Síndrome de Prader-Willi

What is Prader-Willi syndrome?

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder affecting metabolic, neurological and endocrine systems. The main features 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. Patients have behavioural, developmental, and intellectual difficulties.¹

Prader-Willi syndrome genetics²

Prader-Willi syndrome was the first human disorder attributed to genomic imprinting. It is caused by lack of expression of genes inherited from the paternal chromosome 15q11-q13 region due to:

• Paternal 15q11-q13 deletions (about 70%); or

• Maternal uniparental disomy 15 or both 15s from the mother (about 25%).¹

Most cases of PWS are sporadic; however, familial instances may occur when paternal genes carry a microdeletion in the imprinting centre, which is inherited from the paternal grandmother.¹

The opposite, ie maternal deletion or paternal uniparental disomy, causes Síndrome de Angelman.

Prader-Willi syndrome epidemiology¹

• The estimated prevalence is 1 in 20,000-30,000 births.

• Worldwide, around 400,000 people are affected.

• Males and females are equally affected; there are no differences between different ethnicities.

• Prader-Willi syndrome is the most prevalent genetic cause of life-threatening obesity in humans.

Criterios diagnósticos³

The diagnostic criteria were agreed in 1993 and are listed below. However, with the advent of reliable genetic tests, the criteria mainly serve to raise suspicion and therefore suggest the need for referral for genetic testing.

• 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 of age. Morphological and hormonal abnormalities of the pituitary gland are found in PWS.⁴

• There is evidence that obesity varies by country of residence, with French children being markedly more likely to be obese than those in Belgium, the United States and the UK but this data is now very old and may be out of date.⁵

• 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).⁶Penis size is often normal at birth but this then falls over the first few years. Hypogonadism often persists into adulthood. ¹

• Cryptorchidism is common.

• Global developmental delay (in a child aged <6 years). They may not sit until 12 months, or walk until 24 months. Older children show mild-to-moderate learning difficulties.

• Hyperphagia with excessive appetite or food obsession.

• Chromosomal abnormality - deletion 15q 11-13 or other appropriate molecular abnormality in this chromosomal 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).⁷ Adults may have psychotic episodes.

• 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.

Prader-Willi syndrome symptoms¹

• Clinical features change with age

• Babies with Prader-Willi syndrome are often born 15-20% smaller than their unaffected siblings.

• Hypotonia and a poor suck often result in failure to thrive during infancy.

• There tend to be dysmorphic facial features, with a narrow frontal diameter, almond-shaped palpebral fissures, strabismus, a slender nasal bridge, a thin upper vermillion border, downturned mouth corners, and enamel hypoplasia.

• Small hands and feet are common but these often develop later than infancy.

• Developmental delay is common with the average age of walking being 27 months.

• Language and intellectual impairments tend to be obvious by school age.

• Behavioural problems, including anxiety, obsessive-compulsive disorder, temper outbursts, and self-inflicted injuries, are prevalent in almost all individuals with PWS.

• Short stature is usually evident by the age of 10. There is a deficiency of growth hormone.

• Central obesity is common. Food seeking behaviour can result in binge eating or eating non food items.

• Hypogonadism is common with almost all boys having cryptorchidism, often requiring orchidopexy. Boys also often have hypoplasia of the scrotum whilst girls may have either hypoplasia or absence of the labia minora and clitoral hypoplasia. Penile size is often significantly reduced. Both males and females are considered to be infertile.

• The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency.

• Obesity and its complications are the major causes of morbidity and mortality in PWS.

Other features of Prader-Willi syndrome which may be present include:

• Sleep disorders,

• Thick, viscous saliva.

• Epilepsia.

• Skin, iris, and hair hypopigmentation (relative to expected family background) occurs in 30% to 50% of patients.

• 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).⁸

• 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 'maturity onset diabetes of the young' (MODY).

• Osteoporosis (because of hypogonadism). Along with a high pain threshold this can lead to pathological fractures that are not instantly recognised.

• Children with Prader-Willi syndrome have been shown to display an unusual skill with jigsaw puzzles⁹but this appears to vary with subtype. ¹⁰

• IQ is usually in the range of 60 to 80 but with expected individual variation. Genetic subtypes of the condition have differing IQ strengths - verbal vs performance IQ.¹¹

Prader-Willi syndrome diagnosis¹²

DNA methylation analysis and fluorescent in situ hybridisation (FISH) techniques can diagnose PWS in all three types of PWS, as well as differentiate PWS from Angelman's syndrome in deletion cases.¹³

Diagnóstico diferencial

• Obesidad.

