title: AIP mutations in young patients with acromegaly and the Tampico Giant: the Mexican experience.
abstract: Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIP mutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIP gene in teeth obtained from the "Tampico Giant". Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIP gene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIP mutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIP mutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.
authors.affiliation: Experimental Endocrinology Unit/Endocrine Service, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Sur 132 number 142, Suite 210, Colonia las Americas, Mexico City, 01120, Mexico.|Neurological Center, Centro Médico ABC, Mexico City, Mexico.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ramírez-Rentería
authors.affiliation: Centre for Endocrinology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Hernández-Ramírez
authors.affiliation: Endocrinology Service, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico.
authors.forename: Lesly
authors.initials: L
authors.lastname: Portocarrero-Ortiz
authors.affiliation: Experimental Endocrinology Unit/Endocrine Service, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Sur 132 number 142, Suite 210, Colonia las Americas, Mexico City, 01120, Mexico.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Vargas
authors.affiliation: Neurological Center, Centro Médico ABC, Mexico City, Mexico.
authors.forename: Virgilio
authors.initials: V
authors.lastname: Melgar
authors.affiliation: Experimental Endocrinology Unit/Endocrine Service, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Sur 132 number 142, Suite 210, Colonia las Americas, Mexico City, 01120, Mexico.|Neurological Center, Centro Médico ABC, Mexico City, Mexico.
authors.forename: Etual
authors.initials: E
authors.lastname: Espinosa
authors.affiliation: Experimental Endocrinology Unit/Endocrine Service, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Sur 132 number 142, Suite 210, Colonia las Americas, Mexico City, 01120, Mexico.
authors.forename: Ana Laura
authors.initials: AL
authors.lastname: Espinosa-de-Los-Monteros
authors.affiliation: Experimental Endocrinology Unit/Endocrine Service, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Sur 132 number 142, Suite 210, Colonia las Americas, Mexico City, 01120, Mexico.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Sosa
authors.affiliation: Experimental Endocrinology Unit/Endocrine Service, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Sur 132 number 142, Suite 210, Colonia las Americas, Mexico City, 01120, Mexico.|Neurological Center, Centro Médico ABC, Mexico City, Mexico.
authors.forename: Baldomero
authors.initials: B
authors.lastname: González
authors.affiliation: Experimental Endocrinology Unit/Endocrine Service, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Sur 132 number 142, Suite 210, Colonia las Americas, Mexico City, 01120, Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: Zúñiga
authors.affiliation: Institute of Anthropology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Unterländer
authors.affiliation: Institute of Anthropology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Burger
authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter, NHS Foundation Trust, Exeter, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Stals
authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter, NHS Foundation Trust, Exeter, UK.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bussell
authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter, NHS Foundation Trust, Exeter, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Centre for Endocrinology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Dang
authors.affiliation: Centre for Endocrinology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Donato
authors.initials: D
authors.lastname: Iacovazzo
authors.affiliation: Centre for Endocrinology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Sonal
authors.initials: S
authors.lastname: Kapur
authors.affiliation: Centre for Endocrinology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Plamena
authors.initials: P
authors.lastname: Gabrovska
authors.affiliation: Centre for Endocrinology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Serban
authors.initials: S
authors.lastname: Radian
authors.affiliation: Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK.
authors.forename: Federico
authors.initials: F
authors.lastname: Roncaroli
authors.affiliation: Centre for Endocrinology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
authors.affiliation: Experimental Endocrinology Unit/Endocrine Service, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Sur 132 number 142, Suite 210, Colonia las Americas, Mexico City, 01120, Mexico. moises.mercado@endocrinologia.org.mx.|Neurological Center, Centro Médico ABC, Mexico City, Mexico. moises.mercado@endocrinologia.org.mx.
authors.forename: Moisés
authors.initials: M
authors.lastname: Mercado
mesh_terms: D000172:Acromegaly / Q000235:genetics*; D000236:Adenoma / Q000235:genetics; D000293:Adolescent; D000328:Adult; D005260:Female; D005787:Gene Frequency; D005877:Gigantism / Q000235:genetics*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008800:Mexico; D009154:Mutation; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein
keywords: AIP; Acromegaly; FIPA; Gigantism