Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

Abstract

Context: Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age %30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population. Objective: We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age %30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. Design: The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. Patients and settings: One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study. Results: Twenty-one out of 174 (12%) patients had AIP (nZ15, 8.6%) or MEN1 (nZ6, 3.4%) mutations. In pediatric patients (age %18 years old), AIP/MEN1 mutation frequency reached nearly 22% (nZ10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (nZ3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. Conclusion: Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis

“…Cazabat et al (39) also detected the mutation in a child with SPA from France, and in the reply to their letter, Stals reported their further haplotype analysis of patients with R304* mutations from several countries, indicating that the mutation can occur independently in various areas of the world and also have a founder effect in some cases. As the sample size of our study was relatively small, it is (20,42), although most studies found no large AIP locus deletions in the germline (34,43,44). Here, large deletions spanning from MEN1 to AIP were observed in tumors of some AIP missense variant-carrying patients but not in the germline.…”

“…There would also be another pathogenic mutation or a deletion in the AIP locus in another allele of the tumor at the beginning of tumorigenesis than that detected in the tumor from the c.90TOG variant, and then chromosome instability in the tumor genome could lead to larger deletions during the progressive stage than those in tumors from the c.784GOA, c.967COT, and c.976GOA variants. If this is the case, MLPA results combined with other tests across the MEN1 to AIP region could be used to determine prognosis, especially in patients carrying AIP or MEN1 germline mutations, as MEN1 mutations are also identified in some sporadic isolated pituitary macroadenoma patients (44).…”

Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas

“…These findings underscore the need to consider multiple endocrine neoplasia type 1 screening in patients younger than 30 years of age presenting with pituitary macroadenomas, particularly if hyperprolactinemia is present. 21 The distinction of silent subtype 3 adenomas from other pituitary adenomas is of clinical significance given their well-known aggressive behavior. Although ultrastructural examination still has an important role in the workup of unusual pituitary adenomas, ultrastructural examination was the only reliable way to subtype and determine the cellular origin of pituitary adenomas in the past.…”

THERAPY OF ENDOCRINE DISEASE: The challenges in managing giant prolactinomas

“…an aryl hydrocarbon receptor interacting protein (AIP) mutation) to develop familial pituitary adenomas (111,115). Appropriate genetic testing is therefore highly recommended in such cases, as detailed in several recent reviews (116,117,118).…”