Abstract 3078: The Poor Prognosis of Diabetic Patients with High Ankle-Brachial Index Depends on the Presence of Masked Peripheral Arterial Disease

Background: A high ankle-brachial index (ABI &gt;1.40) is associated with poor prognosis. An underlying peripheral arterial disease (PAD) is frequent in diabetic patients with high ABI, although it cannot be adequately diagnosed by the ankle pressure measurement, due to stiff arteries. We hypothesized that in diabetic patients, the poor cardiovascular disease (CVD) prognosis associated with high ABI would depend on the coexistence of masked PAD. Methods: We reviewed the data of 403 consecutive diabetic patients who had a Doppler assessment of their lower limbs between 1999 and 2000. They were classified as “normal” when Doppler waveform patterns (DWP) were normal and ABI within the 0.91–1.39 range, “PAD only” in case of ABI ≤0.90, “stiff only” if ABI ≥1.40 with normal DWP, and “mixed disease” when ABI ≥1.40 with abnormal DWP. Patients were followed until 04/2008. The primary endpoint was the occurrence of any of the following events: death, stroke or myocardial infarction. Results: The patients (age: 65.6 ± 13.2 yrs, 54.6% females; 90.2% type-2 diabetes) were classified as “normal” (14.4%), “PAD only” (48.4%), “stiff only” (16.4%) and “mixed disease” (20.8%). During a mean follow-up of 6.5 years, the event-free survival curves of “PAD only” and “mixed disease” groups showed poorer prognosis than the “stiff only” and “normal” groups (figure ). In a model adjusted for age, sex, diabetes type and duration, traditional CVD risk factors, renal failure and CVD history, only the presence of PAD was significantly associated with the primary endpoint (OR: 3.36 (1.25 – 4.44), p=0.008). Conclusions: In diabetic patients with high ABI (&gt;1.40), only those with an associated PAD have a poorer prognosis. </jats:p

Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA

Evaluation of the occurrence of the manifestations of Carney complex in a french cohort of 70 patients during a three years standardized follow-up

International audienceIntroductionThe Carney Complex is a multiple endocrine and non endocrine neoplasia mostly due to PRKAR1A mutations. Spectrum of manifestations and genotypephenotype correlations have been previously described by retrospective studies. A prospective study evaluating the occurrence of the different manifestations was needed to precise the optimum follow-up.MethodsMulti-center national prospective study (Clinical Trials NCT00668291) including 70 patients mutated or wild-type for PRKAR1A followed prospectively during 3years with screening of the different manifestations by annual clinical, biological and radiological evaluation.ResultsThe cohort was compound of 50 females and 20 males with a mean age at 35.4years C/K16.7. Prevalence of cardiac myxomas at the end of the follow-up was 22.9% with newly diagnosis during the study period for 3 patients. Fortyfour% of patients with myxomas had related stroke attack and 56% had recurrences. Median delay between recurrences was 3.8years (minimummaximum: 0.8–24). Primary pigmented adrenal nodular disease was diagnosed in 57.1%. Skin manifestations, abnormal somatotroph hormonal tests and thyroid tumors were observed respectively in 58.6, 21.4 and 12.9%. Four% had melanotic shwannomas confirmed by histology. Spinal magnetic resonance imagery revealed lesions for 8.6%. Characteristic multiples calcified tumors on testicular ultrasonography were present in 35% of male patients. Ten% of female patients had surgery for breast myxoma or adenofibroma. Forty% had lesions classified ACR2-3 at mammography. Interestingly, four patients (8%) had breast adenocarcinomas (11.1% of female older than 30years). Eighty-three% of patients had PRKAR1A mutations. Patients carrying the mutation c.709-7del6 (34% of the cohort) had no manifestation or phenotype restricted to adrenal, lentigines and abnormal somatotroph test.ConclusionThe penetrance of the disease is high after screening except for patient carrying the c.709-7del6 mutation. This study highlights the importance of an annual follow-up, with especially annual cardiac imaging for patients with history of cardiac myxomas and earlier and regular senologic evaluation.DOI: 10.1530/endoabs.49.GP12

2018 Consensus of the French Society of Endocrinology: endocrine toxicities of cancer immunotherapies

Immunotherapy induced side effects: Are frequent, usually well-tolerated, and can lead to thyroid, pituitary, and less frequently adrenals and pancreas (fulminant diabetes) disease,. Do not contra-indicate immunotherapy, and rarely require high dose glucocorticoids; Need to be screened for, as there are acute manifestations, and replacement treatments can be given lifelong; Require a pre-immunotherapy evaluation; Require a careful follow-up at least during the first 6 months of immunotherapy

Unravelling the intra-familial correlations and heritability of tumor types in MEN1, a GTE study.

BACKGROUND: Multiple Endocrine Neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the GTE-cohort associated with a mutations in the JunD interacting domain, suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intra-familial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs), pituitary, adrenal, bronchial and thymic tumors (ThNETs) and the presence of metastasis. Intra-familial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intra-familial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and th-NETs. The heritability of these three tumor types was consistently strong and significant with 64% (Standard Error [SE]=0.13; p < 0.001) for pituitary tumor, 65% (SE=0,21; p < 0.001) for adrenal tumors, and 97% (SE=0.41; p=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step towards personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity

Therapeutic indications and metabolic effects of metreleptin in patients with lipodystrophy syndromes: Real-life experience from a national reference network

International audienceAim: To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real-life setting.Patients and methods: Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow-up during treatment.Results: Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6-47.6) years, body mass index was 23.8 (21.2-25.7) kg/m2 and serum leptin was 3.2 (1.0-4.9) ng/mL, 94% of patients had diabetes (66% insulin-treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2-76.0) months, was ongoing in 77% of patients at the latest follow-up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5-9.9)% [68 (48-85) mmol/mol] to 6.8 (5.6-7.4)% [51(38-57) mmol/mol], and 3.6 (1.7-8.5) mmol/L to 2.2 (1.1-3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1-9.1]% [61 (54-76) mmol/mol] at baseline vs. 7.7 [7.4-9.5]% [61(57-80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9-9.9] mmol/L to 2.5 [1.6-5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2-11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group.Conclusions: In this real-life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD