Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is the first human disorder attributed to genomic imprinting.¹ Genes are expressed differentially based upon the parent of origin. An imprinting centre in chromosome 15q11-13 is involved.² Prader-Willi syndrome results from the loss of imprinted genomic material in the paternal 15q11.2-13 locus. The loss of maternal genomic material at the same locus results in Angelman syndrome. About 70% of PWS arise from deletion of 15q11-13 on chromosome 15. 28% come from maternal uniparental disomy caused by chromosomal nondisjunction. Sibling studies suggest there are various genetic sub-types of the condition.³

Similarities in morphology and hormonal profile related to the abnormalities in the hypothalamo-pituitary axis in both early morbid obesity and Prader-Willi patients suggest this mechanism is involved in the aetiology of the syndrome.⁴

It occurs somewhere between 1 in 8,000 children⁵ and 1 in 16,000 adults.⁶ Despite the genetic cause it appears to be sporadic rather than inherited in a Mendelian pattern. Sex ratio is equal and it occurs in all races.

This may be seen as a disease in 2 stages:

• After birth there is hypotonia, failure to thrive and sleepiness. The child usually has blue eyes and blond hair. They tend to lag behind other children in the transition to solid food.
• The second stage becomes apparent between 1 and 3 years old when an exceptional interest in food becomes apparent. Hyperphagia, obesity, hypogonadism, short stature and sleep apnoea and cor pulmonale occur.⁷ They have markedly elevated levels of ghrelin, a hormone associated with hunger.⁸ One study found a marked difference in obesity in patients living in different countries. It was thought that these differences could be explained by differences in management.⁹

A survey of 232 adults with Prader-Willi syndrome¹⁰ showed an equal sex distribution. Most were short, overweight, cognitively impaired, emotionally labile, had poor gross motor skills and were always hungry. Males were taller and heavier than females but both sexes were far shorter and heavier than normal people. Micropenis and cryptorchidism in males and primary amenorrhoea, late menarche and irregular menstrual cycles in females indicated hypogenitalism in both sexes.

One study found that Prader-Willi patients had a different gait from individuals who were simply obese. This was thought to be related to the effect of precocious obesity on motor skills in childhood.¹¹

Look for deletions and other rearrangements using high resolution chromosome banding ± fluorescence in-situ hybridisation (FISH) with probes from the 15q11-q13 region. The gene for SNRPN RNA (small nuclear ribonucleoprotein polypeptide N) is expressed only on the paternally acquired chromosome 15 and its absence forms the basis of a leucocyte RT-PCR polymerase chain reaction of reverse transcribed RNA test.¹²

Chromosome analysis is important as it differentiates Prader-Willi from another recently discovered condition which has similar clinical features: this has been called Prader-Willi-like syndrome but most patients have fragile X syndrome rather than an abnormality on Chromosome 15.¹³

Diagnosis is based on points from major and minor criteria.¹⁴

• From birth to age 3 requires 5 points including 4 major criteria.
• Age 3 to adult requires 8 total points including 5 major criteria.

Major criteria (1 point each)

• Neonatal or infantile central hypotonia with a poor suck. This gradually improves with age.
• Feeding problems in infancy or failure to thrive.
• Excessive weight gain between 1 and 6 years old.
• Characteristic facial features (narrow face, almond-shaped eyes etc.).
• Hypogonadism - genital hypoplasia and/or delayed or incomplete gonadal maturation (this is not always associated with infertility in boys).¹⁵
• Cryptorchidism is common.
• Global developmental delay (in child <6 years). They may not sit until 12 months nor walk until 24 months. Older children show mild to moderate mental retardation with learning difficulties and an IQ of 50 to 70.
• Hyperphagia with excessive appetite or food obsession.
• Chromosomal abnormality - deletion 15q 11-13 or other appropriate molecular abnormality in this chromosome region.

