Multiple Endocrine Neoplasia Type 4 (MEN4): Case Report and Review of Literature

Background:

MEN4 is an autosomal dominant disorder caused by a germline CDKN1B mutation, characterized by the occurrence of hyperparathyroidism, pituitary adenomas, and neuroendocrine tumors (NET). Less than 60 MEN4 cases were described thus far.

Aim:

To describe a family harboring a pathogenic variant in CDKN1B and review the literature on MEN4 clinical course.

Methods:

A Pubmed search using the terms CDKN1B and MEN4.

Results:

Case report: A 40-year-old male with aortic root dilatation was referred to our clinic due to genetic workup for suspected Marfan syndrome yielding a CDKN1B variant (c.320delA, p.Q107fs). The patient`s medical history is negative otherwise. However, family history was positive of hyperparathyroidism (age 40) and aortic root dilatation in his father, and small intestine NET and hypercalcemia in his paternal grandmother. On Sanger sequencing of alive family members, the patient’s father (72 y/o), asymptomatic son (6 y/o), sister (44 y/o), and her daughter (18) harbored the same CDKN1B variant.

Literature search yielded 23 case reports/series on MEN4, describing 60 patients (53 symptomatic, 29% males). The most frequent clinical manifestation was hyperparathyroidism (61.6%, median age at presentation 50 years [range 15-74])), pituitary adenoma (33.3%, age 12 years [5-62]) and NET (16.6%, age 50 years [35-69]), either variable presenting feature. Of note, hyperparathyroidism presented as either single or multiple adenomas.

Conclusions:

MEN4 is a rare syndrome with clinical presentation similar to MEN1 yet with a relatively late presentation of hyperparathyroidism and NET. In contrast, MEN4-related pituitary adenomas may present at an early age, possibly calling for earlier surveillance.