Caracterização genética da Neoplasia Endócrina Múltipla do Tipo 1 no Baixo Jaguaribe, Ce: o impacto do rastreamento molecular da variante germinativa, MEN1 c.654G>T

Abstract

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant inherited syndrome caused by pathogenic germline variants in the MEN1 gene, predisposing affected individuals to the development of endocrine and non-endocrine neoplasms, most commonly involving the parathyroid glands, pituitary gland, and duodenopancreatic endocrine cells. The clinical diagnosis of MEN1 is established when at least one of the following criteria is met: the presence of tumours affecting at least two MEN1-associated endocrine tissues; the occurrence of a single MEN1- associated tumour in a first-degree relative of an individual with a confirmed clinical diagnosis; or the identification of a pathogenic germline variant in the MEN1 gene. This study defined a geographical microregion in Baixo Jaguaribe, in the interior of Ceará, Brazil, to investigate the clinical variability of MEN1 cases in carriers of the pathogenic germline variant NM_001370259.2(MEN1):654+1G>T and to assess the impact of implementing molecular screening for this variant among at-risk relatives residing in the region. A care pathway was proposed, offering Sanger sequencing to patients with a clinical diagnosis and their at-risk relatives, in addition to the construction of pedigree charts for family investigation. The study included 50 individuals: five index cases with a confirmed clinical diagnosis and 45 relatives, all belonging to five families from the same geographical region, with no known parental relationship between the families. The index cases were genetically confirmed through identification of the pathogenic MEN1 variant. Among the 45 at-risk relatives, 18 (40.0%) had inherited the variant, whereas 27 (60.0%) did not carry it and were therefore excluded from clinical follow-up. Of the total number of variant carriers, ten were asymptomatic (43.5%). In the study cohort, the 23 individuals carrying the variant were divided into three groups: index cases (n = 5), with a mean age of 45.6 years (±15.2); relatives with clinical manifestations (n = 8), with a mean age of 48.1 years (±14.3); and asymptomatic family members (n = 10), with a mean age of 27.8 years (±13.9). Age analysis revealed a significant difference between symptomatic and asymptomatic family members (p = 0.027), suggesting that early access to genetic testing in this at-risk population may improve prognosis and reduce morbidity and mortality. Furthermore, the mean ages of the index cases and symptomatic relatives suggest a prolonged interval between symptom onset and referral to specialized care, delaying family screening, whereas the younger age of asymptomatic individuals underscores the importance of early diagnosis. No significant differences were observed between sexes. Regarding clinical manifestations, pituitary tumours were prevalent among index cases, with the classic MEN1 triad present in four of the five individuals. Among symptomatic relatives, primary hyperparathyroidism and gastroenteropancreatic neuroendocrine tumours were the most frequent initial manifestations. Skin lesions suggestive of collagenomas were identified in three individuals and may represent important clinical warning signs. The study involved active and systematic screening, including pedigree construction and genetic sequencing across multiple generations of five families, revealing a pattern of vertical transmission consistent with highly penetrant autosomal dominant inheritance. The identification of the same pathogenic variant in unrelated index cases, in a region without previously described MEN1 mutational hot spots, suggests a possible founder effect, potentially associated with geographical isolation and/or inbreeding characteristic of rural communities.