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Clinical Review - Prader-Willi syndrome

Prader-Willi syndrome is a rare genetic disorder that causes characteristics such as obesity due to an excessive appetite.

Controlling obesity is an important part of managing patients with PWS
Controlling obesity is an important part of managing patients with PWS

Section 1: Epidemiology and aetiology

Prader-Willi syndrome (PWS) was first described by Andrea Prader, Alexis Labhart and Heinrich Willi in 1956. It is the most common genetic form of obesity. In the UK, the prevalence of PWS is estimated to be one in 15,000 to 25,000. PWS occurs sporadically and is seen equally in all ethnic groups.

PWS is a genetic disorder attributed to genomic imprinting. For most genes, mammals inherit two copies of genes, one from each parent.

Genomic imprinting is a normal phenomenon where a chromosomal region in one of the parental copies is expressed, while the other is silenced (imprinted). The chromosome region 15q11.2-13 (long arm of chromosome 15 in the region between 11.2 and 13) is paternally expressed and maternally imprinted.

PWS arises due to the loss of the paternal copy of 15q11.2-13. Within this region lies a non-coding segment, HBII-85 'small nucleolar RNA' (snoRNA) cluster, which guides post-transcriptional modification of ribosomal RNA and other small nuclear RNAs.

The major clinical features of PWS are caused by the loss of paternal HBII-85 (the maternal allele is imprinted or silenced).

Loss of additional genes within 15q11.2-13 (NDN, SNURF-SNRPN, MAGEL2 and MKRN3) may account for additional features.

Deletion of the paternal arm of 15q11.2-13 accounts for approximately 65-70% of cases of PWS. Some 20-30% of cases arise from maternal uniparental disomy of 15q11.2-13, in which the paternal copy of the gene is replaced by a second maternal copy. Other patients with PWS have imprinting disorders or mutations isolated to 15q11.2-13.

Section 2: Making the diagnosis

The clinical features of PWS are distinct at each developmental stage.

Prenatal and infancy
Pregnant women universally report distinctly delayed onset and reduced fetal activity during pregnancies with children who have PWS.

Neonatal hypotonia is the hallmark of PWS and should be considered in the differential diagnosis, with congenital muscle disorders.

Hypotonia also causes poor suck, feeding difficulties and resulting failure to thrive. Most male infants have cryptorchidism and scrotal hypoplasia. Feeding difficulties improve by around six months of age.

Childhood
Uncontrollable hyperphagia causes major physical and behavioural problems, with development of obesity if food supply is unrestricted.

Craniofacial features evolve and become prominent, with narrow bifrontal diameter, almond-shaped eyes, strabismus, full cheeks, narrow nasal bridge, thin upper vermilion and downturned mouth corners.

Children exhibit motor developmental delay, with mild to moderate learning difficulties, and require additional support with statements of special needs at school.

Short stature improves with growth hormone (GH) therapy.

Adolescence and adulthood
Pubertal development is generally delayed or incomplete. If diet is not controlled, obesity worsens, with development of complications such as sleep apnoea, cor pulmonale, diabetes mellitus and atherosclerosis. Behavioural problems are common in adolescents and adults with PWS.

During adulthood, appetite is no longer insatiable. Most adults with PWS are unable to live independently and require continued support.

Complications of obesity, such as type 2 diabetes, hyperlipidaemia, hypertension and cardiovascular disease, begin to manifest during adulthood. Psychosis is exhibited by young adulthood in at least 5-10% of patients.

Investigations
Any child presenting with this constellation of clinical and phenotypic features should be referred to a secondary or tertiary endocrine service to rule out PWS. Clinical scenarios for considering genetic testing are summarised in table 1.

Some children with PWS can manifest GH insufficiency, adrenal insufficiency and hypothyroidism. Polyuria, polydipsia and recent onset of rapid weight loss should prompt measuring fasting blood glucose and/or performing oral glucose tolerance tests.

