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.
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.
Stratakis
C A
CA
Section on Endocrinology Genetics, Program on Developmental Endocrinology Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institute of Health (NIH), Bethesda, MD 20892, USA. stratakc@mail.nih.gov
Tichomirowa
M A
MA
Boikos
S
S
Azevedo
M F
MF
Lodish
M
M
Martari
M
M
Verma
S
S
Daly
A F
AF
Raygada
M
M
Keil
M F
MF
Papademetriou
J
J
Drori-Herishanu
L
L
Horvath
A
A
Tsang
K M
KM
Nesterova
M
M
Franklin
S
S
Vanbellinghen
J-F
JF
Bours
V
V
Salvatori
R
R
Beckers
A
A
D000293:Adolescent; D002648:Child; D002864:Chromogranins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D010375:Pedigree; D047748:Pituitary ACTH Hypersecretion / Q000175:diagnosis / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000175:diagnosis / Q000235:genetics*
C436291:CDKN1B protein, human; C493971:CDKN2C protein, human; D002864:Chromogranins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D050763:Cyclin-Dependent Kinase Inhibitor p18; D047908:Intracellular Signaling Peptides and Proteins; C517834:PRKAR1A protein, human; C103265:aryl hydrocarbon receptor-interacting protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs