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.

Somatic and germline mutations in the pathogenesis of pituitary adenomas

“…In the FIPA setting, AIP pathogenic variants are demonstrated in about 20% of families, while in cohorts of unselected apparently sporadic pituitary adenomas AIP pathogenic variants are rarely found -in less than 4% (11,84). However, in young adults (diagnosed < 30 years of age) with apparently sporadic adenomas (mostly macroadenomas), the prevalence of AIP pathogenic variants was higher, ranging between 1.6 and 13% (85,86,87,88,89,90,91,92,93). Further decreasing the age of diagnosis (pediatric/ adolescent patients <18 year/old) increases the frequency of AIP pathogenic variants to 11-25% (85,87,94,95,96,97,98).…”

Increased Population Risk ofAIP-Related Acromegaly and Gigantism in Ireland

“…We demonstrate that all 18 R304 * ‐positive pedigrees of Irish origin identified in the study inherited this allele from a common ancestor, the R304 * founder. In addition, we have shown that R304 * in pedigrees of English, Indian, Romanian, US Italian, Irish, and Mexican origin derives from independent recurrent mutational events [Chahal et al., ; Ramirez‐Renteria et al., ]. Founder AIP mut alleles have also been identified through haplotype analysis in Finnish [Vierimaa et al., ], Italian [Occhi et al., ], Comoros [Cuny et al., ], and English [Salvatori et al., ] populations, involving the p.Q14 * , p.R304 * , p.G117Afs * 39, and p.F269_H275dup alleles, respectively, but the present population frequency of all these founder alleles remains unknown.…”

Hereditary Pituitary Tumor Syndromes: Genetic and Clinical Aspects

“…Two-thirds of the AIP mutations lead to protein truncations, which remove segments of the TPR domains and/or carboxy-terminal end, and therefore, lead to loss of function of the protein 62,64,65 . A common genetic "hotspot" for mutations in the AIP protein is the 304 residue (R304X and R304Q), which affects a CpG sequence and has been shown to be present in several independent families from different parts of the world [65][66][67][68] . Other potential hotspots include the 271 and the 81 loci (65)(66).…”

“…Inactivating AIP mutations are responsible for 20% of FIPA cases 62,65 . Germline, heterozygous AIP mutations are also present in 5-10% of cases of sporadic GH-secreting adenomas [65][66][67] . Acromegaly patients with AIP mutations are usually diagnosed before age 30, usually harbor macroadenomas, frequently cosecrete prolactin and appear to be somewhat less responsive to treatment with somatostatin analogs [65][66][67] .…”