Obesity is a complex, heritable trait influenced by the interplay of genetics, epigenetics, metagenomics and the environment. With the increasing access to high precision diagnostic tools for genetic investigations, numerous genes influencing the phenotype have been identified, especially in early onset severe obesity. This review summarizes the current knowledge on the known genetic causes of obesity and the available therapeutic options. Furthermore, we discuss the role and potential mechanism of epigenetic changes that may be involved as mediators of the environmental influences and that may provide future opportunities for intervention.

Genetic and epigenetic causes of obesity.

PWS is a severe neurodevelopmental genetic disorder now usually diagnosed in the neonatal period from hypotonia and feeding difficulties. Our study analyzed the birth incidence and care of infants with early diagnosis. Data were collected on 61 infants with a molecular diagnosis of PWS born in 2012 and 2013 in France. Thirty-eight infants with PWS were born in 2013. The median age at diagnosis was 18 days. Birth incidence calculated for 2013 was 1/21,000 births. No case was diagnosed prenatally, despite 9 amniocenteses, including 4 for polyhydramnios. Five infants had delayed diagnosis, after 3 months of life. For 2 of them, the diagnosis was not suspected at birth and for 3, FISH analysis in the neonatal period was normal, with no further molecular studies. Ninety-three percent of the neonates were hospitalized, and 84% needed nasogastric tube feeding for a median of 38 days. Swallowing assessment was performed for 45%, at a median age of 10 days. Physiotherapy was started for 76% during hospitalization. Eighty percent of those diagnosed within the first 3 months were seen by a pediatric endocrinologist within the first week of life. Our study is the first to assess the birth incidence of PWS in France, at 1/21,000 births. Some prenatal or neonatal cases remain undiagnosed because of unrecognized clinical signs and the inappropriate choice of the initial molecular test. We also underscore the need to optimize neonatal care of infants with PWS.

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Early diagnosis and care is achieved but should be improved in infants with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a complex multisystem disorder due to the absent expression of the paternally active genes in the PWS critical region on chromosome 15 (15q11.2-q13). The syndrome is considered the most common genetic cause of obesity, occurring in 1:10,000-1:30,000 live births. Its main characteristics include neonatal hypotonia, poor feeding, and lack of appetite in infancy, followed by weight gain, lack of satiety, and uncontrolled appetite, frequently after the age of 2-3 years. The clinical picture includes short stature, multiple endocrine abnormalities (hypogonadism, growth hormone/insulin-like growth factor-I axis dysfunction, hypothyroidism, central adrenal insufficiency), dysmorphic features, scoliosis, osteoporosis, mental retardation, and behavioral and psychiatric problems. Subjects with PWS will become severely obese unless their food intake is strictly controlled. Constant and obsessive food seeking behavior can make life very difficult for both the family and caretakers. Prevention of obesity is mandatory in these patients from the first years of life, because once obesity develops it is difficult to maintain the control of food intake. In fact, PWS subjects die prematurely from complications conventionally related to obesity, including diabetes mellitus, metabolic syndrome, sleep apnea, respiratory insufficiency, and cardiovascular disease. The mechanisms underlying hyperphagia in PWS are not completely known, and to date no drugs have proven their efficacy in controlling appetite. Consequently, dietary restriction, physical activity, and behavior management are fundamental in the prevention and management of obesity in PWS. In spite of all available therapeutic tools, however, successful weight loss and maintenance are hardly accomplished. In this context, clinical trials with new drugs have been initiated in order to find new possibilities of a therapy for obesity in these patients. The preliminary results of these studies seem to be encouraging. On the other hand, until well-proven medical treatments are available, bariatric surgery can be taken into consideration, especially in PWS patients with life-threatening comorbidities.

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Obesity management in Prader-Willi syndrome: current perspectives.

