Adrenal insufficiency in patients with Prader-Willi syndrome

Background Prader-Willi Syndrome (PWS) is a neurodevelopmental genomic imprinting disorder with lack of expression of genes inherited from the paternal chromosome 15q11-q13 region usually from paternal 15q11-q13 deletions (about 60%) or maternal uniparental disomy 15 or both 15s from the mother (about 35%). An imprinting center controls the expression of imprinted genes in the chromosome 15q11-q13 region. Key findings include infantile hypotonia, a poor suck, failure to thrive and hypogonadism/hypogenitalism. Short stature and small hands/feet due to growth and other hormone deficiencies, hyperphagia and marked obesity occur in early childhood, if uncontrolled. Cognitive and behavioral problems (tantrums, compulsions, compulsive skin picking) are common. Objective Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS. This report will describe an accurate diagnosis with determination of specific genetic subtypes, appropriate medical management and best practice treatment approaches. Methods and Results An extensive literature review was undertaken related to genetics, clinical findings and laboratory testing, clinical and behavioral assessments and summary of updated health-related information addressing the importance of early PWS diagnosis and treatment. A searchable, bulleted and formatted list of topics is provided utilizing a Table of Contents approach for the clinical practitioner. Conclusion Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections pertinent in the context of clinical practice. Frequently asked questions by clinicians, families and other interested participants or providers will be addressed.

Prader-Willi syndrome (PWS) is a complex neurobehavioral condition which has been classically described as having two nutritional stages: poor feeding, frequently with failure to thrive (FTT) in infancy (Stage 1), followed by hyperphagia leading to obesity in later childhood (Stage 2). We have longitudinally followed the feeding behaviors of individuals with PWS and found a much more gradual and complex progression of the nutritional phases than the traditional two stages described in the literature. Therefore, this study characterizes the growth, metabolic, and laboratory changes associated with the various nutritional phases of PWS in a large cohort of subjects. We have identified a total of seven different nutritional phases, with five main phases and sub-phases in phases 1 and 2. Phase 0 occurs in utero, with decreased fetal movements and growth restriction compared to unaffected siblings. In phase 1 the infant is hypotonic and not obese, with sub-phase 1a characterized by difficulty feeding with or without FTT (ages birth-15 months; median age at completion: 9 months). This phase is followed by sub-phase 1b when the infant grows steadily along a growth curve and weight is increasing at a normal rate (median age of onset: 9 months; age quartiles 5-15 months). Phase 2 is associated with weight gain-in sub-phase 2a the weight increases without a significant change in appetite or caloric intake (median age of onset 2.08 years; age quartiles 20-31 months;), while in sub-phase 2b the weight gain is associated with a concomitant increased interest in food (median age of onset: 4.5 years; quartiles 3-5.25 years). Phase 3 is characterized by hyperphagia, typically accompanied by food-seeking and lack of satiety (median age of onset: 8 years; quartiles 5-13 years). Some adults progress to phase 4 which is when an individual who was previously in phase 3 no longer has an insatiable appetite and is able to feel full. Therefore, the progression of the nutritional phases in PWS is much more complex than previously recognized. Awareness of the various phases will aid researchers in unraveling the pathophysiology of each phase and provide a foundation for developing rational therapies. Counseling parents of newly diagnosed infants with PWS as to what to expect with regard to these nutritional phases may help prevent or slow the early-onset of obesity in this syndrome. Copyright © 2011 Wiley-Liss, Inc.

Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks.