Temporal deep learning framework for retinopathy prediction in patients with type 1 diabetes.

The adoption of electronic health records in hospitals has ensured the availability of large datasets that can be used to predict medical complications. The trajectories of patients in real-world settings are highly variable, making longitudinal data modeling challenging. In recent years, significant progress has been made in the study of deep learning models applied to time series; however, the application of these models to irregular medical time series (IMTS) remains limited. To address this issue, we developed a generic deep-learning-based framework for modeling IMTS that facilitates the comparative studies of sequential neural networks (transformers and long short-term memory) and irregular time representation techniques. A validation study to predict retinopathy complications was conducted on 1207 patients with type 1 diabetes in a French database using their historical glycosylated hemoglobin measurements, without any data aggregation or imputation. The transformer-based model combined with the soft one-hot representation of time gaps achieved the highest score: an area under the receiver operating characteristic curve of 88.65%, specificity of 85.56%, sensitivity of 83.33% and an improvement of 11.7% over the same architecture without time information. This is the first attempt to predict retinopathy complications in patients with type 1 diabetes using deep learning and longitudinal data collected from patient visits. This study highlighted the significance of modeling time gaps between medical records to improve prediction performance and the utility of a generic framework for conducting extensive comparative studies.

Association Between the Tissue and Circulating Advanced Glycation End-Products and the Micro- and Macrovascular Complications in Type 1 Diabetes: The DIABAGE Study.

INTRODUCTION: Type 1 diabetes is associated with an increased risk of vascular complications. We aimed to investigate the association between serum and tissue advanced glycation end-products (AGEs) and micro- and macrovascular complications in type 1 diabetes (T1D). METHODS: We conducted a cross-sectional study on 196 adults with T1D (mean age 44.53 ± 16, mean duration of diabetes 22 ± 12 years, mean HbA1c 8 ± 1.2%). AGEs were measured in blood serum (i.e., carboxymethyllysine (CML), methylglyoxal-hydroimidazolone-1 (MGH1), and pentosidine) and by measurement of skin autofluorescence (SAF). Associations between AGEs levels and vascular complications were analyzed using binary logistic regression. Correlations between AGEs and pulse wave velocity (PWV) were also assessed by linear regressions. Significant differences were set for p values less than 0.05. RESULTS: We found positive associations between different AGEs and vascular complications. SAF was associated with both microangiopathy (retinopathy: OR = 1.92, p = 0.011; neuropathy: OR = 2.02, p = 0.04; any microangiopathy: OR = 2.83, p < 0.0001) and macroangiopathy (coronaropathy: OR = 3.11, p = 0.009; any macroangiopathy: OR = 2.78, p = 0.003). For circulating AGEs, pentosidine was significantly associated with coronaropathy (OR = 1.61, p = 0.01) and any macroangiopathy (OR = 1.52, p = 0.005) while MGH1 was associated with nephropathy (OR 1.72, p = 0.03). Furthermore, a significant linear correlation was found between PWV and SAF (r = 0.43, p < 0.001), pentosidine (r = 0.28, p < 0.001), and MGH1 (r = 0.16, p = 0.031), but not for CML (r = 0.03, p = 0.598). CONCLUSIONS: Skin autofluorescence appears to be a useful marker for investigating both micro- and macrovascular complications in T1D. In this study, pentosidine was associated with macroangiopathy and MGH1 with nephropathy among the circulating AGEs. Furthermore, the correlations between PWV and AGEs may suggest their value in early prediction of vascular complications in T1D.

Efficacy of subcutaneous Levothyroxine in a case of refractory hypothyroidism: A case report.

