Multiple Endocrine Neoplasia Type 1
Parathyroid Tumors and PHPT
Other MEN1-Associated Tumors
Making the Diagnosis of MEN1
Molecular Genetics of MEN1
Genetic Testing and Differential Diagnosis
Multiple endocrine neoplasia type 1 (MEN1) (OMIM) is an autosomal dominant syndrome with an estimated incidence in the general population of 1 to 2 per 100,000. The major endocrine features of MEN1 include the following:
- Parathyroid tumors and primary hyperparathyroidism (PHPT).
- Pancreatic neuroendocrine tumors (PNETs) of the duodenum.
- Pituitary tumors.
A diagnosis of MEN1 is made when an individual has two of these three major endocrine tumors. Familial MEN1 is defined as at least one MEN1 case plus at least one first-degree relative with one of these three tumors.[2-4] The age-related penetrance of MEN1 is 45% at age 30 years, 82% at age 50 years, and 96% at age 70 years.[2,5]Parathyroid Tumors and PHPT
The most common features and often the first presenting signs of MEN1 are parathyroid tumors, which result in PHPT. These tumors occur in 80% to 100% of patients by age 50 years.[2,6-8] Unlike the solitary adenoma seen in sporadic cases, MEN1-associated parathyroid tumors are typically multiglandular and often hyperplastic. The average age at onset of PHPT in MEN1 is 20 to 25 years, in contrast to that in the general population, which is typically age 50 to 59 years. Parathyroid carcinoma in MEN1 is rare but has been described.[9-12]
Individuals with MEN1-associated PHPT will have elevated parathyroid hormone (PTH) and calcium levels in the blood. The clinical manifestations of PHPT are mainly the result of hypercalcemia. Mild hypercalcemia may go undetected and have few or no symptoms. More severe hypercalcemia can result in the following:
- Nausea and vomiting.
- Decreased appetite and abdominal pain.
- Kidney stones.
- Increased bone resorption with resultant increased risk of bone fracture.
- Shortened QT interval.
Since MEN1-associated hypercalcemia is directly related to the presence of parathyroid tumors, surgical removal of these tumors may result in normalization of calcium and PTH levels and relief of symptoms; however, high recurrence rates following surgery have been reported in some series.[13-15] (Refer to the Interventions section of this summary for more information.)PNETs
PNETs of the duodenum, the second most common endocrine manifestation in MEN1, occur in 30% to 80% of patients by age 40 years.[2,8] Gastrinomas represent 50% of the gastrointestinal neuroendocrine tumors in MEN1 and are the major cause of morbidity and mortality in MEN1 patients.[2,13] Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum. Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis.[13,16,17]
Other functioning PNETs seen in MEN1 include the following:
- Insulinomas (10%–20% penetrance).
- Vasoactive intestinal peptide tumors (~1% penetrance).
- Glucagonomas (1%–5% penetrance).
- Somatostatinomas (~1% penetrance).
Nonfunctioning PNETs were originally thought to be relatively uncommon tumors in individuals with MEN1, with early penetrance estimates of 20%.[18,19] With the advent of genetic testing and improved imaging techniques, however, their prevalence in MEN1 has increased, with one study showing a frequency as high as 55% by age 39 years in MEN1 mutation carriers undergoing prospective endoscopic ultrasound of the pancreas.[20,21] These tumors can be metastatic. One study of 108 MEN1 mutation carriers with nonfunctioning PNETs showed a positive correlation between tumor size and rate of metastasis and death, with tumors larger than 2 cm having significantly higher rates of metastasis than those smaller than 2 cm. (Refer to the Molecular Genetics of MEN1 section for more information about MEN1 gene mutations.)Pituitary Tumors
Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor.[2,8] Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting. Other functioning pituitary tumors can include somatotropinomas and corticotropinomas.Other MEN1-Associated Tumors
Other manifestations of MEN1 include carcinoids of the foregut (5%–10% of MEN1 patients). These are typically bronchial or thymic and are sometimes gastric. Skin lesions are also common and can include facial angiofibromas (up to 80% of MEN1 patients) and collagenomas (~75% of MEN1 patients). Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients), including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common.[25-27] The following manifestations have also been reported:[28-30]
- Thyroid adenomas.
- Spinal ependymoma.
- Leiomyoma (e.g., esophageal, lung, and uterine).
