What is the management approach for Multiple Endocrine Neoplasia type 4 (MEN 4)?

Multiple Endocrine Neoplasia Type 4 (MEN4)

Overview and Genetic Basis

MEN4 is a rare autosomal dominant syndrome caused by pathogenic variants in the CDKN1B gene, presenting with a phenotype similar to MEN1 but typically with later onset, milder features, and predominantly affecting the parathyroid glands (100% of cases) and pituitary gland. 1, 2

• The CDKN1B gene encodes p27kip1, a cell cycle inhibitor that regulates cellular proliferation, motility, and apoptosis 1, 3
• Only 9 pedigrees with 13 pathogenic germline variants have been reported to date, including frameshift, nonsense, and missense variants 1
• Pathogenic variants result in normal transcript levels but low or undetectable protein levels, suggesting reduced translation or protein half-life as the mechanism of pathogenesis 1
• Loss of heterozygosity has been detected in parathyroid adenomas, confirming CDKN1B acts as a tumor suppressor gene 4

Clinical Manifestations

Primary Hyperparathyroidism (PHPT)

• PHPT occurs in 100% of affected individuals and represents the hallmark feature of MEN4 1, 5, 4
• Disease onset is typically later than MEN1, with the youngest reported case presenting at age 30 1
• The clinical course is generally more indolent compared to MEN1 2, 6

Pituitary Neuroendocrine Tumors (PitNETs)

• PitNETs are the second most common manifestation, including somatotroph adenomas (causing acromegaly/gigantism), corticotroph adenomas (causing Cushing's disease), and non-functioning adenomas 1, 4
• Both functioning and non-functioning pituitary tumors occur with significant frequency 4

Other Manifestations

• Gastroenteropancreatic neuroendocrine tumors occur but appear less prevalent than in MEN1 2, 4
• Additional reported features include uterine neoplasms, adrenocortical masses, and thyroid tumors, though none occur frequently enough to mandate routine surveillance 1
• Notably, despite animal model data showing pheochromocytomas and medullary thyroid carcinoma, no MEN2-spectrum tumors have been identified in human carriers 1

Diagnostic Approach

Genetic Testing Indications

• Consider CDKN1B testing in patients with PHPT who test negative for MEN1 gene variants 1
• Testing is also appropriate for familial isolated parathyroid adenoma or isolated PitNET when MEN1 testing is negative 1
• Genetic testing should be offered to all first-degree relatives of confirmed carriers 1

Distinguishing MEN4 from MEN1

• MEN4 presents with later age of onset compared to MEN1 2, 6
• Clinical features are generally milder in MEN4 2, 6
• Gastrointestinal neuroendocrine tumors are less common in MEN4 than MEN1 4
• Both syndromes share the primary manifestations of PHPT and PitNETs 1, 2

Surveillance Recommendations

Biochemical Screening

Based on expert consensus, annual biochemical surveillance should begin at adolescence and include: 1

• Annual serum calcium (corrected for albumin) to screen for PHPT 1
• Annual IGF-1 levels to screen for growth hormone-secreting pituitary adenomas 1

Clinical Monitoring

• Focus surveillance on detecting growth hormone excess (gigantism/acromegaly) and glucocorticoid excess (Cushing's syndrome) 1
• Routine anthropometric assessment with growth chart review is essential in children, as PitNETs may present with growth acceleration (GH hypersecretion) or growth retardation with weight gain (ACTH hypersecretion) 1
• Any clinical concern for hormonal excess should prompt immediate endocrine consultation 1

Imaging Considerations

• A role for baseline or serial pre-symptomatic CNS imaging has not been established due to limited data 1
• The decision for pituitary imaging should be guided by biochemical abnormalities or clinical symptoms 1

Management Approach

General Principles

• Patients with MEN4 should be managed at specialized centers with multidisciplinary expertise in MEN syndromes 7
• Treatment should involve endocrinologists, surgeons, radiologists, and other specialists as needed 7
• The primary aim is curative treatment when possible, focusing on maintaining disease-free status and quality of life 7

Parathyroid Disease Management

• Surgical intervention is the definitive treatment for symptomatic PHPT 1
• Preoperative localization with ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT should be performed 1
• Given the high penetrance of PHPT in MEN4, early detection through surveillance allows for timely intervention 4

Pituitary Tumor Management

• Management depends on tumor functionality, size, and clinical manifestations 1
• Functioning adenomas causing acromegaly or Cushing's disease require prompt treatment to prevent morbidity 1
• Treatment options include surgical resection, medical therapy, and radiation therapy depending on tumor characteristics 7

Key Clinical Pitfalls

• Do not assume MEN2-spectrum tumors (pheochromocytoma, medullary thyroid carcinoma) will occur in MEN4 patients despite animal model data—these have never been documented in human carriers 1
• Avoid dismissing PHPT in younger patients as sporadic disease without genetic evaluation, particularly if MEN1 testing is negative 1
• Do not delay endocrine consultation when clinical signs of hormonal excess are present, as early intervention improves outcomes 1
• Given the rarity of MEN4, surveillance protocols are based on expert consensus rather than robust outcome data, requiring clinical judgment in implementation 1

Prognosis and Natural History

• The complete natural history remains incompletely defined due to the small number of reported cases 1, 2
• Disease penetrance and age-specific risks have not been thoroughly established as they have for MEN1 and MEN2 2
• The generally milder phenotype and later onset suggest a more favorable prognosis compared to MEN1, though long-term outcome data are lacking 2, 6
• Further studies are needed to assess the true oncological risk of MEN4 carriers and establish standardized screening protocols 2