RATIONALE: Daily oral synthetic levothyroxine (LT4) is the main treatment for hypothyroidism, which, in most cases, allows the regression of symptoms and the normalization of the thyroid function. However, rarely, despite a high dose of oral LT4, hypothyroidism persists and is called refractory hypothyroidism. Intravenous or intramuscular treatment is then often necessary. We report the case of a patient with refractory hypothyroidism successfully treated with subcutaneous LT4. INTERVENTIONS AND OUTCOMES: After 4 weeks of weekly intravenous injections of 200 µg LT4 in complement to the oral treatment, thyroid balance was improved (TSH: 21.8 mIU/L). We tested the replacement of intravenous with subcutaneous injections of LT4 and gradually increased injection frequency from 1 to 3 injections per week (600 µg/week). Simultaneously, oral treatment was gradually tapered off, and within a few months, thyroid function tests were normalized. Two years later, hormone levels remained normal without symptoms of hypothyroidism. The only side effect was a local reaction in the first few weeks of injections, which spontaneously resolved. LESSONS: In this case of unexplained oral LT4 malabsorption, subcutaneous injection allowed a self-administrated physiological dose of LT4 3 times weekly. Considering the efficacy of subcutaneous injection of LT4, this treatment could be a safe and easy alternative for patients with malabsorption.

Characteristics of newly diagnosed type 1 diabetes in paediatric and adult population from Reims University Hospital, France from 1997 to 2019.

French health insurance data showed that the incidence of type 1 diabetes mellitus (T1DM) in children increased over the years to 2015. The objective of our study was to assess the evolution of the number of incident cases of paediatric and adult type 1 diabetes in our institution, and to describe their clinical presentation and its evolution. All patients with T1DM managed at diagnosis at Reims University Hospital between 1997 and 2019 were included. The clinical and biological data were extracted from the Champagne-Ardenne Diabetes Network database. Included were 847 patients with a median age of 10.3 years. Diagnosis was established in 71% of cases before 15 years, 7.4% after 35 years. The number of newly diagnosed cases was 3.6-times higher in 2019 compared to 1997. Ketoacidosis, the frequency of which decreased with age (P < 0.0001), revealed diabetes in a total of 32% of cases and in 46% of children under 5 years. It was more severe in children than in adults (P = 0.03), and its frequency increased over the study period. Hypotrophy was found in 23% of children under 15 years of age, and was more pronounced before 5 years of age, with no improvement over time. We saw an increase in the frequency of obesity or overweight among adults. Our study showed an increase in incident cases of diabetes in our hospital that continued over time for both children and adults. Clinical features at diagnosis deteriorated during this period for those under 15 years of age with an increase in ketoacidosis frequency.

Comparative Evaluation of Two SD-OCT Macular Parameters (GCC, GCL) and RNFL in Chiasmal Compression.

Purpose: To evaluate the relationship between different macular thickness parameters analyzed by SD-OCT and the central visual field (VF) evaluated with automated kinetic perimetry in a cohort of patients with pituitary tumors. Methods: Data from patients with pituitary adenoma treated at Reims University Hospital between October 1st, 2017, and May 31st, 2018 were collected. All patients underwent an automated kinetic perimetry and a SD-OCT to map the ganglion cell complex (GCC), the ganglion cell layer (GCL) thickness and the retinal nerve fiber layer (RNFL) using devices from two different manufacturers. Univariate and multivariate analysis were used to evaluate the correlation between the area of central VF in square degrees (deg2) and the SD-OCT parameters (µm). Results: Eighty-eight eyes were included in the analysis. All the thickness parameters measured in SD-OCT decreased with the visual field alteration. The best correlation was observed between superior thickness parameters (GCC, GCL) and the inferior central visual field. The most pertinent predictive factors for visual field loss were the inferior central GCL and the nasal RNFL (both AUC=0.775) with a sensitivity respectively of 86% and 70%. Conclusion: This study suggests that both GCC, GCL thickness parameters could be reliable predictors of central visual field impairment in patients with pituitary tumors. There was no significative difference between both devices.

Contraception use and knowledge related to pregnancy in diabetic women.

