Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) has been recently linked to biallelic mutation of the peptidyl-tRNA hydrolase 2 gene PTRH2. Two index patients with IMNEPD in the original report had multiple neurological symptoms such as postnatal microcephaly, intellectual disability, developmental delay, sensorineural deafness, cerebellar atrophy, ataxia, and peripheral neuropathy. In addition, distal muscle weakness and abnormalities of thyroid, pancreas, and liver were found. Here, we report five further IMNEPD patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation. We thereby hope to better define IMNEPD and promote recognition and diagnosis of this novel disease entity

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood

Diagnosis and management of Silver-Russell syndrome: First international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood

Approche gène candidat dans le développement précoce de l'obésité

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Prédisposition génétique de l'obésité infantile (exemple des enfants porteurs de mutations du gène MC4R, recherche d'un phénotype associé)

Résumé : L obésité liée aux mutations de MC4R est la première cause d obésité génétique connue. Sa prévalence est de 2 à 4%. Des facteurs génétiques influencés par des facteurs environnementaux, sont responsables du développement d une obésité chez l enfant. Une trentaine de caractéristiques phénotypiques ont été étudiées chez 976 enfants recrutés en consultation d obésité à l hôpital Armand Trousseau. La présence d une mutation rare de MC4R ou d un polymorphisme de ce même gène ont été recherchés chez tous ces enfants. Une caractérisation phénotypique complète a également été réalisée chez tous les enfants obèses. Trois groupes ont été constitués: patients n ayant pas de mutation de MC4R (n=877), patients ayant une mutation rare de MC4R (n=26) et patients ayant un polymorphisme génétique de MC4R (n=73). Aucune différence significative n a été mise en évidence dans la comparaison des phénotypes, notamment pour ce qui concerne le métabolisme glucidique, et la pression artérielle. Ces résultats contrastent avec ceux d études récentes ayant retrouvé une meilleure régulation du métabolisme glucidique chez les patients adultes ayant une mutation de MC4R ainsi qu un rôle protecteur des mutations de MC4R sur la pression artérielle. De nombreuses recherches sont encore nécessaires pour déterminer les bases génétiques de l obésité. Elles permettront peut-être d apporter des solutions efficaces pour sa prise en charge dans laquelle le médecin généraliste devra participer activement.Summary: MC4R deficiency is the most common genetic form of obesity. Its prevalence ranges from 2 to 4 %. Genetic factors influenced by environmental factors are responsible for the development of children obesity. Around thirty phénotypic characteristics were studied at 976 children recruited among patients consulting for obesity at the Armand-Trousseau hospital. The occurrence of a rare mutation of MC4R or a polymorphism of the same gene was looked for all these child s. A complete phenotypic characterization of MC4R mutation was also realized at all obese childs. We determined three groups: patients without MC4R mutation (n=877), patient with a rare MC4R mutation (n=26) and patients having a MC4R genetic polymorphism (n=73). We then compared phenotypes and observed no significant difference in particular in glucose metabolism and blood pressure according to the presence or not of MC4R mutation. Nevertheless, recent studies showed that glucose metabolism and blood pressure are better regulated in adult patients bearing a mutated MC4R gene. Many researches are still necessary to determine the genetic bases of the obesity. They will maybe allow to bring effective solutions for its care in which the general practitioner will have to participate actively.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF

Les particularités pubertaires de l'enfant obèse

PARIS6-Bibl. St Antoine CHU (751122104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Devenir des nouveaux-nés opérés d'une occlusion intestinale néonatale

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Implication de trois régions chromosomiques soumises à empreinte dans l obésité infantile (DLK1 ; H19-IgF2 ; SNRPN)

Introduction : Les facteurs génétiques et épigénétiques jouent un rôle-clé dans la genèse de l obésité infantile. Le syndrome de Silver-Russell, modèle extrême de retard de croissance intra-utérin (RCIU), est lié à des anomalies de méthylation sur des gènes soumis à empreinte et notamment la région H19-IGF2. En raison du lien décrit entre RCIU et obésité, nous avons fait l hypothèse que des anomalies dans certaines régions soumises à empreinte pourraient être impliquées dans l obésité infantile. L objectif de notre étude était donc d évaluer l implication de trois régions chromosomiques soumises à empreinte dans l obésité infantile. Matériels et méthodes : Dans un 1er temps, nous avons repris 2 observations d adolescentes obèses nées petites pour l âge gestationnel (PAG) et chez lesquelles une anomalie de méthylation du gène DLK1 ou de la région H19-IGF2 a été diagnostiquée. Puis, nous avons effectué un profil de méthylation de 3 gènes soumis à empreinte parentale (DLK1 ; H19-IGF2 et SNRPN) à partir de la technique ASMM RTQ- PCR chez 15 enfants obèses ayant des antécédents de RCIU. Résultats : Dans le groupe des 15 enfants obèses étudiés, une hypométhylation du gène DLK1 a été diagnostiquée chez un enfant. Une hypométhylation au niveau de la région DMR0 de IGF2, a aussi été mise en évidence chez un autre sujet, la signification physiopathologique de cette hypométhylation n étant pour l instant pas élucidée. La fréquence de ces anomalies dans notre cohorte était donc de 6,7%. L analyse du phénotype a permis de mettre en évidence des similitudes comme l absence d antécédents familiaux d obésité, des difficultés alimentaires dans la petite enfance, l accélération de la croissance pondérale après l âge de 5 ans et des anomalies endocriniennes comme une hyperandrogénie et/ou une puberté précoce avec une petite taille définitive chez les patients porteurs de telles anomalies. Discussion : Cette étude préliminaire a confirmé que des anomalies de méthylation dans des régions chromosomiques soumises à empreinte sont impliquées dans l obésité infantile. Elles sont associées à un phénotype spécifique évocateur. Ces résultats préliminaires sont à confirmer dans une cohorte plus large d enfants obèses ayant des antécédents de PAG/RCIU afin de déterminer la fréquence de telles anomalies dans l obésité infantile.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

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

Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016

Obesity results from a synergistic relationship between genes and the environment. The phenotypic expression of genetic factors involved in obesity is variable, allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. This is mainly due to autosomal recessive mutations in genes of the leptin-melanocortin pathway which plays a key role in the hypothalamic control of food intake. Melanocortin 4 receptor(MC4R)-linked obesity is characterized by the variable severity of obesity and no notable additional phenotypes. Mutations in the MC4R gene are involved in 2-3% of obese children and adults; the majority of these are heterozygous. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. Additional genes participating in the development of hypothalamus and central nervous system have been regularly identified. But to date, not all involved genes have been identified so far. New diagnostic tools, such as whole-exome sequencing, will probably help to identify other genes. Managing these patients is challenging. Indeed, specific treatments are available only for specific types of monogenic obesity, such as leptin deficiency. Data on bariatric surgery are limited and controversial. New molecules acting on the leptin-melanocortin pathway are currently being developed