Multiple endocrine neoplasia, type 4 (MEN 4) is an autosomal dominant syndrome characterized by adenomas and sometimes hyperplasia of the parathyroid glands and tumors of the pancreatic islet cells and/or pituitary gland. Hyperparathyroidism and asymptomatic hypercalcemia commonly occur. Diagnosis is by hormonal and imaging tests. Tumors causing symptoms are surgically removed when possible. Tumors are removed surgically if they cause symptoms or for suspected malignancy based on size criteria.
MEN 4 is caused by an inactivating mutation of the CDKN1B gene, which codes for the cyclin dependent kinase inhibitor 1B protein, also known as p27 or p27KIP1. The protein is involved in cellular growth and development and has an important role in regulating the cell cycle. It acts as a tumor suppressor and when the protein is lost, cells can undergo unscheduled replication, which may eventually lead to cancer.
Although MEN 4 involves the same primary organs as MEN 1 (parathyroids, pancreas, and pituitary), patients tend to present later in life and have a more indolent course of disease than those with MEN 1.
MEN 4 is much less common that MEN 1, with fewer than 100 patients currently described in the world literature.
Symptoms and Signs of MEN 4
Clinical manifestations of MEN 4 are essentially the same as those for MEN 1, although with some differences. The majority of patients with MEN 4 and hyperparathyroidism have single parathyroid adenomas as compared to hyperplasia of all four parathyroid glands in MEN 1. In the pituitary, adrenocorticotropic hormone–producing adenomas are the most common tumor (33%), whereas tumors that secrete prolactin (24%) or growth hormone (19%) are slightly less common. Pancreatic neuroendocrine tumors have been characterized either as gastrinomas (33%) or nonfunctioning tumors (66%) (1).
Довідковий матеріал щодо симптомів та ознак
1. Singeisen H, Renzulli MM, Pavlicek V, et al. Multiple endocrine neoplasia type 4: a new member of the MEN family. Endocr Connect 2023;12(2):e220411. doi:10.1530/EC-22-0411
Diagnosis of MEN 4
Serum calcium, parathyroid hormone (PTH), gastrin, and prolactin levels
Diagnosis of MEN 4 follows the same approach as for MEN 1 and includes blood testing for hormone excess and genetic testing to identify the causative mutation in the CDKN1B gene. Because of the clinical similarity between MEN 1 and MEN 4, patients with this constellation of symptoms should undergo genetic testing utilizing a panel of genes that includes both MEN1 and CDKN1B.
Initial laboratory studies include serum calcium, parathyroid hormone, gastrin, and prolactin levels. Additional laboratory or radiologic tests may be needed if these tests suggest an endocrine abnormality related to MEN 1.
A gastrin-secreting gastroenteropancreatic neuroendocrine (GEP-NET) tumor of the pancreas or duodenum is diagnosed by elevated basal plasma gastrin levels, an exaggerated gastrin response to infused calcium, and a paradoxical rise in gastrin level after infusion of secretin. An insulin-secreting beta-cell tumor of the pancreas is diagnosed by detecting fasting hypoglycemia with an elevated plasma insulin level. An elevated basal level of pancreatic polypeptide or gastrin or an exaggerated response of these hormones to a standard meal may be the earliest sign of pancreatic involvement.
Acromegaly is diagnosed by elevated growth hormone levels that are not suppressed by glucose administration and by elevated levels of serum insulin-like growth factor 1 (somatomedin C).
Ultrasonography or computed tomography (CT) can help localize tumors. Because these tumors are often small and difficult to localize, other imaging tests (eg, helical [spiral] CT, angiography, MRI, endoscopic ultrasonography, intraoperative ultrasonography) may be necessary. Thoracic imaging with fluorine-18 [18F]–labeled deoxyglucose (18F-FDG) or gallium Ga 68 dotatate positron emission tomography (PET)/CT may be useful in distinguishing bronchopulmonary neuroendocrine tumors from benign pulmonary nodules and in identifying thymic carcinoid. For pancreatic and duodenal neuroendocrine tumors, gallium Ga 68 dotatate positron emission tomography/CT was threefold more sensitive than octreotide scanning or CT scanning in a study of multiple imaging modalities in 26 cases of MEN 1; when available, this test should replace octreotide scanning for periodic imaging.
Treatment of MEN 4
Surgical excision when possible
Pharmacologic management of endocrinopathies
Treatment of MEN 4 is similar to that of MEN 1 and begins with tumor resection when possible. Because patients with MEN 4 and hyperparathyroidism typically exhibit a single adenoma, exploration and/or removal of other glands may not be necessary if a single adenoma is identified before surgery.
When complete excision of tumors is not possible, medications are used to treat hormone excess. These include
Octreotide and cinacalcet for recurrent or persistent hypercalcemia due to hyperparathyroidism
Dopamine agonists for hyperprolactinemia due to prolactin-secreting pituitary tumors
Proton pump inhibitors for symptomatic control of symptomatic peptic ulcer disease due to hypergastrinemia
Diazoxide or a somatostatin analogue (octreotide, lanreotide) for hypoglycemia due to insulinoma
Streptozocin or other cytotoxic drugs to reduce tumor burden
Somatostatin analogues also can block hormone secretion from other nongastrin-secreting pancreatic tumors, including carcinoid tumors, and are well tolerated.
Palliative treatments for metastatic pancreatic tumors include hepatic debulking surgery and hepatic artery chemoembolization.
Ключові моменти
Consider multiple endocrine neoplasia, type 4 (MEN 4) in patients with tumors of the parathyroids, pancreas, and/or pituitary, particularly in patients with a family history of one or more of these tumors.
The main clinical manifestations are those of hormone excess, particularly hypercalcemia due to hyperparathyroidism, although these typically occur at older ages compared with patients with MEN 1.
Patients should have genetic testing for the CDKN1B gene mutation and clinical evaluation for other tumors as part of the syndrome.
Tumors are excised when possible, but lesions are often multiple and/or difficult to find.
Sometimes hormone excess can be managed with medication.