BACKGROUND: Diabetes mellitus prevalence is increasing among women of child-bearing age. Diabetic pregnancy is associated with major maternal and fetal risks, and these can be reduced by preconception care. Pregnancy can be planned using appropriate effective contraception. The objective of this study was to assess diabetic patients' knowledge about pregnancy and to describe their contraceptive use. STUDY DESIGN: An observational study was conducted from February to July 2020 at Reims University Hospital, France. Inclusion criteria were: women aged 18 to 40years, with type 1 (T1D) or type 2 diabetes (T2D). Patients filled out a survey about contraceptive use and knowledge regarding diabetic pregnancy and data were completed from medical records. RESULTS: Eighty-nine T1D and 33 T2D patients were included, with mean ages of 27.9±6.3 and 32.6±4.6years, respectively. Seventy-five percent reported that they had been informed about pregnancy-related risks and 67% about the need to plan pregnancy. The preconception HbA1c target was known by 33% of patients. Appropriate knowledge about pregnancy was greater in T1D patients (65.9%, versus 36.4% in T2D patients; P=0.003). The rate of patients using an effective contraceptive method was 66.4%. Fifteen percent patients for whom contraception was recommended reported having no contraceptive method; 12.5% of contraception users were using a contraindicated method. CONCLUSION: A large majority of diabetic women were aware of pregnancy-related risks and the importance of pregnancy planning, but there are still gaps, especially in T2D patients. We need to improve our practices by providing more information and better access to appropriate effective contraception. GOV NUMBER: NCT04350879.

Pegvisomant treatment in acromegaly in clinical practice: Final results of the French ACROSTUDY (312 patients).

OBJECTIVE: We report the final analysis of the French ACROSTUDY, using data revised and enriched since the 2013 interim analysis. Our objective was to validate the use of pegvisomant (PEGV) in the treatment of acromegaly and to determine efficacy and safety. PATIENTS AND METHODS: Patients with acromegaly treated with PEGV and followed up for at least 5 years were included. Eighty-eight investigators from 62 clinical centers in France included patients from April 2007 to April 2014. PEGV dose and administration frequency were determined by the physicians, based on their clinical evaluation and local habits. No additional examinations beyond those performed in normal follow-up were required. Minimum recommended follow-up included check-ups at treatment initiation, 6 months, 12 months and then annually. RESULTS: In total, 312 patients were enrolled. Mean age was 46.1±14.3 years at introduction of PEGV. Median PEGV treatment duration was 6.3 years and median follow-up was 5.6 years. Median dose at initiation was 10mg/day. The percentages of patients with IGF-1 ≤ ULN (upper limit of normal) were 10% (n=300) at baseline, 54% at 6 months (n=278), and 61.7% (n=253) at 2 years, then stabilizing at 64.4% (n=180) at 5 years. Mean PEGV dose was 17.4±11.7mg in patients with controlled disease versus 21.1±17.3mg in those without control at 5 years. At 5 years, 21.8% of patients (54/248) were receiving >30mg PEGV per day. In patients with at least one pituitary imaging procedure during the 5-year follow-up (n=292), the most recent image showed stable tumor volume in 212 subjects (72.6%), increased volume in 13 (4.5%), and decreased volume in 30 (10.3%). No PEGV treatments were permanently discontinued due to transaminase elevation. There were no cases of liver failure. CONCLUSION: The French ACROSTUDY showed normalization of IGF-1 levels in 64.4% of a real-life cohort of patients, mostly with uncontrolled disease despite multiple prior therapies. Long-term follow-up showed a sustained effectiveness and good long-term safety.

Sex disparities in COVID-19 outcomes of inpatients with diabetes: insights from the CORONADO study.

OBJECTIVE: Male sex is one of the determinants of severe coronavirus diseas-e-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19. METHODS: We performed a sex-stratified analysis of clinical and biological features and outcomes (i.e. invasive mechanical ventilation (IMV), death, intensive care unit (ICU) admission and home discharge at day 7 (D7) or day 28 (D28)) in 2380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736). RESULTS: The study population was predominantly male (63.5%). After multiple adjustments, female sex was negatively associated with the primary outcome (IMV and/or death, OR: 0.66 (0.49-0.88)), death (OR: 0.49 (0.30-0.79)) and ICU admission (OR: 0.57 (0.43-0.77)) at D7 but only with ICU admission (OR: 0.58 (0.43-0.77)) at D28. Older age and a history of microvascular complications were predictors of death at D28 in both sexes, while chronic obstructive pulmonary disease (COPD) was predictive of death in women only. At admission, C-reactive protein (CRP), aspartate amino transferase (AST) and estimated glomerular filtration rate (eGFR), according to the CKD-EPI formula predicted death in both sexes. Lymphocytopenia was an independent predictor of death in women only, while thrombocytopenia and elevated plasma glucose concentration were predictors of death in men only. CONCLUSIONS: In patients with diabetes admitted for COVID-19, female sex was associated with lower incidence of early severe outcomes, but did not influence the overall in-hospital mortality, suggesting that diabetes mitigates the female protection from COVID-19 severity. Sex-associated biological determinants may be useful to optimize COVID-19 prevention and management in women and men.

