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

AIM: 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.

Identification of factors associated with the management of childhood obesity: Results from a French pediatric cohort study.

BACKGROUNDS: Childhood obesity is a real public health concern because of its association with a higher risk of adulthood obesity and comorbidities (metabolic, cardiovascular, etc.). The factors associated with the effectiveness of care are poorly described. The objective of this study was to identify factors associated with body mass index (BMI) variation in the management of childhood obesity. MATERIAL AND METHODS: Children followed up for obesity in the Pediatric Endocrinology Department of the University Children Hospital of Nancy were included. Data were retrospectively collected in medical files. The characteristics of patients with a decrease in BMI (in standard deviation score, SDS) were compared with patients with an increased BMI (SDS)after 1 year of follow-up through univariate analysis. RESULTS: Overall, 141 patients were included, and for 107 patients (55 girls and 52 boys) there were 1-year follow-up data. The mean BMI variation after 1 year of follow-up was-0.068 SD and for 63 patients (58.9%) there was a decrease in BMI SDS. Female patients (66% vs. 41%, p=0.012), hypercholesterolemia (33% vs. 4%, p=0.049), and type 1 diabetes (14% vs. 2%, p=0.019) were more frequent in patients with an unfavorable evolution of BMI SDS at 1 year. A family history of bariatric surgery (36% vs. 11%, p=0.042) or eating behavior disorders (76% vs. 24% of patients; p<0.001) or diabetes (1st or 2nd degree;81% vs. 60%, p=0.044) were also more frequent in children with an unfavorable evolution of BMI SDS at 1 year. CONCLUSION: Several negative factors in the evolution of BMI were identified such as female sex, hypercholesterolemia, family history of bariatric surgery, or eating behavior. Early identification of these patients at risk of failure of obesity management is important to control BMI during childhood.

Congenital hypothyroidism in children with eutopic gland or thyroid hemiagenesis: prognostic factors for transient vs. permanent hypothyroidism.

OBJECTIVES: More than one third of children with congenital hypothyroidism (CH) and thyroid gland in situ (or eutopic gland) have transient hypothyroidism. It remains difficult to determine early on whether hypothyroidism will be transient which may cause overtreatment and its complications in these children. Our primary aim was to determine prognostic factors for transient hypothyroidism in children with congenital hypothyroidism and eutopic gland or thyroid hemiagenesis. METHODS: We retrospectively reviewed medical records of 111 children, born between 1996 and 2017, diagnosed with congenital hypothyroidism and eutopic gland or hemiagenesis and treated at the Nancy Regional and University Hospital. RESULTS: Fifty four infants (48.6%) had permanent congenital hypothyroidism (PCH) and 57 (51.4%) transient congenital hypothyroidism (TCH). Prognostic factors for TCH included prematurity, twin pregnancy, low birth weight and Apgar score <7, while low FT3 at diagnosis, maternal levothyroxine treatment, a family history of thyroid dysfunction and TSH ≥10 mUI/L while receiving treatment were associated with PCH. Knee epiphyses on X-ray at diagnosis were absent only in children with PCH. The median levothyroxine dose during follow-up was significantly lower in the TCH group compared to the PCH group. A levothyroxine dose of ≤3.95, ≤2.56, ≤2.19 and ≤2.12 µg/kg/day at 6 months, 1, 2 and 3 years of follow-up, respectively, had the best sensitivity-to-specificity ratio for predicting TCH. CONCLUSIONS: Even though it remains difficult to predict the course of hypothyroidism at diagnosis, we were able to identify several prognostic factors for TCH including perinatal problems and lower levothyroxine requirements that can guide the physician on the evolution of hypothyroidism. Clinical Trial Registration Number: NCT04712760.

Additional autoimmune diseases associated with type 1 diabetes in children and adolescents: A French single-center study from 2014 to 2021.

CONTEXT: Patients with type 1 diabetes (T1D) are more likely to develop other autoimmune diseases than the general population. OBJECTIVES: To describe additional autoimmunity in a cohort of children and adolescents with T1D, as well as to identify factors associated with the presence of additional autoantibodies (AABs) and of additional autoimmune diseases (AADs). SETTING: This was a single-center retrospective cohort study of 179 children and adolescents (median age: 9.1 years) diagnosed with T1D between 2014 and 2020 in a specialized center in France. Patients were screened for autoimmune thyroiditis and celiac disease at T1D diagnosis and once every 1-2 years during follow-up. Other AADs and their specific autoantibodies were screened for only if clinical or laboratory signs were present. RESULTS: At T1D diagnosis, 15.6% of participants presented with at least one type of AAB including antibodies specific to Hashimoto's disease (TPOAb and/or TGAb) and/or to celiac disease (tTGAb and/or EMAb). Only 2.8% of participants presented with an AAD as early as T1D diagnosis. The median follow-up was 37 months. The cumulative incidence of AABs and AADs at 2 years of follow-up was, respectively, 3.9% and 5.4%, and it doubled at 3 years of follow-up. Only one patient, also affected by Down syndrome, was diagnosed with 2 AADs. Hashimoto's disease was the most frequently diagnosed AAD, followed by celiac disease, both at an asymptomatic stage. Vitiligo and Graves' disease were also diagnosed in this cohort but affected few patients. Children aged 6-12 years were more likely to present with an AAD at diabetes diagnosis (p = 0.043). CONCLUSION: The high prevalence and incidence of additional autoimmunity in children and adolescents with T1D justifies regular screening of AABs and AADs.

Atypical phenotype of a patient with Bardet-Biedl syndrome type 4.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. There is a large clinical and also genetic heterogeneity in BBS. Here, we report a patient with polydactyly, hyperechogenic kidneys increased in size with normal corticomedullary differentiation, anal imperforation, and malformation of genitals with presence of a genital tubercle with ventral urethral meatus associated with two unfused lateral genital swelling and absent urethral folds, in the context of 46, XY karyotype. METHODS: Karyotype and solo exome sequencing were performed to look for a genetic etiology for the features described in our patient. RESULTS: We identified a homozygous in-frame deletion of exons 4 to 6 in the BBS4 gene (NM-033028 (BBS4-i001): c.[(157-?)_(405 +?)del] p.(Ala53-Trp135del), which is classified as pathogenic variant. This analysis allowed the molecular diagnosis of BBS type 4 in this patient. CONCLUSION: Complex genital malformations are only reported in female BBS6 patients yet, and genital abnormalities and anal imperforation are not reported in male BBS4 patients to date. We discuss the possible hypotheses for this phenotype, including the phenotypic overlap between ciliopathies.