The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes

Abstract

The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex.

Figure 1

Pedigree of the FIPA family with the p.Gln307ProfsX104insC AIP mutation. Magnetic resonance imaging shows a saggital view of a pituitary adenoma in the proband (patient PT105.03, Table 1). Panels A, B and C show the hematoxylin and eosin, GH-staining and reticulin, respectively, in this aggressive pituitary tumor that was excised from patient PT105.03; the patient’s father was an unaffected AIP mutation carrier, while the paternal grandmother had a prolactinoma (but declined genetic studies).

Figure 2

A proposed algorithm for genetic testing in pituitary adenomas; abbreviations: FIPA = familial isolated pituitary adenomas; MEN 1= multiple endocrine neoplasia type 1.