A large extended family with hyperparathyroidism-jaw tumor syndrome due to deletion of the third exon of CDC73: clinical and molecular features.

PURPOSE: We described the phenotype of a large 4-generation family with Hyperparathyrodism-Jaw Tumor syndrome (HPT-JT) associated with a rare deletion of exon 3 of the CDC73 gene. METHODS: We collected medical, genetic data on 24 family members descended from a common ancestor carrying a heterozygous deletion of exon 3. RESULTS: Thirteen carried the deletion, the penetrance was estimated at 50% at 40 years. Seven patients (39 ± 14.5 years) presented with HPT which could start at 13. Median plasmatic calcium and PTH levels were 3.13 ± 0.7 mmol/L and 115 ± 406 pg/ml, respectively. Kidney disease related to hypercalcemia were present in 57.1% of patients. All seven patients underwent surgery to remove a single parathyroid adenoma. One recurrence occurred 7 years post-surgery. No parathyroid carcinoma has been found to date. We found two atypical parathyroid adenomas. We described an additional somatic variant in exon 1 of gene CDC73 in two tumors. Jaw tumors were not necessarily associated with hyperparathyroidism, as shown in one case. Two kidney cysts were also reported. Variable phenotype expressivity was emphasized by clinical presentations in 2 monozygotic twins: acute hypercalcemia, kidney failure and ossifying fibroma in one twin, versus normocalcemic parathyroid adenoma in the other one. CONCLUSION: We report a family carrier of a deletion of exon 3 of the CDC73 gene. This is characterized by a high level of hypercalcemia, deleterious kidney effects and atypical parathyroid adenomas without carcinomas. Onset and intensity of HPT remain unpredictable. The additional somatic mutation found in the parathyroid tumor could lead to these phenotypical variations.

Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: A propensity score analysis from the CORONADO study.

AIM: To investigate the association between routine use of dipeptidyl peptidase-4 (DPP-4) inhibitors and the severity of coronavirus disease 2019 (COVID-19) infection in patient with type 2 diabetes in a large multicentric study. MATERIALS AND METHODS: This study was a secondary analysis of the CORONADO study on 2449 patients with type 2 diabetes (T2D) hospitalized for COVID-19 in 68 French centres. The composite primary endpoint combined tracheal intubation for mechanical ventilation and death within 7 days of admission. Stabilized weights were computed for patients based on propensity score (DPP-4 inhibitors users vs. non-users) and were used in multivariable logistic regression models to estimate the average treatment effect in the treated as inverse probability of treatment weighting (IPTW). RESULTS: Five hundred and ninety-six participants were under DPP-4 inhibitors before admission to hospital (24.3%). The primary outcome occurred at similar rates in users and non-users of DPP-4 inhibitors (27.7% vs. 28.6%; p = .68). In propensity analysis, the IPTW-adjusted models showed no significant association between the use of DPP-4 inhibitors and the primary outcome by Day 7 (OR [95% CI]: 0.95 [0.77-1.17]) or Day 28 (OR [95% CI]: 0.96 [0.78-1.17]). Similar neutral findings were found between use of DPP-4 inhibitors and the risk of tracheal intubation and death. CONCLUSIONS: These data support the safety of DPP-4 inhibitors for diabetes management during the COVID-19 pandemic and they should not be discontinued.

Relationship between obesity and severe COVID-19 outcomes in patients with type 2 diabetes: Results from the CORONADO study.

