Professor John Burgess, Physician In-charge,
Endocrine Neoplasia Clinic, Royal Hobart Hospital
Multiple Endocrine Neoplasia Type 1 is commonly associated with tumours and overactivity of the parathyroid glands, the pancreas and the pituitary gland. However, a much broader range of endocrine and non-endocrine abnormalities can develop:
- Primary hyperparathyroidism (>95% of patients))
- Enteropancreatic neuroendocrine tumours (>50%)
- Pituitary adenomas (20-30%)
- Adrenal macronodular hyperplasia (20-30%)
- Malignancy (up to 30%)
- Bronchial carcinoid tumour and malignant thymoma (<10%)
- Cutaneous lesions (>70%)
Whilst some cases of MEN 1 are due to the chance occurrence of multiple endocrine tumours, in the typical situation, there is an underlying genetic predisposition (Familial MEN 1). This article will concentrate on the features of Familial MEN 1.
Familial MEN 1 results from loss of function of a gene located on chromosome 11. The MEN1 gene normally acts as a “suppressor” of tumour formation. An individual inherits two copies of this gene, one from each parent. Whilst only one normally functioning copy of the gene is required for a cell to prevent tumour formation, in familial MEN 1, the combination of an inherited non-functioning MEN1 gene, in conjunction with chance mutations acquired during life (somatic mutation) to the remaining functional MEN1 gene, results in endocrine overactivity and tumour formation.
Familial MEN 1 is an autosomal dominant disease, which means that children of an affected individual have a 50% chance of inheriting the gene responsible for the condition. People who inherit MEN 1 are highly likely at some point in life to develop one or more of the conditions associated with MEN 1. These vary, from mild and asymptomatic changes on laboratory and medical imaging tests, through to symptomatic health consequences. Fortunately, many patients with MEN 1 develop only benign endocrine tumours and hormonal overactivity, most of which are controllable using either medical or surgical therapy.
The evaluation of patients with MEN 1 usually involves confirmation of inheritance of MEN 1 by genetic testing. It is important that genetic testing occurs in conjunction with appropriate genetic counselling, particularly in the case of children and adolescents. It is usually recommended that genetic testing of children is delayed until approximately 10‑12 years of age. This allows informed discussion with the child regarding the consequences of genetic testing. Screening of children at a younger age may be undertaken to allay anxiety, or if a child has symptoms or features of an MEN 1 related disorder. It is however uncommon for children to present with a clinically significant MEN 1 related problem prior to puberty.
Once the diagnosis of MEN 1 is confirmed genetically, life long clinical follow-up and periodic endocrine screening to identify endocrine disease is required. This usually involves 6-12 monthly biochemical studies of parathyroid, pituitary and endocrine pancreatic function. Imaging (CT, ultrasound and MRI) of the pituitary, chest and abdomen is also periodically performed. Whilst the underlying genetic predisposition to endocrine system overactivity in MEN 1 cannot be corrected, treatments do exist for specific problems should they occur. Whilst most tumours in MEN 1 are benign, malignancy can occur in up to 30% of patients, usually involving either the thymus, pancreas or upper intestinal tract/stomach.
Primary hyperparathyroidism (resulting in elevated blood calcium level) occurs in the majority of patients who inherit the MEN1 gene by age 30. Initially, patients are typically asymptomatic for raised calcium, but left untreated, complications such as kidney stones, renal impairment and osteoporosis can develop. Treatment involves a parathyroidectomy in which most of the overactive parathyroid glands are removed surgically.
Benign tumours of the pancreas develop in many patients with MEN 1, the majority of these are asymptomatic and do not require treatment. Over secretion of hormones such as gastrin and insulin can occur in some patients. High gastrin levels can lead to severe peptic ulcer disease whilst high insulin can result in low blood sugar symptoms. Surgical removal of pancreatic tumours is sometimes required, typically when they are producing insulin or if they are of large size. Medications are usually used for treatment of peptic ulcer disease associated with raised gastrin levels.
Other conditions associated with MEN 1 include adrenal nodular hyperplasia (enlargement of the adrenal glands) which generally does not require treatment or produce symptoms. Patients may also develop benign changes involving the skin and subcutaneous tissue including lipoma and angiofibroma.
Pituitary tumours occur in approximately one third of the patients with MEN 1. Pituitary disease in MEN 1 typically relates to benign non-functioning pituitary microadenoma. These are small (< 1cm) pituitary adenomas which do not overproduce pituitary hormones or produce pressure symptoms. They are often detected in patients without symptoms when they undergo MRI imaging of the pituitary as part of routine periodic screening. Treatment is not usually recommended provided such pituitary adenoma remain stable in size and are asymptomatic. Whilst these adenoma can expand and require surgery, most remain stable, even when followed over the course of many years.
Hyperprolactinaemia is also a common feature of MEN 1. This may be in the context of a normal pituitary MRI, or in association with a pituitary adenoma. Macroadenomas account for the minority of these lesions. Fortunately, most of MEN 1 patients with hyperprolactinaemia respond with dopamine agonists such as cabergoline. This therapy usually produces excellent results, both controlling the raised prolactin and its related consequences, as well as reducing the size of the adenoma. Occasionally, surgical intervention in the form of transphenoidal surgery is required.
Growth hormone secreting pituitary adenomas are also a recognised feature of MEN 1 although they are less common in occurrence than non-functioning pituitary adenoma and prolactinomas. The symptoms and presentation of patients with growth hormone excess, as well as its diagnostic evaluation, is identical to that recommended for somatotrophinoma occurring in the general population. Similarly, the treatment options typically involve transphenoidal surgery or medical therapy with somatostatin analogues.
Cushing’s disease in the context of MEN 1 is evaluated and treated in line with the general recommendations for sporadic ACTH secreting pituitary adenoma. The prognosis for both acromegaly and Cushing’s disease following transphenoidal surgery is good with cure, a reasonable expectation in the majority of the patients with microadenoma. Rare causes of pituitary disease in MEN 1 include TSH secreting pituitary adenoma resulting in thyrotoxicosis. Pituitary malignancy is very rarely described in the context of MEN 1.
Whilst the presentation and treatment of pituitary disease in MEN 1 accords with that of sporadic disease, it is recognised that pituitary tumours in MEN 1 can be more difficult to control than similar lesions that occur in the general population. Screening for pituitary disease in MEN 1 involves routine 5th yearly pituitary MRI with annual assessment of prolactin, growth hormone, IGF-1 and thyroid function. Clinical assessment for features of Cushing’s syndrome, visual field impairment and pituitary space occupying lesion, is also appropriate during routine clinical consultations.
More information regarding MEN 1 can be found at the following website:
Burgess J. How should the patient with multiple endocrine neoplasia type 1 (MEN 1) be followed? Clin Endocrinol (Oxf). 2010 Jan; 72(1):13-6
Reviewed: May 2013