Multiple Endocrine Neoplasias Type 4

Etiology

Germline mutations in CDKN1B result in MEN4. In humans, the CDKN1B gene is located on chromosome 12p13.1.[2] The CDKN1B gene encodes a protein called p27, a CDK 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, resulting in uncontrolled cell-cycle progression.[4] Conversely, in MEN1, there is an inactivation of menin (encoded by the MEN1 gene) that affects cell division and gene transcription of the CDKN1B regulator p27.[3]

This mutation in CDKN1B was first identified in rats. Subsequently, Franklin et al tested their theory that CDKIs may work as tumor suppressor genes in mouse models. They found that the loss of function of p18 and p27 leads to a wide range of multiple endocrine gland tumors that predominantly affect the pituitary, thyroid, adrenal, and parathyroid glands.[5] In 2002, Fritz et al 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, which has an autosomal recessive inheritance pattern in rats. In 2006, the same team reported the first case of MEN4 in humans after studying 3 generations of a family 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 MENs in Delphi, Greece.[8] Frederiksen et al reviewed 29 cases published before June 2020 and suggested 16 mutations involved in MEN4 (12 missense, three small deletions, and one duplication).[3] 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 non-functional) and gastroenteropancreatic neuroendocrine tumors.

Epidemiology

MEN4 is a new member of MEN syndromes that 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 challenging to estimate, but it is likely around 3%.[2] 

Given that very few cases of MEN4 are reported (and many are undiagnosed), the exact incidence and prevalence of MEN4 are uncertain. The age of onset is also not apparent; it may be earlier than in MEN1, but the evidence is conflicting, and additional research is required for confirmation.[3]

Pathophysiology

As previously discussed, MEN4 occurs due to mutations in the CDKN1B gene (located on chromosome 12p13.1), a tumor suppressor gene that encodes protein p27Kip1 (commonly called p27 or Kip1).[6] The reduced expression of p27 by this mutation results in uncontrolled cell-cycle progression. The reported incidence of CDKN1B mutations in patients with a MEN1-related phenotype is 1% to 4%.[10]

MEN4 can impact various glands and organ systems:  

Parathyroid Gland

Primary hyperparathyroidism has been reported in up to 80% to 90% of cases with MEN4.[11] Primary hyperparathyroidism presents later in MEN4 compared with MEN1, predominantly in females.[12] Only one case of recurrent hyperparathyroidism has been reported after parathyroidectomy, suggesting a milder disease spectrum than MEN1.[13] The histology of resected glands in MEN4 is consistent with parathyroid adenoma.[3]

Pituitary Gland

The second most common presentation of MEN4 is pituitary adenoma (nonfunctional and functional). It is proposed that 10% of patients with MEN4 have acromegaly, and 5% have Cushing disease. These findings are similar to those for MEN1.[3] A recent study found that 2.6% of patients with Cushing disease have the CDKN1B mutation.[14] Prolactinomas are rare in MEN4.[3]

Pancreas

The prevalence of gastrinomas and nonfunctional pancreatic tumors in MEN4 is approximately 25%. This is much lower than in MEN1. No case reports of insulinoma, vasoactive intestinal peptide-secreting tumor (VIPoma), glucagonoma, or ectopic adrenocorticotropic hormone (ACTH)–secreting neuroendocrine tumors exist in MEN4 cases.[4]

Other 

There have also been reports of adrenal tumors, testicular cancer, cervical carcinoma, papillary thyroid cancer, colon cancer, carcinoid, and meningioma associated with MEN4.[3][4] A recent report presented 2 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.[15]

History and Physical

A detailed and comprehensive family history is essential when evaluating those with suspected MEN4. This is because MEN4 has a heterogeneous phenotypic expression that can lead to different syndrome manifestations within members of the same family.

It is also important to assess patients for hypercalcemia symptoms due to primary hyperparathyroidism and its associated clinical complications (eg, renal calculi and osteoporosis); signs and symptoms of nonfunctional and functional pituitary tumors (eg, visual changes); and signs and symptoms of neuroendocrine gastropancreatic tumors (eg, heartburn).

Past medical history should be evaluated, with specific inquiries about peptic ulcers, cancer (especially breast and reproductive organs), and surgical history. 

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, reinforcing the need for a detailed personal 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 is similar to MEN1. Investigations evaluate parathyroid, pituitary, neuroendocrine, and reproductive organ tumors. Carcinoid tumors and meningioma can also occur in patients with MEN4. 

Specifically, evaluations should focus on the following:

Parathyroid Gland

Primary hyperparathyroidism is the most common presentation of MEN4. Biochemical investigations include calcium, parathyroid hormone, vitamin D, 24-hour urine calcium, and creatinine to confirm the diagnosis; after that, an ultrasound of the parathyroid glands is recommended. If the parathyroid ultrasound result is unclear, a ^99mtechnetium (^99mTc) sestamibi scan should be undertaken.

If both parathyroid ultrasound and ^99mTc sestamibi scan are unclear, 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 (dual-energy x-ray absorptiometry [DXA]) can be considered to evaluate 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, 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, such as an oral glucose tolerance test for growth hormone excess and an overnight dexamethasone suppression test for cortisol excess, can be undertaken if initial history or initial investigation is suggestive of hormone excess. Prolactinomas are rare in MEN4, but nonfunctioning pituitary adenomas can occur, causing pressure effects or hypopituitarism; accordingly, 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]

Pancreas

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.[11][16] 

It is recommended to check fasting gastrointestinal hormones annually, including gastrin, chromogranin A, pancreatic polypeptide, vasointestinal polypeptide, glucagon, and fasting glucose level C-peptide and insulin. Radiological investigations, including CT, MRI, endoscopic ultrasound, octreotide scan, and ⁶⁸Ga-labelled DOTA⁰-Tyr³ octreotide (⁶⁸Ga-DOTATOC) positron emission tomography (PET), can be undertaken depending on local availability and preference.[11] 

Other Organs

As previously discussed, MEN4 can affect multiple other organs; however, due to the paucity of literature on MEN4, it is difficult to provide any guidance regarding evaluating 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 performed 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] One such test is the CDKN1B gene.

Treatment / Management

The treatment and management of MEN4 is dependent upon where it presents:

Parathyroid Gland

Currently, there is no specific guidance with regard to the treatment of primary hyperparathyroidism in MEN4. The indication for surgery (parathyroidectomy) remains similar to the MEN1 guidelines.[4][11] It is important to individualize surgical treatment. Furthermore, surgery should be carried out by an experienced endocrine surgeon.(A1)

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 causes a visual-field defect. Medical treatment includes somatostatin receptor analogs (octreotide or lanreotide) for acromegaly and dopamine agonists (cabergoline or bromocriptine) for prolactinomas. Radiotherapy can be considered if the pituitary tumor has aggressive features on radiological or histological examination.

Pancreas

The management approach for nonfunctional or functional neuroendocrine gastropancreatic tumors is similar to that of 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. There are no reported cases of insulinoma, VIPoma, glucagonoma, or ectopic ACTH-secreting neuroendocrine tumors in MEN4.[3](B3)

Others

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

Differential Diagnosis

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

Prognosis

Current evidence is too limited to conclude the prognosis of MEN4, and disease onset is still to be elucidated. According to Frederiksen et al, disease onset in MEN4 might be earlier than in MEN1.[3] However, de Laat et al found that those with the MEN1 phenotype, which was mutation-negative, developed manifestations later in life and had improved life expectancy.[17] Although this group may have had MEN4, conclusions cannot be drawn. As additional cases of MEN4 are diagnosed, this area of the debate will have more definite answers.

Complications

Complications associated with MEN4 are related to the disease burden 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 associated manifestations.