AIM: To assess the relationship between body mass index (BMI) classes and early COVID-19 prognosis in inpatients with type 2 diabetes (T2D). METHODS: From the CORONAvirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study, we conducted an analysis in patients with T2D categorized by four BMI subgroups according to the World Health Organization classification. Clinical characteristics and COVID-19-related outcomes (i.e. intubation for mechanical ventilation [IMV], death and discharge by day 7 [D7]) were analysed according to BMI status. RESULTS: Among 1965 patients with T2D, 434 (22.1%) normal weight (18.5-24.9 kg/m2 , reference group), 726 (36.9%) overweight (25-29.9 kg/m2 ) and 805 (41.0%) obese subjects were analysed, including 491 (25.0%) with class I obesity (30-34.9 kg/m2 ) and 314 (16.0%) with class II/III obesity (≥35 kg/m2 ). In a multivariable-adjusted model, the primary outcome (i.e. IMV and/or death by D7) was significantly associated with overweight (OR 1.65 [1.05-2.59]), class I (OR 1.93 [1.19-3.14]) and class II/III obesity (OR 1.98 [1.11-3.52]). After multivariable adjustment, primary outcome by D7 was significantly associated with obesity in patients aged younger than 75 years, while such an association was no longer found in those aged older than 75 years. CONCLUSIONS: Overweight and obesity are associated with poor early prognosis in patients with T2D hospitalized for COVID-19. Importantly, the deleterious impact of obesity on COVID-19 prognosis was no longer observed in the elderly, highlighting the need for specific management in this population.

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome.

BACKGROUND: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. RESULTS: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. CONCLUSION: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

Evolution of macroprolactinomas during pregnancy: A cohort study of 85 pregnancies.

OBJECTIVE: Pregnancy in patients with macroprolactinomas has been associated with a higher risk of pituitary tumour growth. However, the incidence and risk factors remain unclear. We aimed to evaluate the evolution of macroprolactinomas during pregnancy and to identify potential risk factors. DESIGN, PATIENTS AND MEASUREMENTS: This is a two-centre, retrospective, observational study. All patients with macroprolactinomas, treated with a dopamine receptor agonist (DA), and who had at least one pregnancy were included. RESULTS: There were a total of 85 viable pregnancies in 46 patients with macroprolactinomas. At diagnosis, mean size of pituitary adenomas was 17.9 ± 8.2 mm (10-43 mm) and mean plasma prolactin level was 1012.2 ± 1606.1 µg/L (60-7804 µg/L). Tumour growth-related symptoms were identified 12 times in 9 patients (19.6%) including 3 cases of apoplexy. Restarting, changing and/or increasing DA treatment was effective in 10 cases. Emergency surgery had to be performed twice (due to pituitary apoplexy). Patients with tumour progression tended to present with larger tumours after initial treatment and before pregnancy (9.9 vs 5.9 mm; P = .0504 and 11.5 vs 7.3 mm; P = .0671, respectively), whereas adenoma size at diagnosis did not seem to be a significant factor. The obstetrical outcomes were comparable to the general population. CONCLUSIONS: Symptomatic growth of macroprolactinoma during pregnancy occurred in 19.6% of medically treated patients. This risk seems higher for patients with poor initial tumour response to the DA treatment. Tumour progression is generally well controlled with medical treatment during pregnancy.

Diagnostic Challenge in PLIN1-Associated Familial Partial Lipodystrophy.

CONTEXT: Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only six families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned because of the absence of lipodystrophy in these individuals and the elevated frequency of PLIN1 null variants in the general population. OBJECTIVES: To reevaluate the pathogenicity of PLIN1 frameshift variants owing to new data obtained in the largest series of patients with FPLD4. METHODS: We performed histological and molecular studies for patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance and carrying PLIN1 frameshift variants. RESULTS: We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in nine patients from four unrelated families. The FPLD4 stereotypical signs included postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, polycystic ovary syndrome and/or hirsutism, metabolic complications (e.g., hypertriglyceridemia, liver steatosis, insulin resistance, diabetes), and disorganized subcutaneous fat lobules with fibrosis and macrophage infiltration. CONCLUSIONS: These data suggest that some FPLD4-associated PLIN1 variants are deleterious. Thus, the evidence for the pathogenicity of each variant ought to be carefully considered before genetic counseling, especially given the importance of an early diagnosis for optimal disease management. Thus, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.

