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Multiple endocrine neoplasia type 2B
MEN2B is a rare inherited condition that can cause certain endocrine glands to develop tumours, particularly in the thyroid, adrenal glands, and parathyroid glands. It also features distinctive physical traits affecting the nervous and musculoskeletal systems.
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Overview
Multiple Endocrine Neoplasia type 2B (MEN2B) is a rare inherited disorder characterised by an increased risk of developing specific types of tumours in various endocrine glands. The endocrine system produces hormones that control many bodily functions, and tumours in these glands can disrupt normal hormone balance. MEN2B is part of a group of conditions known as Multiple Endocrine Neoplasia type 2 (MEN2), but it has a unique set of clinical features distinguishing it from other types [PMID:33678036].
Individuals with MEN2B typically develop medullary thyroid carcinoma (MTC) at a young age, often in early childhood. They are also at high risk for phaeochromocytomas, which are tumours of the adrenal glands, and may occasionally develop primary hyperparathyroidism, affecting the parathyroid glands. In addition to endocrine tumours, MEN2B presents with distinct physical characteristics and neurological features that help clinicians recognise the condition.
Symptoms & clinical features
The symptoms of MEN2B are varied and can appear at different ages, though often early in life. One of the most common and earliest signs is the development of medullary thyroid carcinoma (MTC), which can manifest as a lump in the neck or hoarseness. Phaeochromocytomas, adrenal gland tumours, can cause symptoms such as high blood pressure, headaches, palpitations, and sweating episodes due to excess hormone release.
Individuals with MEN2B also have distinct physical features that set the condition apart. These include a characteristic facial appearance with thick, bumpy lips, and neuromas (benign growths of nerve tissue) on the tongue, lips, and eyelids [PMID:20301323]. Gastrointestinal issues like constipation or diarrhoea are common due to ganglioneuromatosis, an overgrowth of nerve cells in the digestive tract. Some individuals may also have skeletal abnormalities, such as a tall, slender body build or scoliosis.
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Affected organs
MEN2B primarily affects several endocrine glands, notably the thyroid gland, adrenal glands, and sometimes the parathyroid glands. The thyroid gland is almost always affected, with the development of medullary thyroid carcinoma. The adrenal glands are also frequently involved, leading to phaeochromocytomas. Less commonly, the parathyroid glands can be affected, resulting in primary hyperparathyroidism.
MEN2B also impacts other body systems beyond endocrine organs. The nervous system is significantly involved, leading to ganglioneuromatosis in the gastrointestinal tract and neuromas in various mucous membranes. The skeletal system may also show abnormalities, and the characteristic facial features are a direct result of these widespread effects.
Risks & severity
MEN2B is considered a severe form of Multiple Endocrine Neoplasia type 2, with a very high lifetime risk of developing medullary thyroid carcinoma (MTC). MTC in MEN2B typically appears at a very young age and can be aggressive, requiring early diagnosis and management. Almost all individuals with MEN2B develop MTC during their lifetime [PMID:20301323].
Phaeochromocytomas occur in a substantial proportion of individuals with MEN2B, and while generally benign, they can cause serious health issues if not detected and managed. Primary hyperparathyroidism is less common than in other MEN2 subtypes. The physical features, such as neuromas and gastrointestinal issues, contribute to the overall clinical picture but are generally not life-threatening. Early diagnosis and proactive management are crucial for improving outcomes and reducing complications.
Genetic causes
Multiple Endocrine Neoplasia type 2B is caused by specific pathogenic variants in RET. This gene encodes a receptor tyrosine kinase protein essential for normal cellular communication and growth. The encoded protein sits at the cell surface, receiving external signals that regulate cell division, survival, and development, particularly within the nervous system and kidneys.
When pathogenic changes occur in RET, the resulting protein typically exhibits a 'gain-of-function,' meaning it signals continuously without requiring normal external triggers. This uncontrolled activity drives excessive cell growth and division, which can lead to tumour formation in the endocrine glands [PMID:33678036]. The specific alterations found in MEN2B differ from those seen in other MEN2 subtypes, accounting for the distinct clinical presentation.
- RET ret proto-oncogeneThe RET gene provides instructions for a receptor tyrosine kinase protein involved in cell signalling, crucial for the development of various nerve cells, kidneys, and spermatogenesis.
