Multiple Endocrine Neoplasias Type 4

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Continuing Education Activity

Multiple endocrine neoplasia type 4 (MEN4) is a rare autosomal dominant endocrine tumor syndrome. The most common tumors seen in this condition involve the parathyroid glands, anterior pituitary, and gastro-entero-pancreatic neuroendocrine tissues. This activity outlines the evaluation and management of MEN4 and highlights the role of the interprofessional team in improving outcomes for patients with this condition.

Objectives:

  • Describe the etiology of MEN4.
  • Outline the clinical presentation of MEN4.
  • Explain the management strategies of MEN4.
  • Review some interprofessional strategies that can lead to better outcomes in patients with MEN4.

Introduction

Multiple endocrine neoplasia (MEN) constitutes a group of autosomal dominant disorders characterized by a wide spectrum of endocrine and non-endocrine diseases. MEN is divided into different types depending on the clinical presentations and genetic mutation. Multiple endocrine neoplasia type 1 (MEN1) is the most common syndrome. MEN1 is characterized by primary hyperparathyroidism secondary to parathyroid gland hyperplasia, pituitary adenoma, and pancreatic neuroendocrine tumors.[1] 

In comparison, multiple endocrine neoplasia type 2 (MEN2) is less common. Depending on clinical phenotype, MEN2 is divided into MEN2A and MEN2B. MEN2A is characterized by medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism. In contrast, MEN2B is characterized by medullary thyroid cancer, pheochromocytoma, marfanoid features, and neuromas of lips, tongue, and colon.

Multiple endocrine neoplasia type 4 (MEN4) is the latest member of MEN syndromes. MEN4 is rare and shares a similar phenotype spectrum to MEN1.[2] The difference between MEN1 and MEN4 is the germline gene mutation. In MEN1, there is a mutation of the MEN1 gene. In MEN4, there is a mutation in the cyclin-dependent kinase inhibitor 1b gene (CDKN1B).[2] Hyperparathyroidism followed by pituitary adenomas is the main clinical manifestation of MEN4. Less frequently, MEN4 may be associated with tumors of the adrenals, kidneys, and reproductive organs. MEN4 is far less reported in the literature compared to other MEN syndromes (e.g., MEN1).[3]

Etiology

Germline mutations in CDKN1B result in MEN4. In humans, the CDKN1B gene is located on chromosome 12p13.[2] The CDKN1B gene encodes a protein called p27, a cyclin-dependent kinase inhibitor (CDKI), a well-known cell cycle regulator. CDKN1B functions as a tumor suppressor gene, and germline mutations in CDKN1B lead to reduced expression of p27, thereby resulting in uncontrolled cell cycle progression.[4] In contrast, in MEN1, there is inactivation of menin (encoded by the MEN1 gene), affecting cell division, gene transcription, and its regulator p27.[3]

This mutation in CDKN1B was first identified in rats. Franklin and his coworkers tested their theory that CDKI may work as tumor suppressor genes in mouse models. They found that loss of function of p18 and p27 leads to a wide range of multiple endocrine gland tumors predominantly affecting the pituitary, thyroid, adrenal, and parathyroid glands.[5] In 2002, Fritz and his coworkers described a MEN-like syndrome in rats with negative mutation for MEN1 or RET genes. This syndrome, involving multiple glands, was thought to be intermediate, or a combination of MEN1 and MEN2, and was termed ‘’MENX’’.[6] 

In 2006, Pellegata et al. mapped this locus of interest on the distal part of chromosome 4 in rats, including the cdkn1b gene encoding the p27 protein. It has an autosomal recessive inheritance pattern in rats. In 2006, the same team reported the first case of MEN4 in humans. They studied a family of 3 generations with negative MEN1 mutation but positive CDKN1B mutation with multiple endocrine neoplasias and renal angiomyolipomas.[7]

In 2008, MENX was renamed MEN4 at the 11th International Workshop on MEN's in Delphi, Greece.[8] Frederiksen et al. reviewed 29 cases published before June 2020 and suggested 16 different mutations involved in MEN4 (12 missense, 3 small deletions, and 1 duplication). This suggests that MEN4 has an autosomal dominant inheritance in humans. The most common presentation is primary hyperparathyroidism due to parathyroid tumors, followed by pituitary tumors (functional and nonfunctional) and gastroenteropancreatic neuroendocrine tumors.

Epidemiology

MEN4 is a new member of MEN syndromes, and it shares phenotypical characteristics of MEN1 with a negative MEN1 gene mutation. The estimated prevalence of MEN1 is exceptionally low; 0.02 to 0.2/1000.[9] The incidence of CDKN1B mutations in patients with MEN1 related neoplasia is difficult to estimate, but it is likely to around 3%.[2] Due to very few cases of MEN4 being reported and many being undiagnosed, there are uncertainties regarding the exact incidence and prevalence of MEN4. The age of onset of disease in MEN4 is still not clear. Whilst it may be earlier than MEN1, the evidence is conflicting, and additional evidence is required to confirm this.[3]

Pathophysiology

MEN4 occurs due to CDKN1B gene mutations. Organs affected by MEN4 are discussed below.

