Impact of exenatide on weight loss and eating behavior in adults with craniopharyngioma-related obesity: the CRANIOEXE randomized placebo-controlled trial.

IMPORTANCE: A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches. OBJECTIVE: To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO. DESIGN: A double-blind multicenter superiority randomized clinical in trial in two parallel arms. SETTING: Eleven French University Hospital Centers. PARTICIPANTS: Adults with CRO (body mass index > 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year. INTERVENTIONS: Exenatide or placebo injected subcutaneously twice a day during 26 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile. RESULTS: At week 26, weight decreased from baseline by a mean of -3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. The adjusted mean treatment difference was -3.1 kg (95% confidence interval [CI] -7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: -2.3, 95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events). CONCLUSIONS AND RELEVANCE: Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity.

Hyperphagia and impulsivity: use of self-administered Dykens' and in-house impulsivity questionnaires to characterize eating behaviors in children with severe and early-onset obesity.

BACKGROUND: The determinants of early-onset obesity (< 6 years) are not completely elucidated, however eating behavior has a central role. To date no study has explored eating behavior in children with severe, early-onset obesity. Self-administered questionnaire data from these children were examined to evaluate eating behavior and the etiology of early-onset obesity. METHODS: Children with severe, early-onset obesity (body mass index [BMI] > International Obesity Task Force [IOTF] 30) of different etiologies (hypothalamic obesity [HO], intellectual disability with obesity [IDO], common polygenic obesity [CO]) were prospectively included. BMI history and responses from the Dykens' Hyperphagia Questionnaire and an in-house Impulsivity Questionnaire at first visit were compared between groups. RESULTS: This cohort of 75 children (39 girls; mean age ± standard deviation [SD] 10.8 ± 4.4 years) had severe, early-onset obesity at an age of 3.8 ± 2.7 years, with a BMI Z-score of 4.9 ± 1.5. BMI history varied between the 3 groups, with earlier severe obesity in the HO group versus 2 other groups (BMI > IOTF40 at 3.4 ± 1.6 vs. 4.6 ± 1.6 and 8.4 ± 4.1 years for the IDO and CO groups, respectively [P < 0.01]). Absence of adiposity rebound was more prevalent in the HO group (87% vs. 63% and 33% for the IDO and CO groups, respectively [P < 0.01]). The Dykens' mean total score for the cohort was 22.1 ± 7.2 with no significant between-group differences. Hyperphagia (Dykens' score > 19) and impulsivity (score > 7) were found in 50 (67%) and 11 children (15%), respectively, with no difference between the HO, IDO and CO groups regarding the number of patients with hyperphagia (10 [67%], 14 [74%], and 26 [63%] children, respectively) or impulsivity (2 [13%], 1 [7%], and 8 [19%] children, respectively). Children with food impulsivity had significantly higher total and severity scores on the Dykens' Questionnaire versus those without impulsivity. CONCLUSION: The Dykens' and Impulsivity questionnaires can help diagnose severe hyperphagia with/without food impulsivity in children with early-onset obesity, regardless of disease origin. Their systematic use can allow more targeted management of food access control in clinical practice and monitor the evolution of eating behavior in the case of innovative therapeutic targeting hyperphagia.

Corrigendum: Kidney disease in adults with Prader-Willi syndrome: international cohort study and systematic literature review.

[This corrects the article DOI: 10.3389/fendo.2023.1168648.].

Management of Severe Malnutrition Post-bariatric Surgery Using Artificial Nutrition.

