RESUMEN
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.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasia Endocrina Múltiple Tipo 1/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Neoplasias Hipofisarias/genética , Adolescente , Niño , Cromograninas , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Mutación de Línea Germinal , Humanos , Masculino , Linaje , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Neoplasias Hipofisarias/diagnósticoRESUMEN
The majority of pituitary adenomas occur sporadically, however, about 5% of all cases occur in a familial setting, of which over half are due to multiple endocrine neoplasia type 1 (MEN-1) and Carney's complex (CNC). Since the late 1990s we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes, a condition named familial isolated pituitary adenomas (FIPA). The clinical characteristics of FIPA vary from those of sporadic pituitary adenomas, as patients with FIPA have a younger age at diagnosis and larger tumours. About 15% of FIPA patients have mutations in the aryl hydrocarbon receptor interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. This review describes the clinical features of familial pituitary adenomas like MEN1, the MEN 1-like syndrome MEN-4, CNC, FIPA, the tumour pathologies found in this setting and the genetic/molecular data that have been recently reported.