Beyond MEN1, when to think about MEN4? Retrospective study on 5600 patients in the French population & literature review.

CONTEXT: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically-negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. DESIGN: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. PATIENTS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French TENGEN network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants, i.e. with genetically-confirmed MEN4 diagnosis, in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. RESULTS: From 5600 MEN1-suspected patients analyzed, four patients with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, PHPT and adrenal nodule, isolated PHPT, PHPT and pNET. We listed 29 patients with CDKN1B class 4/5 variants from literature. Compared to matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. CONCLUSION: The prevalence of MEN4 is low. PHPT and PA represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Diagnostic Performance of Cervical Ultrasound, 99mTc-Sestamibi Scintigraphy, and Contrast-Enhanced 18F-Fluorocholine PET in Primary Hyperparathyroidism.

Preoperative localization of pathologic parathyroids is crucial for minimally invasive treatment of primary hyperparathyroidism (PHPT). This study compared contrast-enhanced 18F-fluorocholine PET/CT, cervical ultrasonography (CU), and conventional scintigraphic imaging modalities (MIBI scintigraphy, consisting of 99mTc-sestamibi/123I-sodium iodide SPECT/CT, 99mTc-sestamibi/123I-sodium iodide planar subtraction imaging, and 99mTc-sestamibi planar dual-phase imaging), combined and individually, for preoperative localization of hyperfunctional parathyroids in PHPT. The gold standard was histologic examination. Methods: Data from consecutive patients with clinically suspected PHPT were retrospectively collected. All 3 imaging modalities were systematically performed. The ability of 18F-fluorocholine PET/CT, CU, and MIBI scintigraphy to identify a hyperfunctional parathyroid and specify the side or identify an ectopic location was noted. Patients underwent surgical exploration if at least 1 examination was positive. The findings of CU + MIBI scintigraphy combined were considered positive if CU and MIBI scintigraphy separately showed a hyperfunctional parathyroid gland on the same side or in the same ectopic location; any findings other than these were considered negative. The composite judgment criterion for pathologic parathyroid was a combination of histologic analysis and normalization of parathyroid hormone and calcium levels. Results: In total, 149 pathologic parathyroids were found in 143 of the 144 included patients. 18F-fluorocholine PET/CT diagnosed 148 of 149 pathologic parathyroids. Only 4 false-positives and 1 false-negative were found. The 18F-fluorocholine PET/CT sensitivity of 99.3% was superior to that of CU, at 75.2% (P < 0.0001); MIBI scintigraphy, at 65.1% (P < 0.0001); and CU + MIBI scintigraphy, at 89.9%, (P = 0.0009). Five of the 5 ectopic locations were diagnosed by 18F-fluorocholine PET/CT, 2 of the 5 by MIBI scintigraphy, and none by CU. Accuracy was better for 18F-fluorocholine PET/CT, at 98%, than for CU, at 84% (P < 0.0001); MIBI scintigraphy, at 81% (P < 0.0001); or CU + MIBI scintigraphy, at 91% (P < 0.0001). Among the 72 (50%) patients who had a negative CU + MIBI scintigraphy result, 18F-fluorocholine PET/CT correctly identified hyperfunctional thyroids in 70 (97.2%). Average uptake in the 18F-fluorocholine PET/CT hyperfunctional parathyroid was higher than that in the adjacent thyroid (SUVmax adjusted for lean body mass, 6.45 vs. 2.15) (P < 0.0001). Conclusion: The accuracy of 18F-fluorocholine PET/CT is higher than that of CU and MIBI scintigraphy for localization of hyperfunctional parathyroids, justifying the systematic use of 18F-fluorocholine PET/CT as the first-line method for PHPT diagnosis.

Adrenal ganglioneuromas: a retrospective multicentric study of 104 cases from the COMETE network.

OBJECTIVE: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management. METHODS: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center. RESULTS: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156)). CONCLUSION: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.

Pre-term birth in women exposed to Cushing's disease: the baby-cush study.

DESIGN: Hypercortisolism during pregnancy is a risk factor for prematurity. Long-term exposure to hypercortisolism may lead to permanent comorbidities, such as hypertension or diabetes, even after remission. Our aim was to determine whether women with a history of Cushing's disease (and being eu-, hypo- or hypercortisolic at the time of pregnancy) had the same risks of comorbidities, and especially prematurity, during pregnancy. METHODS: It was a retrospective multicentric study focusing on mothers with a history of Cushing's disease or diagnosed during pregnancy, followed in French tertiary referral centers. We compared the outcomes of pregnancies depending on the cortisolic status at the time of pregnancy. RESULTS: A total of 60 patients (78 pregnancies including 21 with hypercortisolism, 32 with hypocortisolism and 25 in eucortisolism in 25) were evaluated. The overall rate of preterm birth was 24.3%, with a peak in women diagnosed during pregnancy (62.5%), a high risk in hypercortisolic (33%) and hypocortisolic (19.3%), and a low risk (8%) in eucortisolic women Gestational diabetes and hypertension were observed in 21% and 10.4% of the whole cohort, with a higher risk in hypercortisolic women. Cesarean delivery was performed in 33.7% of the cohort. CONCLUSIONS: Being non-eucortisolic at the time of pregnancy increases the risk of prematurity and comorbidities compared to the general population. Women with a history of Cushing's disease should thus be carefully monitored during pregnancy. The high rate of cesarean delivery emphasizes the fact that these pregnancies should always be considered at risk.

Levothyroxine dose adjustment in hypothyroid patients following gastric sleeve surgery.

INTRODUCTION: Euthyroid patients show decreased TSH level following sleeve gastrectomy. However, studies of levothyroxine absorption after bariatric surgery reported contradictory results and data on levothyroxine dose adjustment according to weight are sparse. The aim of this study was to evaluate levothyroxine dose adjustment during weight loss following sleeve surgery. METHOD: This retrospective study assessed change in levothyroxine dose in patients undergoing sleeve gastrectomy at the university hospital center of Nîmes (France) between January 2010 and March 2016. Patients were receiving standard bariatric surgery follow-up with levothyroxine therapy for hypothyroidism. RESULTS: Fifty-two of the 271 patients who underwent sleeve gastrectomy (19.2%) were being treated with levothyroxine. Among these patients, 31 were followed up for 12 months, including 12 who were followed up for 24 months. Mean weight loss was 35±11kg at 12 months and 41.8±10.2 kg at 24 months. Daily levothyroxine dose decreased from 108 [88-144] µg/day to 94 [63-125] µg/day at 12 months and 69 [44-134] µg/day at 24 months, with positive correlation between dose and weight loss at 12 months (P=0.03). Weight-adjusted dose was 1.04 [0.81-1.24] µg/kg/day at baseline, 1.14 [0.85-1.66] µg/kg/day at 12 months, and 0.85 [0.53-2.10] µg/kg/day at 24 months, showing no correlation with weight loss. Median TSH level dropped to 1.30 [0.63-2.27] mIU/l at 12 months and 1.48 [1.08-2.42] mIU/l at 24 months. CONCLUSION: Despite a decrease in daily levothyroxine dose correlating with weight loss at 12 months, the absence of correlation with weight-adjusted dose suggests the involvement of confounding factors such as poor levothyroxine absorption or altered thyroid function. Further studies are required to elucidate the absorption of levothyroxine.