New approaches in Prader Willi management

Prader Willi Syndrome (PWS), first described in 1956 by Prader, Labhart and Willi, represents the most common genetic cause of obesity with an estimated incidence of 1:15,000-1:25,000 live births. Reported prevalence rates vary between countries, but both sexes appear to be equally affected. PWS has a recognisable pattern of physical findings with significant cognitive, neurological, endocrine and behavioural abnormalities caused by lack of expression of genes from an imprinted region of the paternally inherited chromosome 15q11-q13.  

Affected infants uniformly have significant hypotonia, early feeding problems and difficulty with weight gain. Later, a second phase of the syndrome ensues with hyperphagia which leads to obesity and characteristic behavioural problems. Without adequate weight control and management of obesity, death typically occurs in the fourth decade of life from complications of obesity such as diabetes, obstructive sleep apnoea and right-sided heart failure. Obesity remains the single biggest challenge as a result of unrelenting hyperphagia and is the major cause of morbidity and mortality in PWS.

PWS was the first recognised disorder related to genomic imprinting in humans and provides an excellent example of how early diagnosis and multidisciplinary management can markedly improve the outcome for people with some genetic disorders.

Genetics

Lack of expression of several genes (missing, defective or silenced) on the paternally inherited chromosome 15 causes PWS. This region contains genes which are normally ‘imprinted’, meaning they are differentially expressed depending on whether the chromosome was inherited from the mother or father. 

In 75% of cases, PWS arises as a result of a deletion of the paternally inherited 15- 15q11-q13 region, 24% as a result of maternal uniparental disomy (MUPD) (both chromosome 15’s inherited from the mother) and 1% as a result of imprinting centre defects. Rarely a deletion occurs as a result of a translocation involving chromosome 15. The recurrence risk for deletions and MUPD is low (<1%). Recurrence risk where PWS is caused by imprinting mutations can be as high as 50%. Most cases occur sporadically.

Typical clinical features

Clinical criteria have been developed and validated but now that reliable molecular testing is available (methylation analysis) these criteria should be considered as guidelines for testing. 

In general, PWS should be considered in any infant with significant hypotonia particularly associated with poor suck, poor feeding and hypogonadism (undescended testis, small phallus, or hypoplasia of female genitalia). In older children the diagnosis should be considered if there is excessive appetite or impaired satiety, especially with rapid weight gain. Poor linear growth in the presence of excessive caloric intake should raise suspicion for PWS. Hypogonadism, hypotonia, developmental delay, speech delay and characteristic physical appearance should all raise the index of suspicion. These physical features include narrow bi-frontal diameter, almond shaped eyes, downturned angles of the mouth, small hands and feet and straight borders of the ulnar sides of the hands. 

As affected individuals age, manifestations such as obesity, short stature, hypogonadism, skin picking, learning disability, scoliosis, behavioural and psychiatric problems become more evident. Many mothers retrospectively report decreased foetal activity and infants are often found in breech position at delivery.

Diagnosis

Diagnostic testing for PWS should begin with a blood sample for methylation analysis.  DNA methylation analysis is the only technique which can both confirm and reject the diagnosis of PWS, and therefore should typically be the initial investigation of choice. If DNA methylation analysis shows only a maternal pattern, then PWS is confirmed. Further methods, including parental blood samples, may then be performed to determine the genetic subtype and allow appropriate genetic counselling, in particular the recurrence risk.

Management

Children with PWS are best managed by a multidisciplinary team including the primary care physician, paediatric endocrinologist, paediatric dietitian, developmental paediatrician and early intervention services, physiotherapist, speech and language therapist, orthopaedic surgeon, ophthalmologist, respiratory paediatrician and psychiatrist. Particular specialists may play a role at different stages.

Most infants require tube feeding to avoid failure to thrive. Cryptorchidism is present in 80% of boys, who should be referred for orchidopexy.  Referral to early intervention services for motor skills and speech and language skills is vital to maximise early development. 

