No abstract

AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

Background: Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments. Methods: We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at !30 years of age. Results: Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas. Conclusion: Germline AIPmut occur in 11.7% of patients !30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations inAIPaccount only for 15–25% of FIPA families.CDKN1Bmutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations inCDKN1Boccur among a large cohort ofAIPmutation-negative FIPA kindreds. Eighty-eightAIPmutation-negative FIPA families were studied and 124 affected subjects underwent sequencing ofCDKN1B. Functional analysis of putativeCDKN1Bmutations was performed usingin silicoandin vitroapproaches. GermlineCDKN1Banalysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T).In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27I119Tshows an abnormal migration pattern by SDS–PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic becauseIn vitroeffects were not seen. In conclusion, two patients had germline sequence changes inCDKN1B, which led to functional alterations in the encoded p27 proteinsin vitro. Such rareCDKN1Bvariants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients makeCDKN1Bsequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role ofCDKN1Bin pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.