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 4 pediatric patients with CD, and 4 with GH/PRL-secreting tumors who had some syndromic feature. 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 syndromic CD patients. There was one MEN1 and 3 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.

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

“…The tumors from AIPmut patients in a FIPA cohort were overwhelmingly macroadenomas (10). However, among 74 children with Cushing's disease, one AIP mutation was found in a patient diagnosed at the age of 6 years with a 3!4 mm ACTH-secreting adenoma (21). Subsequently, data are missing in the pediatric population to support the exclusion of children with microadenoma from the AIP genetic screening that we suggest in Fig.…”

“…There are few data assessing the prevalence of MEN1 mutations in the specific case of isolated and sporadic macroadenoma. Stratakis et al (21) reported one MEN1 mutation in a 11-year-old male with macroprolactinoma among six patients with isolated GH-or PRL-secreting adenoma. In our study, MEN1 mutations were identified in 3.4% of cases and this frequency reaches 6.5% in the pediatric population (nZ3/46).…”

“…No mutation was found in corticotroph adenoma patients and in the single thyrotropinoma patient. However, AIP mutations have already been reported in several young patients with isolated sporadic corticotroph adenomas (7,21), justifying AIP screening in such populations (Fig. 1).…”

Familial isolated pituitary adenomas experience at a single center: clinical importance of AIP mutation screening

“…In sporadic pituitary adenomas, the occurrence of AIP mutations is much less frequent (17,18). However, it has been previously described that younger patients with somatotropinomas have a higher frequency of germline mutations, especially those less than 25 years old (19,20). Thus, it seems reasonable to screen young patients with apparently sporadic invasive somatotropinomas or prolactinomas for AIP mutations.…”

A giant? Think of genetics: growth hormone-producing adenomas in the young are almost always the result of genetic defects

“…PRKAR1A mutations that lead to increased cAMP signaling, just like GNAS mutations, are responsible for gigantism or acromegaly in the context of Carney complex (CNC) but have never been found in sporadic GHPAs [4]. MEN1 (menin) gene mutations lead to gigantism and/or acromegaly in the context of multiple endocrine neoplasia (MEN) type 1 (MEN 1) but only rarely in sporadic acromegaly [5]. Mutations in the cyclin-dependent kinase (CDKN) 1B (CDKN1B) are found in MEN type 4 (MEN 4) [6]; other CDKNs, all essential molecules in the regulation of cell cycle, growth, and proliferation, are mutated, rarely, in MEN 1/MEN 4-like syndromic gigantism and/or acromegaly but not in sporadic GHPAs [7].…”