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Three Novel MEN1 Variants in AIP-Negative Familial Isolated Pituitary Adenoma Patients

Sema Yarman¹, Feyza Nur Tuncer², Esin Serbest³

¹Division of Endocrinology and Metabolic Diseases, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Pathobiology : Journal of Immunopathology, Molecular and Cellular Biology

|January 11, 2019

Abstract

Objectives:

Pituitary adenomas (PAs) may rarely occur in well-defined hereditary conditions, like multiple endocrine neoplasia type 1 (MEN1) syndrome and familial isolated pituitary adenoma (FIPA) associated with germline mutations in MEN1 and AIP, respectively. This study aimed to assess MEN1 genetic abnormalities in AIP mutation-negative FIPA patients, not associated with MEN1 components.

Methods:

Among 20 patients evaluated in 13 FIPA families, 12 were previously reported as AIP mutation-negative. In this study, 6 new families with 8 patients were recruited. All patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in AIP and MEN1, and AIP sequencing was performed in additional patients. AIP mutation-negative patients were subjected to MEN1 sequencing.

Results:

Our cohort revealed only 3 novel heterozygous MEN1 variants including c.1846T>A p.(*616Argext*21), rs778272737:T>C, and rs972128957:C>T in 2 families, with patients diagnosed with Cushing disease, nonfunction al adenoma, and acromegaly, respectively. Among them, c.1846T>A p. (*616Argext*21) is a stop codon read-through, whereas the others are 3'UTR variations. MEN1 variation frequency was detected as 15%.

Conclusions:

MEN1 alterations can be of significance in FIPA patients and screening could be offered to AIP mutation-negative patients without MEN1 features. Further studies are needed to clarify the role of MEN1 in FIPA patients.

Insights

Genetic testing for MEN1 (multiple endocrine neoplasia type 1) variants is significant in familial isolated pituitary adenoma (FIPA) patients lacking AIP mutations. This screening can identify potential hereditary pituitary adenoma causes.

Area of Science:

Endocrinology
Genetics
Oncology

Background:

Familial isolated pituitary adenoma (FIPA) is a rare condition, often linked to AIP or MEN1 gene mutations.
While AIP mutations are frequently screened, the role of MEN1 in AIP-negative FIPA cases requires further investigation.

Observation:

This study analyzed 20 patients from 13 FIPA families, focusing on AIP mutation-negative individuals.
Genetic analysis included multiplex ligation-dependent probe amplification and sequencing for AIP and MEN1 genes.
Six new families (8 patients) were recruited, expanding the cohort for genetic assessment.

Findings:

Three novel heterozygous MEN1 variants were identified in two families, with an overall MEN1 variation frequency of 15%.
These variants were associated with Cushing disease, nonfunctional adenoma, and acromegaly.
One variant, c.1846T>A p.(*616Argext*21), involved a stop codon read-through, while others were 3'UTR variations.

Implications:

MEN1 gene alterations are clinically significant in AIP-negative FIPA patients.
Screening for MEN1 mutations should be considered in FIPA patients without identified AIP mutations or MEN1 syndrome features.
Further research is necessary to fully elucidate the contribution of MEN1 to FIPA pathogenesis.

Read full analysis

Keywords:

3′UTR variation Familial isolated pituitary adenoma MEN1 gene Stop codon read-through variation

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