BACKGROUND: Bariatric surgery (BS) results in major and sustained weight loss and improves comorbidities in patients with obesity but can also lead to malnutrition, especially through severe malabsorption and/or surgical complications. Little is known about the efficacy of artificial nutrition (AN) in this setting. METHODS: In this case series, we describe data from consecutive severely malnourished patients after BS (resectional and non-resectional), managed by AN at our hospital unit over a 4-year period. RESULTS: Between January 2018 and June 2022, 18 patients (mean ± SD age 42.2 ± 10.4 years, 94% women) required AN following BS complications. At the time of AN initiation, more than half of the patients (53%) had multiple revisional surgeries (up to four). Mean BMI was 49.7 ± 11.3 kg/m2 before BS and 29.6 ± 9.6 kg/m2 when AN was initiated. Most patients (n=16, 90%) received enteral nutrition. AN management resulted in weight regain (+4.7kg ± 8.0, p=0.034), increased serum albumin (+28%, p=0.02), pre-albumin (+88%, p=0.002), and handgrip strength (+38%, p=0.078). No major AN complication nor death was observed. Median total AN duration was 4.5 months [1-12]. During follow-up, the cumulative duration of hospitalization was 33 days [4-88] with a median of 2.5 hospitalizations [1-8] per patient. CONCLUSION: Malnutrition can occur after any BS procedure, and AN when required in this setting appears safe and effective on nutritional parameters. It is important to recognize the potential risk factors for malnutrition, which include excessive weight loss resulting from surgical complications, eating disorders, multiple revisional BS, and pregnancy.

Serum Versus Fecal Calprotectin Levels in Patients with Severe Obesity Before and 6 Months After Roux-Y-Gastric Bypass: Report of the Prospective Leaky-Gut Study.

INTRODUCTION: Obesity is associated with low-grade inflammation, including intestinal inflammation based on fecal or serum calprotectin (FC-SC) measurement. Roux-en-Y gastric bypass (RYGB) improves obesity-related parameters. However, the association between FC-SC levels and postoperative course and the link with metabolic and inflammatory phenotypes before and after RYGB remains unclear. METHODS: We determined SC levels in 48 patients before (T0) and 6 months after (T6M) RYGB. We then analyzed postoperative changes in FC-SC levels and the relationship with inflammation and metabolic status. RESULTS: Twenty-three patients (48%) had elevated SC levels (˃2.9 µg/mL) at T0 and T6M. Six of 29 patients (20.7%) had elevated FC concentrations (>50 µg/g) at T0 vs. 16 of 17 patients (94.1%) at T6M (p=0.006). At T0, FC levels correlated with BMI (Rho=0.63; p=0.001) and systemic inflammation (CRP: Rho=0.66, p=0.0006; IL-6: Rho=0.48, p=0.03; haptoglobin: Rho=0.75; p= 0.0006). SC tended to be positively associated with triglyceride levels (Rho=0.34; p=0.08), BMI (Rho=0.34; p=0.08), and inflammatory markers (CRP: Rho=0.33; p=0.09; IL-6: Rho=0.36; p=0.06). FC levels were associated with increased jejunal IL-17+CD8+ T-cell densities (Rho:0.90; p=0.0002). FC and SC were correlated together at T0 (Rho=0.83; p<0.001) but not at T6M. At T6M, SC decreased by 53.6%, whereas FC increased by 79.7%. SC and FC were not associated with any of the variables studied at T6M. CONCLUSION: FC is a surrogate marker of systemic and intestinal inflammation and adiposity, whereas SC only tends to correlate with systemic inflammation. At 6 months after RYGB, SC-based systemic inflammation decreased, whereas FC-based intestinal inflammation increased. FC and SC levels follow different trajectories and are unrelated to improvements following bariatric surgery.

A novel pathogenic variant in MRAP2 in an obese patient with successful outcome of bariatric surgery.

Mutations in genes encoding proteins located in the leptin/melanocortin pathway have been identified in the rare cases of genetic obesities. Heterozygous variants of MRAP2, encoding a G coupled-protein receptor accessory protein implicated in energy control notably via the melanocortin-4 receptor, have been recently identified. A 24-year-old patient with early-onset severe obesity (body mass index [BMI]: 64 kg/m2) associated with hypertension, respiratory complications, nonalcoholic fatty liver disease, and type 2 diabetes was referred to our department. Sleeve gastrectomy was successful. A new heterozygous variant in MRAP2 (NM_138409.4: c.154G>C/p.G52R) variant was identified in the patient DNA. Functional assessment confirmed that this new variant was pathogenic. We report a new pathogenic loss-of-function mutation in MRAP2 in a patient suffering from a severe multicomplicated obesity. This confirms the metabolic phenotype in patients with this monogenic form of obesity. Longer follow-up will be necessary. Our finding will allow a personalized medicine.

