Endocrine Abstracts

JOINT1868

Introduction: MEN4 syndrome is a rare autosomal-dominant disorder characterised by the co-presence of multiple neuroendocrine tumors, mainly of pituitary and parathyroid origin, with fewer than 100 cases reported since the diagnosis was established in 2006.[1,2] The prevalence of genetically confirmed MEN4 resulting from likely pathogenic or pathogenic variants is 0.07% in patients with suspected MEN1.[2] The underlying molecular mechanism involves loss of function of the tumor suppressor protein p27 due to heterozygous mutation in the CDKN1B gene.[3] We present a case of a patient diagnosed with MEN4 syndrome resulting from a reported once across databases but never published in literature, pathogenic variant in the CDKN1B gene.

Case presentation: A 45-year-old female patient presented to the ward with suspected hypopituitarism. Symptoms on admission comprised amenorrhoea for a year, fatigue, dyssomnia, and arthralgia. She denied headaches, vision impairment, polydipsia, or polyuria. The patient’s history included obesity, hypertension, and hepatic steatosis. The hormonal work-up confirmed anterior hypopituitarism with mild hyperprolactinemia. The pituitary MR visualized a pituitary tumor sized 24x22x25 mm. The patient was scheduled for trans-sphenoid surgical excision. The pathology result indicated pituitary neuroendocrine tumor, with a weak-positive immunostaining for LH and alpha-subunit and a Ki67 proliferative index of less than 1%. Furthermore, the patient was diagnosed with mild primary hyperparathyroidism. Both parathyroid scintigraphy and neck ultrasound failed to detect affected glands. A single nodule was found on the thyroid ultrasound and later confirmed as a BIII lesion on FNA biopsy. Given the suspicion of multiple endocrine neoplasia, genetic testing was performed. After ruling out MEN1 syndrome, Sanger sequencing confirmed the presence of a heterozygotic, pathogenic variant of CDKN1B gene – a deletion at coding DNA position 285, located in the first exon of the gene. Resultant frame-shift mutation leading to premature termination codon presence precipitates nonsense-mediated decay of the aberrant mRNA. The patient’s family history was non-specific (parents or siblings are not available for testing, and the only child was negative on genetic screening). Computed tomography of the chest, abdomen and pelvis did not reveal any other pathological lesions so far. Since then, the patient has remained under active surveillance.

References: 1. Ruggeri RM, Benevento E, De Cicco F, et al. Endocrine. 2023;82:480-490.

2. Chevalier B, Coppin L, Romanet P, et al. J Clin Endocrinol Metab, 2024;109:e1482–e1493.

3. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, et al. Proc Natl Acad Sci USA. 2006;103:15558-63.