ACTH, and blood sugar levels are usually performed. Characteristic findings include low cortisol levels despite high ACTH levels. An ACTH stimulation test may also be used to confirm the adrenal glands' inability to respond to ACTH. Confirmation of FGD is then typically achieved through genetic testing, often via a blood sample. This testing identifies pathogenic variants in genes such as MC2R or MRAP. In the UK, genetic testing for suspected FGD falls under the NHS Genomic Medicine Service, often initiated by a paediatrician or endocrinologist and supported by Clinical Genetics services. Relevant R-codes for genetic testing may include those for inherited adrenal disorders.
Management & lifestyle
Management of familial glucocorticoid deficiency primarily involves lifelong hormone replacement therapy with hydrocortisone, a synthetic glucocorticoid. This medication replaces the cortisol the body cannot produce, preventing symptoms and reducing the risk of adrenal crises. The dose needs to be carefully adjusted according to age, weight, and individual needs, and increased during times of stress, illness, injury, or surgery (known as 'sick day rules'). Individuals and their families receive education on managing the condition, including emergency protocols for adrenal crises. Regular follow-up appointments with an endocrinologist are crucial for monitoring treatment effectiveness and making any necessary adjustments. Genetic counselling is also an important part of managing FGD, offering information and support to affected families.
UK care pathway
In the UK, suspected cases of familial glucocorticoid deficiency are typically referred to paediatric endocrinology services. If a genetic cause is suspected, specialists may then refer to a Clinical Genetics service or directly order genomic testing through the NHS Genomic Medicine Service. This testing is often guided by specific R-codes for inherited endocrine conditions. Genetic counsellors play a key role, providing information about the condition, inheritance patterns, and support for families. Integrated care ensures that diagnosis, management, and ongoing support align with national guidelines and best practices.
Frequently asked questions
What happens if a child with FGD gets sick?
When a child with FGD gets sick or experiences significant stress (like a fever or injury), their body needs more cortisol than usual. Parents are taught 'sick day rules', which typically involve increasing the hydrocortisone dose temporarily to prevent an adrenal crisis. This adjustment should always be done under medical guidance.
Will my child need to take medication for their whole life?
Yes, individuals with familial glucocorticoid deficiency usually require lifelong daily treatment with hydrocortisone to replace the cortisol their body cannot produce. This helps to prevent symptoms and ensures normal growth and development.
Can FGD be detected before birth?
For families where familial glucocorticoid deficiency has been previously diagnosed and the specific genetic change identified, prenatal genetic testing may be an option. This would involve testing during pregnancy to determine if the baby has inherited the condition. You can discuss this with a genetic counsellor if it is relevant to your situation.
Are there other types of glucocorticoid deficiency?
Yes, there are other causes of glucocorticoid deficiency beyond the familial genetic forms. These can include problems with the pituitary gland (secondary adrenal insufficiency) or autoimmune conditions (Addison's disease). Familial glucocorticoid deficiency refers specifically to the inherited forms where the adrenal glands themselves are unable to respond to ACTH.
What is an adrenal crisis?
An adrenal crisis is a life-threatening medical emergency caused by extremely low levels of cortisol. Symptoms can include severe weakness, confusion, vomiting, dehydration, and very low blood pressure. Immediate medical attention and usually an emergency injection of hydrocortisone are required.
References
- Cooray SN, Chan L, Metherell L. Adrenocorticotropin resistance syndromes. Endocrine development. 2008. PMID: 18493136
- Maharaj A, Maudhoo A, Chan LF. Isolated glucocorticoid deficiency: Genetic causes and animal models. The Journal of steroid biochemistry and molecular biology. 2019. PMID: 30817990
- Meimaridou E, Hughes CR, Kowalczyk J. Familial glucocorticoid deficiency: New genes and mechanisms. Molecular and cellular endocrinology. 2013. PMID: 23279877
- Corkery-Hayward M, Metherell LA. Adrenal Dysfunction in Mitochondrial Diseases. International journal of molecular sciences. 2023. PMID: 36674647
- Huebner A, Elias LL, Clark AJ. ACTH resistance syndromes. Journal of pediatric endocrinology & metabolism : JPEM. 1999. PMID: 10698592
- Feingold KR, Adler RA, Ahmed SF. ACTH Action on the Adrenals. 2000. PMID: 25905342
- Maharaj AV. Familial Glucocorticoid Deficiency: the changing landscape of an eponymous syndrome. Frontiers in endocrinology. 2023. PMID: 38189052
- Al Jneibi F, Hen T, Rajah J. Early diagnosis in familial glucocorticoid deficiency. Dermato-endocrinology. 2017. PMID: 28458768