Revisional Roux-en-Y Gastric Bypass After Sleeve Gastrectomy for Gastro-esophageal Reflux Disease and or Insufficient Weight-Loss: a Comparative Study.

INTRODUCTION: Sleeve gastrectomy (SG) is a popular surgical weight-loss procedure, but there are increasing reports of revisional Roux-Y-gastric-bypass (R-RYGB) to manage weight-loss failure (WLF) or proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) after SG, with little data available in these settings. METHODS: This retrospective study included all consecutive patients undergoing R-RYGB for WLF or RGERD after SG in two bariatric care centers from 2012 to 2018. RESULTS: Of 720 patients, 46 (3.6%) underwent R-RYGB (RGERD, n = 25; 54.4%; WLF, n = 21; 45.6%) within 44.8 ± 27.5 months post-SG. SG had enabled 27% ± 11.6 total weight loss (TWL) in the RGERD group vs. 7.2% ± 12.5% TWL in the WLF group (p < 0.001). At R-RYGB, WLF-group patients had a higher BMI (47.8 ± 8.4 vs. 34.7 ± 6.1 kg/m2; p < 0.001) and a higher number of comorbidities (2.4 ± 1.5 vs 1.5 ± 1.2; p < 0.02) compared to RGERD-group patients, while severe morbidity (Clavien-Dindo ≥ IIIb) was not significantly different between groups (6.5% vs 2.1%, p = 0.6). %TWL was still higher in the RGERD group at 12 months post-R-RYGB (35.6% ± 10.4 vs. 23.8% ± 9.2; p < 0.01) but not after 24 months post-R-RYGB. R-RYGB corrected reflux symptoms in 32 (94%) patients and reduced PPI use in 29 (97%) patients (p < 0.001), with no significant between-group difference. A history of adjustable gastric banding (AGB) (N = 8;17.4%) prior to SG was associated with a similar prevalence of GERD at R-RYGB and a lower %TWL (AGB:13.1 ± 10.2 vs. No AGB:31.6 ± 8.5; p < 0.05) at 3 years post-R-RYGB. CONCLUSION: R-RYGB following SG provides remission of reflux symptoms in 94% of patients and extra weight loss in patients with WLF, except in patients with a history of AGB prior to SG.

Kidney disease in adults with Prader-Willi syndrome: international cohort study and systematic literature review.

Background: Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria. Methods: We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS. Results: We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (p=0.027, p=0.019, p<0.001, p<0.001, p=0.011 and respectively). Conclusion: Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS.

Correlates of Weight Bias in Adults From the NutriNet-Santé Study.

INTRODUCTION: Explicit weight bias is an underlying cause of weight stigma, but its associations with individual characteristics are not well known. This study aimed to assess explicit weight bias in French adults and to explore the associations with weight status and sociodemographic characteristics. METHODS: Adults from the NutriNet-Santé cross-sectional study (France, 2020, n=33,948, 52% women after weighting procedures) completed the Anti-Fat Attitudes Questionnaire assessing three dimensions: Dislike (antipathy toward people with obesity), Fear of fat (concerns about body weight), and Willpower (belief in weight controllability). Associations with weight status and sociodemographic characteristics were examined using multivariable ANCOVA models in 2022. RESULTS: Fear of fat and Willpower scores were higher than Dislike scores (mean [SD]=4.0 [2.0], 3.3 [1.7] and 1.9 [1.3], respectively). Fear of fat was higher among women, whereas Dislike and Willpower were higher among men (all p<0.0001). Obesity was associated with greater Fear of fat scores (p<0.0001, mean difference versus normal-weight participants [95% CI]=0.35 [0.24, 0.46] in women, 0.36 [0.17, 0.56] in men), lower Dislike scores (-0.38 [-0.45, -0.32] in women, -0.43 [-0.56, -0.30] in men), and lower Willpower scores (-1.00 [-0.18, -0.90] in women, -0.40 [-0.57, -0.23] in men). In both genders, lower income was associated with lower Dislike, Fear of fat, and Willpower scores (all p<0.0001), and lower education was associated with greater Fear of fat and Willpower scores (all p<0.0001). CONCLUSIONS: Explicit weight bias was driven by the fear of gaining weight and the belief in weight controllability. This study provides new insights into which population subgroups should be targeted by interventions aimed at reducing explicit weight bias.