Prader-Willi syndrome (PWS) is a complex genetic disorder with implications on the endocrine and neurologic systems, metabolism, and behavior. Early in life, PWS is characterized by hypotonia and failure to thrive, followed by obesity and hyperphagia. Patients with PWS develop hypothalamic dysfunction which may lead growth hormone deficiency (GHD), hypogonadism, hypothyroidism, adrenal insufficiency, and poor bone mineral density (BMD). In addition to hypothalamic dysfunction, individuals with PWS have increased risk for obesity which may be complicated by metabolic syndrome and type 2 diabetes mellitus (T2DM). In this paper, we will review the current literature pertaining to the endocrine concerns of PWS and current recommendations for screening and management of these conditions.

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Review of Prader-Willi syndrome: the endocrine approach

Endocrine disorders in Prader-Willi syndrome: a model to understand and treat hypothalamic dysfunction.

BACKGROUND AND OBJECTIVES: Patients with Prader–Willi syndrome (PWS) display poor feeding and social skills as infants and fewer hypothalamic oxytocin (OXT)-producing neurons were documented in adults. Animal data demonstrated that early treatment with OXT restores sucking after birth. Our aim is to reproduce these data in infants with PWS. METHODS: We conducted a phase 2 escalating dose study of a short course (7 days) of intranasal OXT administration. We enrolled 18 infants with PWS under 6 months old (6 infants in each step) who received 4 IU of OXT either every other day, daily, or twice daily. We investigated the tolerance and the effects on feeding and social skills and changes in circulating ghrelin and brain connectivity by functional MRI. RESULTS: No adverse events were reported. No dose effect was observed. Sucking assessed by the Neonatal Oral-Motor Scale was abnormal in all infants at baseline and normalized in 88% after treatment. The scores of Neonatal Oral-Motor Scale and videofluoroscopy of swallowing significantly decreased from 16 to 9 (P CONCLUSIONS: OXT is well tolerated in infants with PWS and improves feeding and social skills. These results open perspectives for early treatment in neurodevelopment diseases with feeding problems.

https://pediatrics.aappublications.org/content/pediatrics/early/2017/01/16/peds.2016-2976.full.pdf

The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader-Willi Syndrome.

Background Infant-mother interaction is a set of bidirectional processes, where the baby is not only affected by the influences of his caregiver, but is also at the origin of considerable modifications. The recent discovery of biological correlates of synchrony during interaction validated its crucial value during child development. Here, we focus on the paradigmatic case of Prader-Willi Syndrome (PWS) where early endocrinal dysfunction is associated with severe hypotonia and early feeding disorder. As a consequence, parent-infant interaction is impaired. In a recent study (Tauber et al., 2017), OXT intranasal infusion was able to partially reverse the feeding phenotype, infant’s behavior and brain connectivity. This article details the interaction profile found during feeding in these dyads and their improvement after OXT treatment. Methods Eighteen infants (≤6 months) with PWS were recruited and hospitalized 9 days in a French reference center for PWS where they were treated with a short course of intranasal OXT. Social withdrawal behavior and mother-infant interaction were assessed on videos of feeding before and after treatment using the Alarm Distress Baby (ADBB) Scale and the Coding Interactive Behavior (CIB) Scale. Raters were blind to treatment status. Results At baseline, infants with PWS showed hypotonia, low expressiveness of affects, fatigability and poor involvement in the relationship with severe withdrawal. Parents tended to adapt to their child difficulties, but the interaction was perturbed, tense, restricted and frequently intrusive with a forcing component during the feeding situation. After OXT treatment, infants were more alert, less fatigable, more expressive, and had less social withdrawal. They initiated mutual activities and were more engaged in relationships through gaze, behavior, and vocalizations. They had a better global tonicity with better handling. These modifications helped the parents to be more sensitive and the synchrony of the dyad was in a positive transactional spiral. Conclusion Dys-synchrony can be induced by children’s pathology as well as parental pathology with emotional and developmental impact in the both cases. The PWS paradigm shows us the necessity to sustain early parents-child relationship to avoid establishment of a negative transactional pattern of interaction that can impact child’s development.

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Pascale Fichaux-Bourin

Papers

The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader-Willi Syndrome.

Dyssynchrony and perinatal psychopathology impact of child disease on parents-child interactions, the paradigm of Prader Willi syndrom.