Multiple Endocrine Neoplasia

BackgroundPathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance.MethodsWe performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives.ResultsA RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were "de novo" and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found.Conclusionsa) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype-phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.

ContextTo date, penetrance figures for medullary thyroid cancer (MTC) for variants in rearranged during transfection (RET) have been estimated from families ascertained because of the presence of MTC.ObjectiveTo gain estimates of penetrance, unbiased by ascertainment, we analyzed 61 RET mutations assigned as disease causing by the American Thyroid Association (ATA) in population whole-exome sequencing data.DesignFor the 61 RET mutations, we used analyses of the observed allele frequencies in ∼51,000 individuals from the Exome Aggregation Consortium (ExAC) database that were not contributed via The Cancer Genome Atlas (TCGA; non-TCGA ExAC), assuming lifetime penetrance for MTC of 90%, 50%, and unbounded.SettingPopulation-based.ResultsTen of 61 ATA disease-causing RET mutations were present in the non-TCGA ExAC population with observed frequency consistent with penetrance for MTC of >90%. For p.Val804Met, the lifetime penetrance for MTC, estimated from the allele frequency observed, was 4% [95% confidence interval (CI), 0.9% to 8%].ConclusionsBased on penetrance analysis in carrier relatives of p.Val804Met-positive cases of MTC, p.Val804Met is currently understood to have high-lifetime penetrance for MTC (87% by age 70), albeit of later onset of MTC than other RET mutations. Given our unbiased estimate of penetrance for RET p.Val804Met of 4% (95% CI, 0.9% to 8%), the current recommendation by the ATA of prophylactic thyroidectomy as standard for all RET mutation carriers is likely inappropriate.

BackgroundSurvival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure.MethodsThe study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used.ResultsPatients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure.ConclusionsPatients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

ContextMultiple Endocrine Neoplasia (MEN) syndromes are rare autosomal dominant hereditary tumor predisposition syndromes affecting multiple family members. Carriers undergo health surveillance from early childhood onwards. Carriership or surveillance may influence Health-Related Quality of Life (HRQoL) for patients or their families.ObjectiveTo evaluate HRQoL in children and adolescents with genetically confirmed MEN1, MEN2A, and MEN2B, and to compare outcomes with their siblings without MEN and healthy Dutch norms. Secondary aims were to explore associations between HRQoL and clinical characteristics.MethodsThis nationwide cross-sectional study included 77 children with MEN (5-18 years) and 26 siblings (8-29 years). The Pediatric Quality of Life Inventory (PedsQL) was used to assess HRQoL, with children completing self-report questionnaires and parents providing proxy reports for their children with MEN. Sociodemographic and clinical data were obtained from medical records.ResultsChildren with MEN1 and MEN2A reported HRQoL comparable to siblings and healthy Dutch norms. Only children with MEN2B showed significantly lower physical HRQoL. No gender or age effects were observed. Parent-proxy scores were significantly higher than child self-reports on all domains, except for emotional functioning. Children with MEN1 and MEN2B having clinical MEN-related manifestations had significantly lower physical, social, and school functioning scores than those without clinical manifestations.ConclusionOverall, children with MEN reported HRQoL comparable to siblings and age-matched Dutch norms, except for reduced physical functioning in MEN2B. Clinical manifestations negatively affected physical, social, and school functioning, suggesting that children with the onset of disease may benefit from closer monitoring and targeted psychosocial support.