Letter

Growth hormone therapy in children with Prader-Willi syndrome

Obesity, defined as an excess fat mass, results from individual genetic and biological susceptibilities in response to the current weight-gain promoting environment. There is thus a synergistic relationship between genes and environment. Depending on the genes involved, different clinical situations are described: (1) monogenic obesity defined as rare and severe early-onset obesity associated with endocrine disorders, which are mainly due to autosomic recessive mutations in genes of the leptin-melanocortin axis – in some cases, such as leptin deficiency, specific treatments are efficient; (2) melanocortin 4 receptor-linked obesity characterized by the variable severity of obesity and the absence of additional phenotypes, which are involved in 2–3% of cases and eventually may benefit from new developed drugs (MC4R agonists); and (3) syndromic obesity where patients are clinically obese, and additionally distinguished by mental retardation, dysmorphic features, and organ-specific developmental abnormalities. No specific treatments are recommended except for hormonal substitution if necessary (growth hormone or gonadotrope deficiency).

This chapter discusses the various forms of obesity. Obesity is mentioned to be marked by an excess fat mass and characterized by a high phenotype heterogeneity linked most notably to differences in the stages of weight evolution. The development of obesity is considered to stem from the interaction of multiple environmental factors with genetic factors. Epidemiological studies have recognized the role of individual genetic and biological susceptibilities with a synergistic relationship between genes and environment. The different clinical presentations of obesity are presented depending on the genes involved. These clinical forms of obesity are: monogenic obesity, melanocortin 4 receptor-linked obesity, syndromic obesity and polygenic obesity. The most frequent obesity syndrome is reported to be the Prader-Willi syndrome, characterized by obesity, hyperphagia, neonatal hypotonia and mental retardation. The genetic pathophysiologies of these forms are further discussed as well as their diagnosis, genetic testing and interpretation. The treatment for various forms of obesity is presented with leptin therapy in monogenic obesity and well-balanced diet and physical activity for melanocortin 4 receptor-linked obesity.

Obesity has become an increasingly prevalent public health problem and results of the complex interaction of genetic and environmental factors. The study of rare syndromic forms of obesity enables progress in identifing molecular and physiological mechanisms, underlying the development of adiposity, food intake and energy expenditure. The identified role of the hypothalamic leptin–melanocortin pathway as major in monogenic forms of obesity, has led to the recognition of of new genes controlling energy homeostasis and new pharmacological targets.

L'obésité est devenue un problème majeur de santé publique, du fait de sa constante progression, et résulte de l'interaction complexe entre des facteurs génétiques et environnementaux. L'étude des formes syndromiques rares de l'obésité permet d'avancer dans l'identification des mécanismes moléculaires et physiologiques, responsables du développement de l'adiposité, de la prise alimentaire et de la dépense énergétique. L'identification du rôle de la voie hypothalamique, leptine–mélanocortine comme primordial dans les formes monogéniques de l'obésité, permet l'émergence, d'une part, de nouveaux gènes régulant l'homéostasie énergétique et, d'autre part, de nouvelles cibles pharmacologiques.

This chapter presents the current state of knowledge in the field of the genetics of human obesity. The molecular approach has proved to be powerful in defining new syndromes associated with obesity. The pivotal role of leptin and melanocortin pathways has been recognized, but only in rare cases of obesity. In the more common form of obesity a multitude of polymorphisms located in genes and candidate regions throughout the genome regulate an individual's susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. Combining these single nucleotide polymorphisms and defining the associated risks for obesity will be a real challenge in the future. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify this field.