Parathyroid Gland

Primary hyperparathyroidism has been reported in up to 80%-90% of cases with MEN4.[10] Primary hyperparathyroidism presents at a later age in MEN4 compared to MEN1, with a female predominance.[11] To date, only one case of recurrent hyperparathyroidism has been reported after parathyroidectomy, which may suggest a milder disease spectrum than MEN1.[12] The histology of resected glands in MEN4 was in keeping with parathyroid adenoma.[3]

Pituitary Gland

The second most common presentation is pituitary adenoma (nonfunctional and functional). It is proposed that 10% of patients with MEN4 have acromegaly, and 5% of patients with MEN4 have Cushing disease. These findings are similar to MEN1.[3] A recent study identified that 2.6% of patients with Cushing disease have the CDKN1B mutation.[13] Prolactinomas are rare in MEN4.[3]

Neuroendocrine Gastropancreatic Tumors

The prevalence of gastrinomas and nonfunctional pancreatic tumors in MEN4 is approximately 25%. This is much lower than MEN1. So far, there are no case reports of insulinoma, VIPoma, glucagonoma, or ectopic ACTH secreting neuroendocrine tumors in MEN4.[4]

Others

There have been reports of adrenal tumors, testicular cancer, cervical carcinoma, papillary thyroid cancer, colon cancer, carcinoid, and meningioma.[3][4] A recent report presented two cases with multiple immunological abnormalities, including myasthenia gravis, sjögren syndrome, type III cryoglobulinemia, autoimmune thyroiditis, and Crohn disease. Additionally, one of the patients had an adrenal nodule causing autonomous cortisol secretion.[14]

History and Physical

A detailed history and comprehensive family history are important in the evaluation of those with suspected MEN4. Assessing for hypercalcemia symptoms due to primary hyperparathyroidism and its associated clinical complications, e.g., renal calculi and osteoporosis. Furthermore, assessing for symptoms and signs of nonfunctional and functional pituitary tumors, e.g., visual changes and neuroendocrine gastropancreatic tumors, e.g., heartburn. The past medical history should be evaluated, specifically enquiring about peptic ulcers, cancer history (especially breast and reproductive organs), and surgical history. MEN4 has heterogeneous phenotypic expression leading to different manifestations of the syndrome in the same family.

Physical examination involves assessing for signs of hyperfunctioning pituitary disease, visual field defects, neck masses, previous surgical scars, and autoimmune diseases. To date, there have not been reports of skin manifestations in MEN4. Furthermore, physical examination can be normal in some patients, emphasizing the need for a detailed history and family history for diagnosis.

Evaluation

MEN4 is phenotypically very similar to MEN1. Therefore, the evaluation (laboratory and radiological) of MEN4 to screen for associated clinical conditions are similar to MEN1. Investigations are used to evaluate parathyroid, pituitary, neuroendocrine, and reproductive organ tumors. Carcinoid tumors and meningioma can also occur in patients with MEN4. 

Parathyroid Gland

Primary hyperparathyroidism is the most common presentation. The biochemical investigations include calcium, parathyroid hormone, Vitamin D, and 24-hour urine calcium and creatinine. Once the biochemical diagnosis is confirmed, an ultrasound of the parathyroid glands is recommended. If the result of the parathyroid ultrasound is not clear, then a 99-Technetium Sestamibi scan should be undertaken. If both parathyroid ultrasound and 99-Technetium Sestamibi scan are unclear, then parathyroid four-dimensional (4D) computed tomography (CT) can be considered. It is suggested that screening for hyperparathyroidism with calcium and parathyroid hormone should be initiated at age 15 years in patients with confirmed MEN4.[3] A bone density scan (DXA) can be considered to evaluated bone density.

Pituitary Gland

Evaluation of the pituitary gland is mainly limited to undertaking biochemical testing of anterior pituitary hormones. These include growth hormone (GH), insulin-like growth factor 1 (IGF-1), cortisol, adrenocorticotropic hormone (ACTH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and thyroxine (T4). As mentioned above, acromegaly and Cushing disease are more common in MEN4. Dynamic testing like oral glucose tolerance test for growth hormone excess and overnight dexamethasone suppression test for cortisol excess, etc., can be undertaken if initial history or initial investigation is suggestive of hormone excess. Prolactinomas are rare in MEN4. Nonfunctioning pituitary adenomas can occur in MEN4. They can cause pressure effects or hypopituitarism. Visual fields may need to be assessed. Radiological evaluation of the pituitary gland includes magnetic resonance imaging (MRI) of the pituitary. Screening investigations (biochemical and radiological) for pituitary pathology can be initiated in adolescence.[3]