Malignancies in Prader-Willi Syndrome: Results From a Large International Cohort and Literature Review.

CONTEXT: Prader-Willi syndrome (PWS) is a complex disorder combining hypothalamic dysfunction, neurodevelopmental delay, hypotonia, and hyperphagia with risk of obesity and its complications. PWS is caused by the loss of expression of the PWS critical region, a cluster of paternally expressed genes on chromosome 15q11.2-q13. As life expectancy of patients with PWS increases, age-related diseases like malignancies might pose a new threat to health. OBJECTIVE: To investigate the prevalence and risk factors of malignancies in patients with PWS and to provide clinical recommendations for cancer screening. METHODS: We included 706 patients with PWS (160 children, 546 adults). We retrospectively collected data from medical records on past or current malignancies, the type of malignancy, and risk factors for malignancy. Additionally, we searched the literature for information about the relationship between genes on chromosome 15q11.2-q13 and malignancies. RESULTS: Seven adults (age range, 18-55 years) had been diagnosed with a malignancy (acute lymphoblastic leukemia, intracranial hemangiopericytoma, melanoma, stomach adenocarcinoma, biliary cancer, parotid adenocarcinoma, and colon cancer). All patients with a malignancy had a paternal 15q11-13 deletion. The literature review showed that several genes on chromosome 15q11.2-q13 are related to malignancies. CONCLUSION: Malignancies are rare in patients with PWS. Therefore, screening for malignancies is only indicated when clinically relevant symptoms are present, such as unexplained weight loss, loss of appetite, symptoms suggestive of paraneoplastic syndrome, or localizing symptoms. Given the increased cancer risk associated with obesity, which is common in PWS, participation in national screening programs should be encouraged.

Current Treatments for Patients with Genetic Obesity

Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation.

Novel therapeutics in rare genetic obesities: A narrative review.

The better understanding of the molecular causes of rare genetic obesities and its associated phenotype involving the hypothalamus allows today to consider innovative therapeutics focused on hunger control. Several new pharmacological molecules benefit patients with monogenic or syndromic obesity. They are likely to be among the treatment options for these patients in the coming years, helping clinicians and patients prevent rapid weight progression and eventually limit bariatric surgery procedures, which is less effective in these patients. Their positioning in the management of such patients will be needed to be well defined to develop precision medicine in genetic forms of obesity.

Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use.

PURPOSE: Recessive deficiency of proopiomelanocortin (POMC) causes childhood-onset severe obesity. Cases can now benefit from the melanocortin 4 receptor agonist setmelanotide. Furthermore, a phase 3 clinical trial is evaluating setmelanotide in heterozygotes for POMC. We performed a large-scale genetic analysis to assess the effect of heterozygous, pathogenic POMC variants on obesity. METHODS: A genetic analysis was performed in a family including 2 cousins with childhood-onset obesity. We analyzed the obesity status of heterozygotes for pathogenic POMC variants in the Human Gene Mutation Database. The association between heterozygous pathogenic POMC variants and obesity risk was assessed using 190,000 exome samples from UK Biobank. RESULTS: The 2 cousins carried a compound heterozygous pathogenic variant in POMC. Six siblings were heterozygotes; only 1 of them had obesity. In Human Gene Mutation Database, we identified 60 heterozygotes for pathogenic POMC variants, of whom 14 had obesity. In UK Biobank, heterozygous pathogenic POMC variants were not associated with obesity risk, but they modestly increased body mass index levels. CONCLUSION: Heterozygous pathogenic POMC variants do not contribute to monogenic obesity, but they slightly increase body mass index. Setmelanotide use in patients with obesity, which would only be based on the presence of a heterozygous POMC variant, can be questioned.

Corrigendum: Prader-Willi syndrome: Symptoms and topiramate response in light of genetics.

[This corrects the article DOI: 10.3389/fnins.2023.1126970.].

Follow-Up, Safety, and Satisfaction with Tele-bariatric Follow-Up Implemented During the COVID-19 French Lockdown: a 2-Year Follow-Up Study.

