Description

Hypothalamic obesity (HO) is defined as a rare obesity secondary to impaired functioning of the hypothalamus nuclei, the central organ of energy and weight homeostasis. Among the causes of HO, there are those related to a hypothalamic lesion (lesional) such as craniopharyngioma (CP) or inflammatory (sarcoidosis, tuberculosis etc ..) and those called genetic, with variations in gene involved in the central regulation of energy homeostasis. The genetic causes of obesity can be either "monogenic" by mutation of genes involved in the leptin / melanocortin pathway, or "syndromic", defined by the association of obesity and other clinical signs (syndrome), especially neuropsychological traits, such as Prader-Willi syndrome (PWS) or Bardet-Biedl syndrome. PWS, which has a frequency of 1/15000 births, is one of the most well-known obesity-related syndromes. PWS is characterized by muscle hypotonia at birth, severe hyperphagia and food impulsivity, dysmorphic features, and intellectual disability with cognitive-behavioral abnormalities. Monogenic obesity involves rare clinical situations with variants in one of the genes in the MC4R pathway, which plays a pivotal role in the hypothalamic control of food intake and energy expenditure. To date, at least 10 genes directly involved in or regulating the leptin/melanocortin pathway are known: leptin (LEP), leptin receptor (LEPR), pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), melanocortin receptor type 4 (MC4R) and its regulator Melanocortin Receptor Accessory Protein 2 (MRAP2), single -minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), neurotrophic tyrosine kinase receptor type 2 (NTRK2) and more recently, adenylate cyclase 3 (ADCY3). It is of interest to mention that some genes involved in syndromic obesity, such as PWS and BBS, are also involved in the MC4R pathway.

Although HO has various pathophysiological origins, there are common linked phenotypes with the presence of severe obesity and abnormal food intake behovior, having a heavy impact on the morbidity and mortality. Obesity is multifactorial, associated with an increase in energy intake, a decrease in energy expenditure and an alteration of peripheral metabolism with abnormal organ cross-talks. People with HO have often cognitive deficits, learning difficulties and social skills disorders. These factors alter patients' quality of life. At present, there is no specific treatment of HO. Drug treatments have been proposed such as melatonin, somatostatin analogue or sympathomimetics but with limited effects on weight and feeding behavior, resulting in no prescribing recommendations given the lack of randomized studies with sufficient patient samples. Sibutramine tested in patients with lesional or genetic HO was withdrawed from the market in France since 2010 for potentially deleterious effects on the cardiovascular system. GLP 1 analogues are an interesting therapeutic approach in patients with craniopharyngioma with some efficacy on weight, but are currently dedicated for diabetic patients in France. Regarding bariatric surgery in rare and secondary obesities, the French Haute Autorité de Santé recommends that "the indication must be exceptional and discussed on a case by case basis".

So current management is essentially behavioral, based on daily support of eating behavior and physical activity. Food management requires from a very young age and during the whole life, a permanent food control, to fight against primary impulsivity of central origin, can be a cause of frustration and behavioral disorders. Indeed, the hypothalamic impairment is characterized by intense and permanent hunger, a lack of satiety and an obsession for food. The affected patients are completely overwhelmed by this addictive behavior. It is extremely difficult or impossible for the child as for the adult with this syndrome to control his dietary intake. The caregivers and relateds must therefore control access to food at home and abroad. This requires constant supervision. An early education of food in the family is essential because today it there is no possible and sustainable autonomy regarding diet for these patients.

So, if the global, specialized and multidisciplinary care is to be implemented as early as possible, from early childhood, the development of new therapeutic strategies is essential due to the severe and early obesity. In recent years, research in therapeutic innovation has developed in an interesting way in genetic obesity, in particular by targeting the melanocortin pathway. HO have various origins but have a common phenotype, that is the presence of eating disorders with hyperphagia and food impulsivity. This is responsible for weight gain which can lead to obesity, having a significant impact on the morbidity and mortality. However, no precise data are available currently on the specific phenotype of each origin, the genotype/phenotype correlation, and national medical history of OH throughout life, from birth to adulthood, as well as the associated phenotypes, are still to be precisely described.