MEN1 is often difficult to diagnose in the absence of a significant family history or a positive genetic test for a mutation in the MEN1 gene. One study of 560 individuals with MEN1 showed a significant delay between the time of the first presenting symptom and the diagnosis of MEN1. This may be because some presenting symptoms of MEN1-associated tumors, such as amenorrhea, peptic ulcers, hypoglycemia, and nephrolithiasis, are not specific to MEN1.
Furthermore, identification of an MEN1-associated tumor is not sufficient to make the clinical diagnosis of MEN1 and may not trigger a referral to an endocrinologist. Other studies have shown similar findings, with median time between first presenting symptom and diagnosis of MEN1 ranging from 7.6 years to 12 years.[5,26] Genetic testing alleviates some of this delay. Several studies have shown statistically significant differences in the age at MEN1 diagnosis between probands and their family members. In one study, clinically symptomatic probands were diagnosed with MEN1 at a mean age of 47.5 years (standard deviation [SD] +/- 13.5 years), while family members were diagnosed at a mean age of 38.5 years (SD +/- 15.4 years; P < .001). In another study of 154 individuals with MEN1, probands were diagnosed at a mean age of 39.5 years (range: 18–74 years), compared with a mean age 27 years (range: 14–56 years; P < .05) in family members diagnosed by predictive genetic testing. These findings underscore the importance of increased awareness of the signs and symptoms of MEN1-related tumors and the constellation of findings necessary to suspect the diagnosis. It also highlights the importance of genetic counseling and testing and communication among family members once a diagnosis of MEN1 is made.
Since many of the tumors in MEN1 are underdiagnosed or misdiagnosed, identifying an MEN1 gene mutation in the proband early in the disease process can allow for early detection and treatment of tumors and earlier identification of at-risk family members. Many studies have been performed to determine the prevalence of MEN1 gene mutations among patients with apparently sporadic MEN1-related tumors. For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an MEN1 mutation.[33,34] In individuals with apparently isolated PHPT or pituitary adenomas, the mutation prevalence is lower, on the order of 2% to 5%,[23,35,36] but the prevalence is higher in individuals diagnosed with these tumors before age 30 years. Some authors suggest genetic testing for mutations in MEN1 if one of the following conditions is present:[37,38]
- Gastrinoma at any age.
- Multifocal pancreatic islet cell tumors at any age.
- Parathyroid hyperplasia/adenomas before age 30 or 40 years.
- Multiglandular parathyroid adenomas/hyperplasia or recurrent PHPT.
- Presence of one of the three main MEN1 tumors plus one of the less common tumors/findings.
- Presence of two or more features (e.g., adrenal adenomas and carcinoid tumor).
The MEN1 gene is located on chromosome 11q13 and encodes the protein menin.[3,39,40] Over 1,300 mutations have been identified in the MEN1 gene to date, and these are scattered across the entire coding region. The majority (~65%) of these are nonsense or frameshift mutations. The remainder are missense mutations (20%), which lead to expression of an altered protein, splice-site mutations (9%), or partial- or whole-gene deletions (1%–4%). There is currently no evidence of genotype-phenotype correlations, and inter- and intra-familial variability is common.[42,43]Genetic Testing and Differential Diagnosis
Genetic testing for MEN1 mutations is recommended for individuals meeting clinical diagnostic criteria and may be considered in a subset of the less common tumors. (Refer to the bulleted list in the Making the diagnosis of MEN1 section of this summary for more information.) For individuals meeting diagnostic criteria, the mutation detection rate is approximately 75% to 90% [42,44] but may be lower in simplex cases. Individuals with isolated parathyroid and/or pituitary tumors are less likely to have an identifiable mutation than those with pancreatic tumors. The majority of commercial laboratories currently offering MEN1 testing use DNA sequencing as their primary method. Several offer additional analysis for partial- or whole-gene deletion and/or duplication, although such mutations are rare and deletion/duplication testing is often reserved for individuals or families in which there is a very high clinical suspicion.