BACKGROUND: The COVID-19 pandemic was initially responsible for a global restricted access to healthcare resources including the follow-up of at-risk populations such as bariatric patients. We substituted face-to-face bariatric follow-up outpatient clinics (FTFC) with teleclinics (TC) during the lockdown. MATERIAL AND METHODS: We retrospectively reviewed data collected on all patients scheduled for TC during the French lockdown period (March 15 to May 15, 2020) (N = 87). Our aims were to present the patients' outcomes at one and 2 years post-TC implementation and describe patient/practitioner satisfaction. RESULTS: Seven (8%) patients required FTFC, and 80 (92%) underwent TC (study population) for preoperative bariatric assessment (N = 3) and postoperative follow-up (N = 77) after 23.6 ± 29 months following surgery. TC was performed with video and audio (N = 46; 57.5%) or audio alone when video was impossible (N = 34; 42.5%). Sixteen (20%) patients presented at least one complication identified at the first TC and were managed accordingly. There were no readmissions at 30/90 days post-TC. At 1-year after the first TC, overall follow-up rate was 94.9% (TC: 73% vs FTFC: 27%). Patients surveyed on the main advantages of TC over FTFC (N = 46) cited: saving time (97.8%) at a mean 3.9 ± 6.4 h saved per TC, work-advantages (94.3%), and comparable relevance of TC (84.8%). At 2 years post-TC implementation, follow-up rate was 93.5% and satisfaction rate was 80%, with 33% of patients preferring to return to FTFC. CONCLUSIONS: TC is a satisfactory substitute for FTFC, enabling continued bariatric follow-up during and beyond the pandemic setting without compromising patient safety. However, the modest satisfaction outcomes at 2 years highlight a need to discuss follow-up preferences in order to achieve optimal outcomes.

Hypersomnia and narcolepsy in 42 adult patients with craniopharyngioma.

STUDY OBJECTIVES: To evaluate sleep, sleepiness, and excessive need for sleep in patients with craniopharyngioma (a suprasellar tumor which can affect sleep-wake systems). METHODS: A retrospective study of all adult patients living with craniopharyngioma referred to the sleep clinic, who received a sleep interview, nocturnal polysomnography, multiple sleep latency tests (MSLT), and 18-h bed rest polysomnography. Their sleep measurements were compared with those of age- and sex-matched healthy controls. RESULTS: Of 54 patients screened with craniopharyngioma, 42 were analyzed, 80% of whom complained of excessive daytime sleepiness. Sleep testing revealed that 6 (14.3%) of them had secondary narcolepsy (including one with cataplexy), and 11 (26.2%) had central hypersomnia associated with a medical disorder. Compared with controls, patients were more frequently obese, had a shorter mean sleep latency on MSLT, and slept longer on the first night. There was a nonsignificant trend for patients with (vs. without) narcolepsy and hypersomnia to be younger, to have a higher body mass index, to be more likely to have received radiation therapy, and to have more severe damage to the hypothalamus after surgery. Treatment with stimulants (modafinil, pitolisant, and methylphenidate) was beneficial in 9/10 patients. CONCLUSIONS: Nearly half of the patients with craniopharyngioma and sleep disorders have a central disorder of hypersomnolence (narcolepsy and hypersomnia), which should be investigated and lead to considerations beyond sleep apnea syndrome in these obese patients.

Perinatal, metabolic, and reproductive features in PPARG-related lipodystrophy.