Neuroendocrine Gastropancreatic Tumors

Only a few cases of gastrointestinal and pancreatic neuroendocrine tumors are reported in MEN4. Gastrinomas are the most common functional tumors in MEN4. Screening for gastrointestinal and pancreatic neuroendocrine tumors should be initiated as per MEN1.[10][15] It is recommended to undertake fasting gastrointestinal hormones that include gastrin, chromogranin A, pancreatic polypeptide, vasointestinal polypeptide, glucagon, and fasting glucose level C-peptide and insulin once a year. Radiological investigations e.g. CT, MRI, endoscopic ultrasound, octreotide scan (Octreoscan), and 68Ga-DOTATOC PET, can be undertaken depending on local availability and preference.[10] 

Others

MEN4 can affect multiple other organs, as discussed above. However, due to the paucity of literature on MEN4, it is difficult to provide any guidance regarding the evaluation of tumors in other organs. Therefore, evaluation should be based on clinical judgment and performed on a case-by-case basis.  

Genetic Analysis

MEN4 screening should be done in all patients with MEN1 in the absence of MEN1 gene mutation. All first-degree relatives of patients with MEN4 should be offered genetic testing.[4]

Treatment / Management

Parathyroid Gland

Currently, there is no specific guidance with regards to the treatment of primary hyperparathyroidism in MEN4. Indication for surgery (parathyroidectomy) remains similar to the MEN1 guidelines.[4][10] It is important to individualize surgical treatment. Furthermore, surgery should be carried out by an experienced endocrine surgeon.

Pituitary Gland

Management of pituitary adenoma in MEN4 is similar to that of non-MEN4 pituitary tumors. Transsphenoidal surgery is undertaken if the pituitary tumor is functional or causing a visual field defect. Medical treatment includes somatostatin receptor analogs (octreotide or lanreotide) for acromegaly and dopamine agonists (cabergoline or bromocriptine) prolactinomas. Radiotherapy can be considered if the pituitary tumor has aggressive features on radiological or histological examination.

Neuroendocrine Gastropancreatic Tumors

The management approach for nonfunctional or functional neuroendocrine gastropancreatic tumors is similar to MEN1. These tumors can cause peptic ulceration due to excess secretion of gastric acid. The clinical syndrome is known as Zollinger-Ellison syndrome. Surgical resection may be curative if the tumor is fully excised and nonmetastatic. Medical treatment includes proton-pump inhibitors and somatostatin analogs. Currently, there are no reported cases of insulinoma, VIPoma, glucagonoma, or ectopic ACTH secreting neuroendocrine tumors in MEN4.[3]

Others

The management approach for other clinical manifestations (adrenal tumor, thyroid, testicular cancer, carcinoid, meningioma, colon cancer) is based on the organ affected. There is no specific guidance due to the paucity of literature.

Differential Diagnosis

Differential diagnosis includes MEN1, neurofibromatosis type 1, tuberous sclerosis, Von Hippel-Lindau syndrome, and isolated primary hyperparathyroidism.

Prognosis

The current evidence is very limited to draw conclusions regarding the prognosis in MEN4. The onset of the disease is still to be elucidated in MEN4. Frederiksen et al. suggested that the onset of disease in MEN4 might be earlier than MEN1 [3]. However, de Laat et al. found those with MEN1 phenotype, which were mutation-negative developed manifestations later in life and had improved life expectancy.[16] Whilst this group may have had MEN4, conclusions cannot be drawn. As further cases of MEN4 are diagnosed, this area of the debate will have more definite answers.

Complications

Complications associated with MEN4 are related to the burden of disease and post-surgical complications. Complications related to endocrine disease burden involve systemic and metabolic effects of acromegaly, Cushing disease, primary hyperparathyroidism, and functional gastropancreatic tumors. Primary hyperparathyroidism can result in osteoporosis and renal calculi. Pituitary disorders can reduce visual acuity, visual field defects, hypopituitarism, and its associated manifestations.

Deterrence and Patient Education

MEN4 is a rare disorder causing tumors of multiple endocrine glands. The patient should be counseled regarding the impact of genetic testing. Patients should be provided education regarding the spectrum of clinical disorders and their impact on them and their families. The patient should be encouraged to discuss the diagnosis with their family and undertake genetic testing. The patient and their family member should have an opportunity to discuss the diagnosis with a clinical geneticist or the genetic team. The patient and their family members should be advised to attend follow-up appointments regularly.

Enhancing Healthcare Team Outcomes

MEN4 is a rare condition causing tumors of multiple endocrine glands. The spectrum of endocrine gland tumors is similar to MEN1, making it important to differentiate the two through genetic testing. To date, very few cases have been reported. As a result, the penetrance of the disease is not fully understood. To optimize outcomes, the management of these patients should be undertaken by an expert multidisciplinary team in a tertiary care center.


Article Details

Article Author

Fahad W. Ahmed

Article Author

Muhammad S. Majeed

Article Editor:

Omar Kirresh

Updated:

4/4/2022 9:54:37 PM

References

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