Obese patients with PWS should be investigated for dyslipidaemia, cholelithiasis, gastroesophageal reflux, non-alcoholic fatty liver disease and hypertension. Sleep-related disturbance requires sleep studies.

TABLE 1: CLINICAL SCENARIOS FOR CONSIDERING GENETIC TESTING FOR PWS
Stage at diagnosis Clinical scenarios
Prenatal  Decreased fetal movement, polyhydramnios,
abnormal positioning of limbs
Infancy  Hypotonia, poor suck, feeding difficulty necessitating nasogastric tube feeds and developmental delay
Childhood Hypotonia, developmental delay, hyperphagia and obesity
Adolescents and adults Cognitive impairment, learning difficulties, hyperphagia, obesity, hypogonadism and typical behavioural pattern

Section 3: Managing the condition

Genetic counselling and early referral to clinical psychology services should be discussed with the family because a diagnosis of PWS has substantial psychosocial impact.

Feeding and obesity
During infancy, hypotonia and poor suck can result in failure to thrive. Speech and language therapy assistance is required for evaluation of feeding and swallowing.

Assisted nasogastric feeding may be required for two to six months. A balanced caloric goal is required to promote cognitive development, while avoiding excessive rapid growth, which increases the long-term predisposition to obesity. Infants will require intensive occupational and physical therapies for muscle tone and strength.

In older children and adolescents, the cornerstone of effective management is controlling obesity through strict limitation of food intake. This is achieved through co-ordinated efforts by the family, school and the multidisciplinary team. Behavioural modification can be helpful.

Many patients with PWS become severely obese, but there is little evidence on invasive treatments. Bariatric surgery may be dangerous, because of the psychobehavioural problems associated with PWS.

Growth hormone treatment
NICE recommends GH therapy for children with PWS. This improves linear growth and has beneficial effects on body composition, including fat-free mass, lipid profile, muscle function and bone density.

Treatment is initiated and monitored by a tertiary endocrinologist, with shared care from primary care. It is commenced at about two years of age, although significant hypotonia and feeding difficulties may warrant earlier initiation.

There were some reports of unexpected death in children with PWS on initiation of GH therapy, which were attributed to obstructive apnoeas. GH therapy is now considered safe provided patients with PWS are monitored for obstructive sleep apnoeas. All children with PWS are subjected to sleep studies before commencing GH therapy.

Type 2 diabetes
Up to 25% of adults with PWS have type 2 diabetes. In children and adolescents, about 4% have impaired glucose tolerance.

Hypogonadism
Most adolescents will fail to progress through puberty and require sex hormone replacement therapy. Most patients will be infertile but sex hormone replacement will be required throughout life for bone health.

Sleep apnoea
Tonsillo-adenoidectomy, positive pressure ventilation treatment or tracheostomy may be required in severe obstructive sleep apnoea.

Behavioural difficulties
Most problems relate to insatiable appetite. A highly structured living environment is recommended, in which access to food is limited.

The multidisciplinary team may need to include a GP, health visitor, social worker, clinical psychologist, dietitian, and child and adolescent mental health team. The community paediatric team manages developmental delay, speech and language therapy, and learning difficulties.

Section 4: Prognosis

There is no cure for the complex problems associated with PWS, although adults with the condition are now surviving beyond 50 years of age. The death rate in PWS has been estimated at 3% per year and there is a suggested sixfold relative risk of death in PWS compared to other patients with developmental disability.

The major cause of morbidity and mortality in PWS is morbid obesity, so the mainstay of management is the prevention of obesity and its associated complications.

Unexpected deaths during childhood can occur from obstructive sleep apnoeas and central adrenal insufficiency. Excessive binge eating and death from choking, gastric necrosis and rupture, and respiratory compromise have been reported.

Most patients with PWS will require supervision and specialised care throughout their lives.