Three Consecutive Pregnancies in a Patient with Chronic Autoimmune Thyroid Disease Associated with Hypothyroidism and Extremely High Levels of Anti-Thyrotropin Receptor Antibodies.

Background: Thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAb) can be present in chronic autoimmune thyroiditis. Transplacental TRAb transfer can lead to fetal thyroid dysfunction and serious complications. Patient Findings: We report the case of a woman with autoimmune hypothyroidism and extremely high TRAb levels, with blocking and stimulating activities (biological activities characterized with Chinese hamster ovary cells expressing TSHR). At week 22 of her first pregnancy, sonography detected fetal growth retardation and cardiac abnormalities (extreme tachycardia, right ventricular dilatation, pericardial effusion). The mother's TRAb level, assayed later, was 4030 IU/L (n < 10). Delivered via caesarean section gestational week 30, the newborn girl had several malformations, signs of malnutrition, goiter and hyperthyroidism associated with elevated TRAb (1200 IU/L). The newborn died 26 days after delivery. Faced with persistently high TRAb levels and a desire to become pregnant again, the woman was treated with three consecutive 740-MBq activities of iodine-131, which resulted in a decrease in TRAb to 640 IU/L. The patient had two subsequent pregnancies 16 and 72 months after the radioiodine administration. During the close follow-ups, fetal development was normal, and initial TRAb levels during the two pregnancies were 680 and 260 IU/L, respectively, which initially decreased but then increased in late pregnancy. In both cases, labor was induced at 34 weeks. The newborns, mildly hyperthyroid at birth, required carbimazole treatment at days 5 and 2, respectively. The mild hyperthyroidism despite high TRAb levels was likely due to the concomitant presence of stimulating and blocking TRAb. The two girls, now aged 12 and 8 years, are in good health. The mother has no detectable thyroid gland tissue and is euthyroid on levothyroxine (175 µg/d). Her TRAb level gradually decreased to 136 IU/L. Summary and Conclusions: This remarkable case illustrates the severe consequences of untreated fetal hyperthyroidism and the need to assay and follow-up TRAb levels in women of reproductive age with autoimmune thyroiditis.

MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue.

BACKGROUND: Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. OBJECTIVE: To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. METHODS: We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. RESULTS: Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. CONCLUSION: MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.

Early predictors of diabetic retinopathy in type 1 diabetes: The Retinopathy Champagne Ardenne Diabète (ReCAD) study.

AIMS: To determine the relationship between early markers of diabetes control and diabetic retinopathy (DR) in type 1 diabetes. METHODS: A historic cohort study was conducted on 712 patients from the CARéDIAB database. HbA1c and usual metabolic parameters were measured one year after diagnosis of diabetes. First occurrences of severe hypoglycemia and ketoacidosis during follow-up were selected as time-dependent markers of diabetes control. Data were analyzed in a Cox model using SPSS software to predict DR with significance level at p-value <0.05. RESULTS: In multivariate regression, any diabetic retinopathy was predicted by HbA1c (HR = 1.38; CI = 1.25-1.52; p < 0.0001), severe hypoglycemia (HR = 3; CI = 1.99-4.52; p < 0.0001), ketoacidosis (HR = 1.96; CI = 1.17-3.22; p = 0.009), and age at diagnosis (HR = 1.016; CI = 1.002-1.031; p = 0.02). Proliferative DR was predicted by HbA1c (HR = 1.67; CI = 1.51-1.79; p < 0.0001), severe hypoglycemia (HR = 3.67; CI = 2.74-5.25; p < 0.0001), and ketoacidosis (HR = 2.37; CI = 1.56-3.18; p < 0.0001). CONCLUSION: This study shows that the failure to achieve diabetes control after the first year of diagnosis as well as early episodes of acute diabetes complications may contribute to the occurrence of diabetic retinopathy in type 1 diabetes patients.