Pharmacological agents and bariatric surgery have not been successful in achieving long-term weight loss as the hyperphagia is ongoing. Due to the variety of sleep-related breathing disorders in PWS, such as obstructive and central sleep apnoea, children need to be referred for polysomnography and ear nose and throat assessment, particularly prior to starting growth hormone. Prevalence of scoliosis is high in PWS and requires specialist orthopaedic assessment and follow-up. At some stage, almost all subjects will require hormonal treatment for induction, promotion or maintenance of puberty. 

Most individuals will have delayed and incomplete puberty. As affected individuals get older, the propensity for psychiatric problems increases, necessitating referral. Skin picking is an ongoing issue. Early screening and correction for myopia, hypermetropia, or other eye problems is recommended. Strabismus is also frequent and may require surgery. Amid this potentially complicated management, ongoing psychological support is often necessary for families.

Growth hormone treatment in PWS

Generalised hypothalamic dysfunction is characteristic of PWS and manifests as dysregulation of the hypothalamic-pituitary axis including growth hormone, thyroid function, appetite, thermoregulation and respiratory control. Length in newborns with PWS is normal but there is a significant decrease in height velocity after two to three years of age with final adult height -2 standard deviations (SD) below the mean for the normal population.  

Growth hormone is insufficient in all but a small percentage of children with PWS. Multiple studies have shown the benefits of growth hormone therapy in individuals with PWS, in particular improvements in lean body mass, decreased body fat, increased bone mineral density and normalisation of adult height. 

The benefits of starting growth hormone as early as two years of age are well established, but there is research ongoing into the benefits of earlier age of treatment such as: motor development, head growth and possibly cognition. It should be stressed that growth hormone therapy should be used in conjunction with caloric restriction and dietary advice and supervision. Growth hormone should not be seen as a substitute for appropriate dietary management and exercise. Treatment is given as a nightly subcutaneous injection using standard dose guidelines (0.035mg/kg/day) with regular careful monitoring of clinical status and growth factor measurements. 

Careful history and assessment of nutritional status, scoliosis, sleep and respiratory abnormalities should be evaluated prior to and during growth hormone treatment. In randomised controlled studies using the currently recommended dose (0.035mg/kg/day), there is a significant increase in height, growth velocity and a decrease in per cent body fat during the first year of growth hormone treatment followed by stabilisation during the second year. Lean body mass increased significantly during the first two years of growth hormone treatment compared with untreated PWS children. After the initial two years, growth hormone therapy for two additional years had continued beneficial effects on body composition but not with a dose reduction. Bone mineral density continued to improve at all doses of growth hormone. Only a few studies have reported data on adult height. 

Since October 2002, several reports of unexpected death in infants and children with PWS have been published. Most of them, whether in patients with or without growth hormone treatment, were related to a complicated course of a relatively mild respiratory tract infection, sleep apnoea, adenoidal and/or tonsil hypertrophy, hypoventilation and aspiration or related to obesity.  

A recent review including 64 children (42 boys and 22 girls, 28 on growth hormone treatment) suggested a high-risk period of death during the first nine months of treatment. For this reason it has been advised that treatment should be started at a low dose, such as 0.25-0.30mg/m2/d or 0.009–0.012mg/kg/d. This dose may be increased   during the first weeks and months to reach a standard replacement growth hormone dosage of around 1.0mg/m2/d or 0.035mg/kg/d. Close monitoring of clinical effects is important noting especially symptoms of sleep apnoea and fluid retention. High IGF-I levels should be avoided, particularly if there is a clinical suspicion of overtreatment (oedema, worsening or new development of snoring, headache, acromegalic clinical features). Decisions about care and management are best made in consultation with a paediatric endocrinologist.

Conclusion

The complex genetics, aetiology, multiple phenotypes, and evolving natural history of PWS means that a multidisciplinary professional, parental, societal, and environmental approach to the management is required, with many challenges to reducing morbidity and mortality and improving quality of life. However, over recent years, an increasing appreciation and availability of important management strategies have already made significant improvements in the life of those with PWS, eg. early diagnosis, use of multidisciplinary teams, introduction of growth hormone treatment, control of the food environment, and better understanding of the behavioural and psychiatric aspects. 

Hopefully, filling the gaps in our understanding of the underlying science will translate and eventually guide clinical management of PWS.