Inheritance pattern
MEN2B is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered RET gene from either parent to develop the condition. If a parent has MEN2B, there is a 50% chance with each pregnancy that their child will inherit the pathogenic variant and therefore the condition.
Some individuals with MEN2B inherit the pathogenic variant from an affected parent, while others develop the condition due to a new, spontaneous pathogenic variant in RET in the affected individual, meaning neither parent carries the altered gene. In these de novo cases, the affected individual can then pass the variant on to their children.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
A diagnosis of MEN2B is typically suspected based on the characteristic clinical features, such as early-onset medullary thyroid carcinoma, phaeochromocytoma, and distinct physical traits like bumpy lips and multiple mucosal neuromas. Confirmation of the diagnosis relies on genetic testing for pathogenic variants in RET.
In the UK, genetic testing for MEN2B is usually initiated following a referral to a clinical genetics service or an endocrinologist, particularly if there is a strong suspicion based on symptoms or a family history. The NHS Genomic Medicine Service (GMS) provides comprehensive genetic testing, and diagnostic testing for MEN2B is available under R-codes such as R189 Medullary thyroid cancer and R202 Multiple endocrine neoplasia type 2. Genetic counsellors play a key role in explaining the testing process, results, and implications for individuals and their families.
Management & lifestyle
Management for individuals with MEN2B is multidisciplinary and focuses on early detection and treatment of tumours, as well as managing associated symptoms. Due to the high risk and early onset of medullary thyroid carcinoma (MTC), a preventative total thyroidectomy (surgical removal of the thyroid gland) is often recommended, sometimes in infancy, to prevent the development or progression of MTC.
Regular surveillance for phaeochromocytomas, typically involving biochemical testing and imaging, is crucial. If a phaeochromocytoma is detected, it is usually surgically removed after appropriate medical preparation to control blood pressure. Long-term follow-up with endocrinologists and other specialists is essential to monitor for potential tumour recurrence and manage any other MEN2B-related health issues. Genetic counsellors can provide ongoing support and information to affected individuals and their families regarding screening protocols and family planning.
UK care pathway
In the UK, individuals suspected of having Multiple Endocrine Neoplasia type 2B (MEN2B) are typically referred to specialist services, often through a General Practitioner (GP) or relevant specialist (e.g., an endocrinologist or paediatrician). The pathway often involves assessment by a clinical genetics team. Genetic testing, available through the NHS Genomic Medicine Service, specifically for MEN2B (covered by R-codes such as R189 for Medullary thyroid cancer and R202 for Multiple endocrine neoplasia type 2), will be arranged if clinically appropriate. Genetic counsellors provide vital support throughout this process, offering information about the condition, inheritance, and implications for family members.
Frequently asked questions
What is the difference between MEN2A and MEN2B?
Both MEN2A and MEN2B are caused by changes in RET and involve medullary thyroid carcinoma and phaeochromocytomas. However, MEN2B is distinguished by specific physical features, such as bumpy lips and neuromas, and an earlier onset of more aggressive thyroid cancer. Primary hyperparathyroidism is also less common in MEN2B than in MEN2A.
If I have MEN2B, what is the risk for my children?
MEN2B is inherited in an autosomal dominant pattern. If you have MEN2B, each of your children has a 50% chance of inheriting the pathogenic RET variant and therefore the condition. Genetic counselling can provide more personalised information and discuss options like pre-implantation genetic diagnosis.
Can MEN2B develop without a family history?
Yes, some MEN2B cases arise from new (de novo) pathogenic variants in RET. This means that an individual can develop MEN2B even if neither parent carries the altered gene. However, once an individual has the condition, they can pass it on to their children.
What kind of surveillance is needed for MEN2B?
Individuals with MEN2B require lifelong surveillance, including regular checks for medullary thyroid carcinoma, often involving blood tests and neck ultrasounds. Monitoring for phaeochromocytomas typically involves periodic blood and urine tests for hormone levels. The specific schedule and tests will be determined by your healthcare team based on your individual circumstances.
Is there a cure for MEN2B?
There is currently no cure for the underlying genetic cause of MEN2B. However, proactive management, including early preventative surgery for medullary thyroid carcinoma and careful surveillance and treatment of other tumours, can significantly improve outcomes and quality of life. Regular follow-up with specialist teams is crucial.
References
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