Minor criteria (0.5 points each)

• Decreased fetal movements, infantile lethargy or weak cry in infancy, which improves with age.
• Characteristic behavioural problems (typically tantrums or obsessive/compulsive behaviour).¹⁰ 5 to 10% of adults may show psychosis.
• Sleep disturbance/sleep apnoea .
• Short stature in childhood and failure of pubertal growth spurt.
• Hypopigmentation - fair skin and hair.
• Small hands and feet.
• Narrow hands with straight ulnar border.
• Eye abnormalities (esotropia, myopia).
• Thick, viscous saliva ± crusting at mouth corners.
• Speech articulation defects.
• Skin picking.

Other features which may be present, many of them related to problems of the hypothalamus:

• High pain threshold.
• Decreased vomiting.
• Temperature instability or altered temperature sensitivity.
• Scoliosis or kyphosis (66.7% at skeletal maturity in one series of 145 patients).¹⁶
• Early adrenarche (pubic or axillary hair before age 8) despite retardation of other sexual development .
• Obesity may cause type 2 diabetes at an early age, also called MODY (maturity onset diabetes of the young).
• Osteoporosis (because of hypogonadism). Along with a high pain threshold this can lead to pathological fractures that are not instantly recognised.
• They display an unusual skill with jigsaw puzzles. IQ is usually in the range of 60 to 80 but with expected individual variation. Not only do they perform better than IQ matched peers at completing jigsaw puzzles (this appears to be related to enhanced visuospatial ability¹⁷) but they perform better than peers of normal intelligence.¹⁸

Diagnosis can be confirmed by DNA testing.

Other tests may then follow:¹⁹

• If the patient is obese, screening for glucose intolerance is advised.
• Endocrine studies include insulin-like growth factor, lipids and thyroid function. LDL tends to be high and HDL low.
• Body composition analysis by DEXA, anthropometry or another method. DEXA is used to assess fat mass rather than bone mineral density in this case.
• Psychological and/or educational testing.
• Strength and endurance testing.

A multidisciplinary approach is essential to control the endocrine problems, to support the family and to keep the child away from food and consequent obesity. Regular exercise is important., A multidisciplinary approach to care is advised, perhaps utilising a paediatric gastroenterologist, endocrinologist, psychologist, psychiatrist and dietitian. Reviews by occupational therapists, speech therapists, exercise advisors and orthopaedic consultants may be helpful. Management of the transition period from childhood to adulthood is important and placement in a residential home may need to be considered.²⁰

Growth hormone is essential to maintain normal growth, muscle development and avoidance of obesity⁷ but only as part of an extensive package.¹⁹ One study found that growth hormone also improved behavioural difficulties.²¹ Growth hormone treatment was initially thought to make scoliosis worse but this is now thought not to be the case.²²

Family support is essential to cope with the behavioural difficulties throughout childhood. Hyperphagia can occasionally be dangerous causing massive stomach dilation. Appetite suppressants have not been successful and all food may have to be kept locked away. Surgery has also had limited benefit.²³ The energy requirements are only about 75% of that of a normal child.¹⁹

The patient is eased from home, through school to sheltered work and housing in the community.

Drugs

• Growth hormone may increase height, decrease obesity and improve muscle strength but it should probably not be started before 2 years old.¹⁹
• Appetite suppressant drugs are of no value.
• Many drugs have been used to modify behaviour but they tend to be ineffective or even counterproductive.
• Haloperidol and fluoxetine are sometimes effective.
• The SSRIs seem to have a nonspecific behaviour-stabilizing effect, with fewer outbursts, a marked reduction in irritability and less perseveration but with no antidepressant effect.
• The antipsychotic agent olanzapine and the anticonvulsant divalproex sodium may have an effect.
• All these drugs may be tried with care. None are universally successful and they may even be counterproductive.

Although this is a genetic defect, the problem appears to be sporadic rather than inherited. Hence antenatal screening is not appropriate.