Genetic testing for MEN1 mutations can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP) (OMIM), hyperparathyroidism–jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). [Note: The hyperparathyroidism in FHH is not primary hyperparathyroidism, which is seen in MEN1, HPT-JT and FIHP.] HPT-JT, which is caused by germline mutations in the HRPT2 gene, is associated with PHPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas, and in some cases, Wilms tumor.[47,48] Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma. FIHP, as its name suggests, is characterized by isolated PHPT with no additional endocrine features; in some families, FIHP is the initial diagnosis of what later develops into MEN1, HPT-JT, or FHH.[50-52] Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1 mutations.[51,53,54] Mutations in the calcium-sensing receptor (CaSR) gene cause FHH, which can closely mimic the hyperparathyroidism in MEN1. Distinguishing between MEN1 and FHH can be critical in terms of management, as removal of the parathyroid glands in FHH does not correct the patient’s hyperparathyroidism and results in unnecessary surgery without relief of symptoms. Given the differential risks and management of these conditions and the increased risk of parathyroid carcinoma in HPT-JT, genetic diagnosis in a patient presenting with early-onset hyperparathyroidism may play an important role in the management of these patients and their families. Refer to Table 1 for a summary of the clinical features of MEN1 and other forms of hereditary hyperparathyroidism.Table 1. Major Clinical Features of MEN1, FIHP, HPT-JT, and FHH
|Condition||Gene(s)||Major Clinical Features|
|CaSR = calcium-sensing receptor gene; FHH = familial hypocalciuric hypercalcemia; FIHP = familial isolated hyperparathyroidism; HPT-JT = hyperparathyroidism–jaw tumor syndrome; HRPT2 = hyperparathyroidism 2 gene; MEN1 = multiple endocrine neoplasia type 1; MEN1 = multiple endocrine neoplasia type 1 gene; PHPT = primary hyperparathyroidism.|
|MEN1||MEN1||PHPT, pituitary adenomas, pancreatic neuroendocrine tumors |
|FIHP||MEN1, HRPT2||PHPT [50-54]|
|HPT-JT||HRPT2||PHPT; osteomas of maxilla and mandible; renal cysts or hamartomas; and rarely, Wilms tumor and parathyroid carcinoma [47-49]|
|FHH||CaSR||Hyperparathyroidism (not primary) [55,56]|
Surveillance Table 2. Practice Guidelines for Surveillance of Multiple Endocrine Neoplasia Type 1 (MEN1)a
|Biochemical Test or Procedure||Condition Screened For||Age Screening Initiated (y)||Frequency|
|Serum prolactin and/or insulin-like growth factor 1||Pituitary tumors||5||Every 1 y|
|Fasting total serum calcium and/or ionized calcium and PTH||Parathyroid tumors and PHPT||8||Every 1 y|
|Fasting serum gastrin||PNETs||20||Every 1 y|
|Chromogranin A, pancreatic polypeptide, glucagon, and vasointestinal polypeptide||PNETs||<10||Every 1 y|
|Fasting glucose and insulin||PNETs||5||Every 1 y|
|Brain MRI||Pituitary tumors||5||Every 3–5 y based on biochemical results|
|Abdominal CT or MRIb ||PNETs||20||Every 3–5 y based on biochemical results|
|Abdominal CT, MRI, or endoscopic USb ||PNETs||<10||Every 1 y|
|CT = computed tomography; MRI = magnetic resonance imaging; PHPT = primary hyperparathyroidism; PNETs = pancreatic neuroendocrine tumors; PTH = parathyroid hormone; US = ultrasound.|
|aAdapted from Brandi et al.  and Thakker et al. .|
|bThe recommendations for abdominal imaging differ between two published guidelines for the diagnosis and management of MEN1.[4,37] There is weak evidence at this time to support annual imaging before age 10 years. Imaging before age 10 years does identify disease in a high proportion of patients, but it is not clear whether this impacts prognosis.[20,57]|
Surgical management of MEN1 is complex and controversial, given the multifocal and multiglandular nature of the disease and the high risk of tumor recurrence even after surgery. Establishing the diagnosis of MEN1 prior to making surgical decisions and referring affected individuals to a surgeon with experience in treating MEN1 can be critical in preventing unnecessary surgeries or inappropriate surgical approaches.Parathyroid tumors
Once evidence of parathyroid disease is established biochemically, the recommended course of action is surgical removal of the parathyroids. The timing and the extent of surgery, however, remain controversial. Some groups reserve surgical intervention for symptomatic patients, with continued annual biochemical screening for those who are asymptomatic. Once surgery is necessary, subtotal parathyroidectomy (removal of 3–3.5 glands) is often suggested as the initial treatment. However, the rate of recurrence is quite high (55%–66%), and reoperation is often necessary.[13-15] Another study has shown that bilateral thymectomy reduces the likelihood of recurrence. Total parathyroidectomy with autotransplantation of parathyroid tissue to the forearm is also an option. A benefit of this approach is the easier removal of recurrent disease from the forearm than from the neck. Although the likelihood of recurrence is lowered by more extensive surgery, this must be weighed against the risk of rendering the patient hypoparathyroid. Management of persistent hypoparathyroidism with oral calcitriol is necessary.References
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