OBJECTIVE: The adipogenic PPARG-encoded PPARγ nuclear receptor also displays essential placental functions. We evaluated the metabolic, reproductive, and perinatal features of patients with PPARG-related lipodystrophy. METHODS: Current and retrospective data were collected in patients referred to a National Rare Diseases Reference Centre. RESULTS: 26 patients from 15 unrelated families were studied (18 women, median age 43 years). They carried monoallelic PPARG variants except a homozygous patient with congenital generalized lipodystrophy. Among heterozygous patients aged 16 or more (n = 24), 92% had diabetes, 96% partial lipodystrophy (median age at diagnosis 24 and 37 years), 78% hypertriglyceridaemia, 71% liver steatosis, and 58% hypertension. The mean BMI was 26 ± 5.0 kg/m2. Women (n = 16) were frequently affected by acute pancreatitis (n = 6) and/or polycystic ovary syndrome (n = 12). Eleven women obtained one or several pregnancies, all complicated by diabetes (n = 8), hypertension (n = 4), and/or hypertriglyceridaemia (n = 10). We analysed perinatal data of patients according to the presence (n = 8) or absence (n = 9) of a maternal dysmetabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of amenorrhea, respectively). As expected, the birth weight was higher in patients exposed to a foetal dysmetabolic environment of maternal origin. In contrast, 85.7% of non-exposed patients, in whom the variant is, or is very likely to be, paternally-inherited, were small for gestational age. CONCLUSIONS: Lipodystrophy-related PPARG variants induce early metabolic complications. Our results suggest that placental expression of PPARG pathogenic variants carried by affected foetuses could impair prenatal growth and parturition. This justifies careful pregnancy monitoring in affected families.

Prader-Willi syndrome: Symptoms and topiramate response in light of genetics.

Introduction: Prader-Willi Syndrome (PWS) is a rare genetic condition, which affects one in 25,000 births and results in various phenotypes. It leads to a wide range of metabolic and endocrine disorders including growth delay, hypogonadism, narcolepsy, lack of satiety and compulsive eating, associated with mild to moderate cognitive impairment. Prognosis is especially determined by the complications of obesity (diabetes, cardiorespiratory diseases) and by severe behavioral disorders marked by impulsivity and compulsion. This heterogeneous clinical picture may lead to mis- or delayed diagnosis of comorbidities. Moreover, when diagnosis is made, treatment remains limited, with high interindividual differences in drug response. This may be due to the underlying genetic variability of the syndrome, which can involve several different genetic mutations, notably deletion or uniparental disomy (UPD) in a region of chromosome 15. Here, we propose to determine whether subjects with PWS differ for clinical phenotype and treatment response depending on the underlying genetic anomaly. Methods: We retrospectively included all 24 PWS patients who were referred to the Reference Center for Rare Psychiatric Disorders (GHU Paris Psychiatrie and Neurosciences) between November 2018 and July 2022, with either deletion (N = 8) or disomy (N = 16). The following socio-demographic and clinical characteristics were recorded: age, sex, psychiatric and non-psychiatric symptoms, the type of genetic defect, medication and treatment response to topiramate, which was evaluated in terms of eating compulsions and impulsive behaviors. We compared topiramate treatment doses and responses between PWS with deletion and those with disomy. Non-parametric tests were used with random permutations for p-value and bootstrap 95% confidence interval computations. Results: First, we found that disomy was associated with a more severe clinical phenotype than deletion. Second, we observed that topiramate was less effective and less tolerated in disomy, compared to deletion. Discussion: These results suggest that a pharmacogenomic-based approach may be relevant for the treatment of compulsions in PWS, thus highlighting the importance of personalized medicine for such complex heterogeneous disorders.

From Dyspnea to Skin Grafting: The Difficulties of Managing a Patient with Extreme Obesity.

While the prevalence of severe obesity is increasing worldwide, caregivers are often challenged with the management of patients with extreme weight. A 30-year-old woman (weight 245 kg, body mass index 85 kg/m2) presented with dyspnea, for which investigations led to suspect pulmonary embolism. The patient's weight made it impossible to perform adapted imaging; thus, an empirical anticoagulant treatment was initiated. A hematoma of the thigh occurred as a consequence of a transient antivitamin K overdose, leading to a 15-cm necrotic wound worsened by a state of malnutrition. Multidisciplinary and comprehensive care was performed including wound trimming, antibiotics, skin grafting, treatment of malnutrition, and psychological support, but with marked difficulties due to the lack of adapted medical equipment and facilities as well as appropriate medical guidelines. Overall, 7 months of hospitalization including 4 months of physiotherapy and rehabilitation were needed before the patient could return home. This case highlights how difficult managing patients with extreme obesity can be and points to the importance for healthcare systems to adapt to the specific needs of these patients and to design specific guidelines for treatment dosage and malnutrition prevention and treatment in this setting.