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

Multiple Endocrine Neoplasia Type 4 (MEN4)

What is MEN4?

MEN4 is a rare autosomal dominant syndrome caused by pathogenic variants in the CDKN1B gene that presents with primary hyperparathyroidism in 100% of cases, followed by pituitary tumors, and should be managed at specialized centers with multidisciplinary expertise. 1

MEN4 clinically resembles MEN1 but typically manifests later in life with milder features and a more indolent course. 1, 2 The CDKN1B gene encodes p27kip1, a cell cycle inhibitor that regulates cellular proliferation, motility, and apoptosis. 1 Only 9 pedigrees with 13 pathogenic germline variants have been reported to date, making this the rarest and least known MEN syndrome. 1

Clinical Manifestations

Primary Hyperparathyroidism (PHPT)

• PHPT occurs in 100% of affected individuals and represents the hallmark feature of MEN4. 1, 3, 4
• Disease onset is typically later than MEN1, with the youngest reported case presenting at age 30. 1
• Hypercalcemia due to PHPT was documented in all 13 carriers in the largest reported family series. 4

Pituitary Neuroendocrine Tumors (PitNETs)

• PitNETs are the second most common manifestation, including somatotroph adenomas (growth hormone-secreting), corticotroph adenomas (ACTH-secreting causing Cushing disease), and non-functioning adenomas. 1, 4
• Both functional and non-functional pituitary tumors occur, with 4 out of 13 carriers in one series developing pituitary disease. 4

Other Manifestations

• Gastrointestinal neuroendocrine tumors appear less prevalent in MEN4 than in MEN1, though metastatic carcinoid tumors have been reported. 4
• Critically, despite animal model data showing pheochromocytomas and medullary thyroid carcinoma, no MEN2-spectrum tumors have ever been identified in human carriers. 1

Genetic Basis and Pathogenesis

• Pathogenic variants include frameshift, nonsense, and missense mutations that result in normal transcript levels but low or undetectable protein levels. 1
• The mechanism of pathogenesis involves reduced translation or protein half-life rather than absent gene expression. 1
• Loss-of-heterozygosity has been detected in parathyroid adenomas, supporting that CDKN1B acts as a tumor suppressor gene. 4

Diagnostic Approach

When to Test for MEN4

• Consider CDKN1B testing in patients with PHPT who test negative for MEN1 gene variants. 1
• Testing is 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

Diagnostic Pitfalls

• Do not assume MEN2-spectrum tumors 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

Surveillance Recommendations

Biochemical Screening

• Annual biochemical surveillance should begin at adolescence and include serum calcium and IGF-1 levels to screen for PHPT and growth hormone-secreting pituitary adenomas. 1
• Focus surveillance specifically on detecting growth hormone excess and glucocorticoid excess. 1

Imaging and Physical Assessment

• Routine anthropometric assessment with growth chart review is essential in children, as PitNETs may present with growth acceleration or growth retardation with weight gain. 1
• The timing and modality of imaging studies should follow established protocols, though specific MEN4 protocols are still being developed given the rarity of the syndrome. 3

Management Approach

Multidisciplinary Care

• Patients with MEN4 should be managed at specialized centers with multidisciplinary expertise in MEN syndromes. 1, 5
• Treatment should involve endocrinologists, surgeons, radiologists, and other specialists as needed. 1, 5
• A "virtual outpatient department" approach coordinating multiple specialist appointments on the same day is recommended. 5

Surgical Management of PHPT

• 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
• Surgical cure rates are significantly higher for presymptomatic patients (89%) compared to symptomatic patients (25%), emphasizing the importance of early detection through surveillance. 5

Pituitary Tumor Management

• Do not delay endocrine consultation when clinical signs of hormonal excess are present, as early intervention improves outcomes. 1
• Treatment decisions should be based on tumor functionality, size, and secretory profile. 5

Key Differences from MEN1

• MEN4 presents later in life with milder clinical features compared to MEN1. 1, 2, 6
• While MEN1 has 95% penetrance for PHPT, MEN4 shows 100% penetrance but at an older age. 3
• Gastrointestinal neuroendocrine tumors appear less common in MEN4 than in MEN1. 4
• MEN1 genetic analysis is conclusive in 90% of patients with typical phenotype, whereas MEN4 accounts for a small subset of MEN1-negative cases. 6

Clinical Implications

• Pre-symptomatic screening of at-risk individuals allows earlier detection and intervention, which significantly improves surgical cure rates. 3, 5
• The primary aim of treatment is curative when possible, with focus on maintaining disease-free status and quality of life. 5
• Further studies are needed to assess the real oncological risk of MEN4 carriers and to establish standardized screening protocols. 2