Prader-Willi Syndrome is a rare (birth incidence 1 in 10,000-30,000), complex and clinically
heterogeneous genetic condition with mean age of death at 30 y. The challenges to management are multiple because PWS affects cognition, which raises multiple ethical and social concerns. The clinical goals of the endocrinologist may be at odds with patient/caregiver needs: hyperphagia, management of behavioral and psychiatric issues and independent living being the top unmet needs voiced by families, while physicians have been focused on growth, body composition and metabolic outcomes. Despite all these difficulties, the life of our patients with PWS has changed markedly over the last 20 years, and this is due to 1) a better genetic, molecular, and clinical understanding of PWS, 2) our caregiver-healthcare team partnerships and 3) better management guidelines.
Care requires multiple specialists because of the large number of co-morbidities that may vary and/or evolve throughout the lifespan. These include hypotonia and developmental delay, early feeding issues, viscous saliva with tooth decay, speech articulation defects, estropia/myopia, skin picking, scoliosis, sleep disturbances and sleep apnea, metabolic syndrome and T2D, epilepsy, autism-like symptoms, anxiousness and distress, temper outbursts, obsessive-compulsive traits leading to repetitive and ritualistic behavior and other psychiatric symptoms including psychotic episodes. Coordinating care and keeping healthcare teams harmonized in their approach, as well as up to date with the clinical care guidelines, is a significant challenge. All these factors place a tremendous burden on caregivers.
Today I will focus on the current recommendations for diagnosis and suggested anticipatory guidance for caregivers. We will address the early nutritional interventions and prevention measures that need to be in place as the infant moves from the hypotonic and failure to thrive nutritional phase (birth to 9 months, phase 1a) through to the hyperphagic phase with some satiety (4.5 to 8 y, phase 2b) to an insatiable appetite (8 y to adulthood, phase 3). We will briefly discuss some of the therapies to manage hyperphagia that have been tested in small case series or larger clinical trials (Liraglutide/semaglutide -GLP-1 agonists; Livoletide -unacylated ghrelin analog; GLWL-01 -inhibitor of ghrelin acylation; topiramate -Na/Ca channel blocker; DCCR/diazoxide choline controlled-release - KATP channel agonist; Carbetocin -oxytocin analog). However, to date there are no approved treatments for hyperphagia judged to be efficacious and safe. Most of the trials have had limited numbers of pediatric subjects and even larger trials must contend with many within subject confounders and protocol limitations (weight and BMI SDS inappropriate primary endpoints, lack of biomarkers, questionnaires relying on caregiver observations - to name a few), making statistical significance difficult to achieve. Bariatric surgery is, in general, felt to be contraindicated.
Guidelines for replacement therapy for the multiple endocrinopathies of hypothalamic and/or end organ origin will be reviewed, including GH deficiency, LH/FSH/sex steroid deficiencies and occasionally TSH and ACTH with consideration of clinical goals and side effect profiles. The recent demonstration of prohormone convertase 1 deficiency in pluripotent stem cell neurons for subjects with PWS is of interest, since not only are PC1 gene (PCSK1) mutations associated with an obesity phenotype, but lack of this important hormone can potentially explain the pleiotropic and widespread hormone deficiencies seen in PWS because of inadequate prohormone processing. Future management will likely require multiple therapies not only because of this, but also because of the complex and interconnected neural and hormonal networks regulating hunger, satiety, energy expenditure and behavior.
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