LM, a 42-year-old Lebanese woman, was referred for investigation of MEN1 syndrome. LM was diagnosed with a parathyroid adenoma aged 33 and a prolactinoma aged 42. LM’s relevant family history includes a sister diagnosed with a parathyroid adenoma. The result of germline testing of the menin gene was inconclusive, with no pathogenic variant identified. Subsequently, utilising a next generation sequencing gene panel, a pathogenic variant in CDKN1B (c.179G>A, p.Trp60Ter) was identified, confirming MEN4 syndrome. This variant results in a premature stop codon, leading to a truncated CDKN1B protein with predicted loss of CDKN1B function.
Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders that increases the likelihood of developing endocrine and non-endocrine tumours. Approximately 5-10% of patients who present with a MEN-1 like phenotype do not have mutations of the menin gene. Studies have found that up to 3% of this population harbour a CDKN1B mutation resulting in MEN4. The prevalence of this very rare disease is thought to be less than 1/million with less than 20 cases documented in the literature.1,2
PHENOTYPE: As with MEN1, primary hyperparathyroidism is the predominant phenotypic feature occurring in 80% of patients, followed by pituitary neoplasia in 37%, and less commonly gastropancreatic neuroendocrine tumours and adrenal neoplasia. These manifestations occur later in life and are less aggressive than MEN1.2,3
GENETICS & TUMORIGENESIS: MEN4 is caused by a germline mutation in the tumour suppressor gene CDKN1B. Interestingly, it does not always follow Knudson's 'two-hit' hypothesis. CDKN1B is located on chromosome 12p13.1 and codes for the protein p27. It plays an inhibitory role as part of the CDKI family of genes, which result in cell cycle arrest. Mutations of this gene therefore trigger uncontrolled cell cycle progression.3 A common pathway for tumorigenesis between MEN1 and MEN4 has been suggested whereby CDKN1B is transcriptionally regulated by menin through epigenetic mechanisms.4