Current Diabetes Reports (2020) 20: 44 https://doi.org/10.1007/s11892-020-01327-7 GENETICS (AP MORRIS, SECTION EDITOR) Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders Niels Vos1 & Sabrina M. Oussaada2 & Mellody I. Cooiman3 & Lotte Kleinendorst1 & Kasper W. ter Horst2 & Eric J. Hazebroek3 & Johannes A. Romijn4 & Mireille J. Serlie2 & Marcel M. A. M. Mannens5 & Mieke M. van Haelst1,6 Published online: 30 July 2020 # The Author(s) 2020 Abstract Purpose of Review The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. Recent Findings In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and develop- mental disorders might have poorer outcomes. Summary There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients. Keywords Obesity . Genetics . MC4R . Bariatric surgery . PWS Introduction global number of patients suffering from obesity has almost tripled over the past 45 years, resulting in an increased prev- Obesity is one of the leading health problems globally. alence of obesity-associated comorbidities, including cardio- According to the World Health Organization (WHO), the vascular diseases and diabetes. These comorbidities are the Sabrina M. Oussaada and Mellody I. Cooiman contributed equally to this work. This article is part of the Topical Collection on Genetics Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11892-020-01327-7) contains supplementary material, which is available to authorized users. * Mieke M. van Haelst 4 Department of Internal Medicine, Amsterdam UMC, University of [email protected] Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands 1 Department of Clinical Genetics, Amsterdam UMC, University of 5 Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam, Amsterdam Reproduction and Development Research Amsterdam UMC, University of Amsterdam, Amsterdam Institute, Meibergdreef 9, Amsterdam, The Netherlands Reproduction and Development Research Institute, Meibergdreef 9, 2 Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam, The Netherlands University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands 6 Department of Clinical Genetics, Amsterdam UMC, Vrije 3 Department of Bariatric Surgery, Rijnstate Hospital and Vitalys Universiteit Amsterdam, Boelelaan 1117, Clinic, Arnhem, The Netherlands Amsterdam, The Netherlands 44 Page 2 of 10 Curr Diab Rep (2020) 20: 44 most common causes of death worldwide [1, 2]. To maintain a Bariatric Surgery for the Treatment healthy weight, a balance between energy intake and energy of Non-syndromic Genetic Obesity expenditure is required [3]. An energy imbalance, with a rel- atively larger energy intake than expenditure, can lead to obe- Non-syndromic genetic obesity is usually the result of a defect sity, which is defined as a body mass index (BMI) ≥ 30 kg/m2 in the leptin-melanocortin pathway (Fig. 1). This pathway for adults or ≥ 2 or 3 standard deviations (SD) for children plays an essential role in energy homeostasis. Signals from over or under the age of 5 years old, respectively [2]. peripheral tissues are processed in the hypothalamus, regulat- Obesity is a complex multifactorial disorder caused by the ing food intake and thus affecting body weight. Most genes interplay of environmental and genetic factors [4, 5]. An un- involved in this pathway have been extensively studied and derlying genetic cause can be identified in 5–10% of patients include MC4R, LEPR, POMC, PCSK1,andSIM1 [18–21]. with severe and/or early-onset obesity [5–10]. A defect in one (monogenic) or multiple genes (polygenic) can result in obe- sity. This can be isolated (non-syndromic obesity) or in a more Melanocortin-4-Receptor complex clinical presentation, where apart from obesity, other organ systems are affected, with or without intellectual deficit The most frequent cause of non-syndromic genetic obesity is a (syndromic obesity). Apart from monogenic and polygenic mutation in the melanocortin-4-receptor (MC4R) gene. causes, there can also be epigenetic changes that play a role Mutations in this gene typically lead to a defect of the in the pathogenesis of obesity, as has been recently described melanocortin-4-receptor, resulting in a phenotype of early- by Rohde et al. [11]. onset severe obesity with hyperphagia [23, 24]. Carriers of a In general, weight loss is achieved by changing the energy single MC4R mutation are typically less severely affected than balance to a point where energy expenditure exceeds intake. patients with compound heterozygous or homozygous muta- Initial therapeutic options focus on lifestyle interventions tions [25]. Bariatric surgery outcomes of patients with obesity aimed at reducing dietary intake, increasing physical activity, resulting from MC4R gene defects (heterozygous, compound treating underlying pathology, and/or pharmacological strate- heterozygous, and homozygous mutations) have been gies. However, when conservative therapeutic options fail to described. result in sustainable weight loss and morbid or severe obesity A 3-year follow-up study showed poor results of AGB in with associated comorbidities persists (respectively, BMI > nineteen patients with MC4R mutations. There was 18% less 40 kg/m2 and BMI > 35 kg/m2 in adults), bariatric surgery total weight loss in carriers of an MC4R mutation, compared becomes a viable treatment option. with non-carriers (p = 0.003). In addition, there were more Bariatric surgery is the most effective treatment for pa- gastric complications (mean 0.303 ± 0.060 SEM versus tients with severe or morbid obesity [12]. Nowadays, the 0.057 ± 0.010 SEM; p < 0.001) and reoperations (57.9% ver- most performed surgical techniques include sleeve gastrec- sus 14.2%, p ≤ 0.001) in the MC4R mutation carriers, com- tomy (SG) and Roux-en-Y gastric bypass (RYGB). pared with non-carriers. However, when reoperation with Adjustable gastric banding (AGB), a technique widely per- RYGB occurred, weight loss was similar between the two formed in the past, showed disappointing results in the long groups. In this specific cohort, a higher frequency of binge termandisassuchnolongerastandardprocedure[13]. eating disorder (BED) was observed in patients with MC4R Besides reducing stomach volume and altering food passage mutations (100% versus 18.1%; p < 0.001), which is thought through the intestines, the neuroendocrine and gut-brain axis to explain, at least in part, the difference in outcome after AGB alterations are thought to play a significant role in the weight [26]. In six other studies, no differences in outcomes were loss response [14–16]. seen 1 year after AGB or RYGB [27–29], 1 to 5 years after Although most patients experience favorable effects of bar- AGB or SG [30, 31], and 84 months after RYGB [32]between iatric surgery, inter-individual variability in surgical outcomes heterozygous MC4R mutation carriers compared with non- is observed [17]. Several etiological factors, such as differ- carriers. Furthermore, a case report with long-term follow-up ences in the underlying pathophysiology of obesity can cause results showed beneficial effects of RYGB in one patient with insufficient weight loss or weight regain. Concerning mono- an MC4R mutation (76% excess weight loss after almost genic non-syndromic and syndromic obesity, it is hypothe- 5 years of follow-up) [33]. sized that some patients might not benefit from certain types Homozygous loss-of-function (LOF) mutations in MC4R of bariatric surgery when compared with patients with non- have been described in four pediatric patients who underwent genetic obesity. This review provides an overview of the cur- SG. While initial results were promising in all patients, one rent knowledge of bariatric surgery outcomes in patients with patient had weight regain after 5 years of follow-up. a proven genetic form of obesity and aims to provide recom- Nonetheless, the authors state that SG is a suitable option for mendations concerning the most suitable treatments in various pediatric patients with severe obesity and homozygous MC4R genetic obesity disorders. mutations [34•]. Curr Diab Rep (2020) 20: 44 Page 3 of 10 44 Fig. 1 The leptin-melanocortin pathway and its effect on energy balance. Reprinted from the Clinical Molecular Medicine: Principles and Practice (p.80), by L. Kleinendorst and M. M. van Haelst, published by Elsevier, Copyright © 2020 by Elsevier Inc. Reprinted with permission [22] In a large recent