Adult-onset familial insulinomatosis is a rare disorder with recurrent, severe hypoglycemia caused by multiple insulin-secreting pancreatic tumors. The etiology was unclear until the variant p.Ser64Phe in the transcription factor MAFA, a key coordinator of β-cell insulin secretion, was defined as the cause in two families. We here describe detailed genetic, clinical, and family analyses of two sisters with insulinomatosis, aiming to identify further disease causes. Using exome sequencing, we detected a novel, heterozygous missense variant, p.Thr57Arg, in MAFA’s highly conserved transactivation domain. The impact of the affected region is so crucial that in vitro expression studies replacing Thr57 have already been performed, demonstrating a phosphorylation defect with the impairment of transactivation activity and degradation. However, prior to our study, the link to human disease was missing. Furthermore, mild hyperglycemia was observed in six additional, heterozygote family members, indicating that not only insulinomatosis but also MODY-like symptoms co-segregate with p.Thr57Arg. The pre-described MAFA variant, p.Ser64Phe, is located in the same domain, impairs the same phosphorylation cascade, and results in the same symptoms. We confirm MAFA phosphorylation defects are important causes of a characteristic syndrome, thus complementing the pathophysiological and diagnostic disease concept. Additionally, we verify the high penetrance and autosomal dominant inheritance pattern.

Background: Calcitonin, a tumor marker primarily used to diagnose medullary thyroid carcinoma (MTC), can also be elevated in other conditions, complicating diagnosis. This study aims to provide a clinical evaluation of the real-world consequences of unexplained calcitonin elevation. Methods: We conducted a retrospective cohort study of patients with elevated basal calcitonin levels who presented at the Department of General, Visceral, and Transplantation Surgery, University Medical Center Mainz, between January 2015 and March 2025. Additionally, we reviewed electronic health records from 2007 onward for patients with ICD codes indicating calcitonin hypersecretion. Patients with confirmed MTC or genetic syndromes were excluded. Results: Of 345 patients with elevated calcitonin levels, 167 (48%) met the inclusion criteria, and 29 additional patients with calcitonin hypersecretion were identified via ICD, resulting in 167 patients analyzed. More than half of the patients were female (52%), had an average age of 53.9 years and a high prevalence of goiter (86%). Calcitonin levels were slightly elevated (<20 pg/mL) in 81% of cases and were above 50 pg/mL in only 10 patients. Surgery was performed in 77% of patients, mainly to exclude malignancy. Postoperatively, calcitonin normalized in 86% of patients but remained elevated in eight patients. Two of these patients were found to have false-positive results due to assay interference. Follow-up data were incomplete for a substantial proportion of patients, with a median follow-up of 4.6 months. The mortality rate was 4%, with causes unrelated to calcitonin levels. Conclusions: Elevated basal calcitonin levels, especially slightly elevated levels (<20 pg/mL), are common in clinical practice and often do not appear to be related to malignant disease, so careful investigation is required. Persistently elevated calcitonin levels justify further examinations, especially if other explanations can be ruled out. Only a few patients attend follow-up appointments, which makes patient follow-up challenging.

Papillary thyroid carcinoma (PTC) is the most common malignant thyroid tumor, with a small proportion of patients presenting with advanced disease. The recent European Society of Endocrine Surgeons (ESES) consensus introduced a refined definition of advanced thyroid cancer. This study aimed to characterize real-world clinical features, treatment patterns, and surgical outcomes of patients with advanced PTC according to the updated ESES definition treated at a high-volume endocrine surgery center. This monocentric, retrospective cohort study included all patients who underwent primary surgery for advanced PTC at a high-volume endocrine surgery center between 2015 and 2023. Clinical data originated from our own patients in the EUROCRINE ^® registry. A total of 33 patients with advanced PTC were included. Median age at diagnosis was 54 years, 52% were male, and median Charlson Comorbidity Index (CCI) was 2, indicating a low comorbidity burden. Among patients disease-free after surgery (n = 27), 11 (41%) experienced tumor recurrence, most frequently in lymph nodes and lung combined (36%) or in lymph nodes alone (27%). Median recurrence-free survival was 98 months. Patients with persistent disease after surgery had a poor prognosis, with a median progression-free survival of 4.5 months. Age > 55 years was associated with reduced overall survival ( p = 0.007), while male sex was associated with increased recurrence risk ( p = 0.047); both findings should be interpreted with caution. Despite advanced disease, most patients achieved disease-free status after primary surgery, with the majority being alive at last follow-up. Due to the limited sample size and missing follow-up data for some patients, these findings should be taken with caution, and larger studies are needed to confirm potential predictors of survival and recurrence.