Section 5: Case study

Jack, a two-year-old, was referred to the tertiary endocrine service for management of PWS. His mother reported that he was born at term by elective caesarean section for breech presentation, with a birthweight of 7lb. She remembered that during her pregnancy, she noticed little fetal movement. Her antenatal scans were normal.

Breathing difficulties
Jack required assistance with his breathing, with continuous positive airway pressure, for his first six days.

He had hypotonia and feeding difficulties. He required nasogastric feeding for two months before oral feeding was established.

At four months, he was noted to have failure to thrive, with weight and length below the 0.4th centile. PWS was suspected and confirmed by genetic testing.

Jack's GP referred him to the community paediatric team for occupational therapy, physiotherapy, and speech and language therapy.

At 18 months, Jack was reported to have significant sleep difficulties, with excessive snoring at night. ENT evaluation revealed enlarged tonsils. Adenotonsillectomy was performed at 20 months of age, following which his sleep improved. A few weeks before the paediatric endocrinology clinic appointment, Jack underwent surgery for cryptorchidism.

On assessment in the tertiary endocrine clinic at two years of age, it was noted that Jack's weight was on the 75th centile and his length was on the second centile. He had almond-shaped eyes, bitemporal narrowing, a thin upper lip with downturned corners of the mouth, and hypotonia.

He had gross and fine motor developmental delay by about nine months. His parents had contacted the Prader-Willi support group and received genetic counselling and support from the clinical psychologist. His family were keen for Jack to commence GH treatment.

Before commencing GH therapy, Jack was referred to the ENT team for sleep studies, which were reported as normal. A plan was put in place to repeat sleep studies once a year.

Family support
In a recent review, at the age of three years, Jack's weight and height were on the 50th centile.

He has been receiving excellent support from his family in restricting his calorie intake and managing his behaviour at home.

His parents reported that with GH therapy, Jack's gross motor development was improving.

A key point to highlight in this case is that children with PWS present with the classic clinical features of hypotonia, poor feeding and failure to thrive during infancy, followed by hyperphagia and developmental delay as toddlers.

Section 6: Evidence base

Clinical trials

  • Lindgren AC, Hagenas L, Muller J et al. Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably. Acta Paediatr 1998; 87(1): 28-31

This is the first evidence from an RCT, which demonstrated that GH treatment is beneficial for most children with PWS.

In the study, children who were treated with GH demonstrated significant increase in height velocity, decrease in fat mass and increase in fat-free mass.

Guidelines

  • NICE. Human growth hormone (somatropin) for the treatment of growth failure in children (review). TA188. London, NICE, May 2010.

PWS support group

Both organisations offer support and information for patients who have PWS, their families and their carers, as well as specific education sections for healthcare professionals.

On the UK site (http://pwsa.co.uk/index.php/what-is-pws/186-publications) there is a free, easy-to-download leaflet for GPs, which provides information about the condition, ranging from diagnosis and management, to matters concerning mental capacity and annual check-ups.

  • Contributed by Dr Raja Padidela, consultant paediatric endocrinologist at Royal Manchester Children's Hospital
CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Review the current literature on pre-pregnancy counselling for parents with a family history of a child with PWS.
  • Discuss a shared care protocol for growth hormone therapy with a tertiary care endocrinologist.
  • Genetics is an important aspect of the GP curriculum - review the literature around initial genetic counselling for pre-pregnancy discussions with families affected by these conditions.

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Resources

  • Emerick JE, Vogt KS. Endocrine manifestations and management of Prader-Willi syndrome. Int J Pediatr Endocrinol 2013; 2013(1): 14.
  • Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med 2012; 14(1): 10-26.
  • Cassidy SB, Driscoll DJ. Prader-Willi syndrome. Eur J Hum Genet 2009; 17(1): 3-13.
  • Miller JL. Approach to the child with Prader-Willi syndrome. J Clin Endocrinol Metab 2012; 97(11): 3837-44. doi: 10.1210/jc.2012-2543

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