• Síndrome del cromosoma X frágil.

• Cryptorchidism.

• Baja estatura.

• Síndrome de talla baja hiperfágica.

Prader-Willi syndrome treatment and management¹¹²

Treatment of Prader-Willi syndrome consists of intensive rehabilitation, psychological care, speech therapy and also, if the appropriate criteria are fulfilled, growth hormone treatment. An extremely important part of management is also properly planned and implemented nutritional management to prevent malnutrition in the first stage of life and the development of excessive weight in subsequent years.^{14 15}

A multidisciplinary approach is essential:

• Family support is essential to cope with the behavioural difficulties throughout childhood. The child must be kept away from excessive food intake, to guard against subsequent obesity.¹⁶ Their energy requirements are only about 70% of that of a normal child and hyperphagia can occasionally be dangerous, causing massive stomach dilation.¹ Regular exercise is important.

• Input from a paediatric gastroenterologist, endocrinologist, psychologist, psychiatrist, dietician, occupational therapists, speech therapists, exercise advisors and orthopaedic consultants may be helpful.

• Although bariatric surgery is still considered as an option in Prader-Willi syndrome,¹ there is plenty of evidence that it is often unsuccessful in maintaining weight loss as it does not manage the underlying hyperphagia. ¹⁷¹⁸

• Monitoring and screening for endocrinopathies are recommended, particularly growth hormone deficiency, hypogonadism, hypothyroidism, central adrenal insufficiency, and bone health/vitamin D deficiency.

• It is recommended to obtain HbA1c, lipids and transaminases in all patients at the age of puberty, and then annually if obese. HbA1c should be checked annually for all those with PWS treated with GH therapy.

Farmacológico

• Growth hormone is essential to maintain normal growth, and muscle development, and to avoid obesity.¹⁹ Growth hormone treatment was initially thought to make scoliosis worse but this has been refuted.²⁰

• The disadvantage of recombinant human growth hormone (rhGH) is the need for daily or weekly injections; however, the treatment is associated with improved growth, reduced obesity, and enhanced bone density and motor function. Patients treated with rhGH during childhood are likelier to approach their predicted final adult height.¹

• Appetite suppressant drugs are of no value. Long-acting octreotide reduces ghrelin secretion but does not affect behaviour or weight²¹

• There is no evidence of benefit from the use of GLP-1 agonists (such as tirzepatide or semaglutide) for weight in people with Prader-Willi syndrome, although they do show benefit in diabetes management.²²

• Diazoxide choline has been shown to be superior to placebo in managing hyperphagia. ²³This was licensed for use by the FDA in the USA in 2025. It is not yet available in the UK but NICE are considering it at the time of writing.²⁴

• SSRIs and atypical neuroleptics are often used to try to manage behavioural disturbances. 50% of children with PWS and 70% of adults are on SSRIs; 34% of people with PWS are on atypical neuroleptics. Polypharmacy is commonly seen with associated adverse effects such as arrhythmias. ²⁵

Asesoramiento genético²⁶

Recurrence risk depends on the mechanism causing PWS in the individual:

• Deletion is sporadic and has a recurrence rate of ≤1% (except in the rare cases where a chromosomal rearrangement is present in the father).

• Maternal uniparental disomy 15 is typically de novo also with a recurrence rate of ≤1% (except if a Robertsonian translocation is present in either parent).

• A proportion of those with an imprinting defect have a microdeletion in the imprinting centre; this can be familial and has a 50% recurrence risk when it is. However, the greater proportion of those with an imprinting defect have an epigenetic mutation and the recurrence risk is ≤1% for this group.

Pronóstico²

• Associated obesity contributes to comorbid conditions, including cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, dyslipidaemia, diabetes, sleep apnoea, and respiratory failure.

Based on population studies, the death rate in PWS is estimated at 3% per year.

In a large survey of causes of death in PWS:

• The most common causes were respiratory failure (31%), cardiac (16%), gastrointestinal (10%), infection (9%), obesity (7%), pulmonary embolism (7%), choking (6%), and accidents (6%).

• The average age of death in the 486 individuals with PWS reported in 2017 was 29.5 years. 80% of those who died were older than 18 years of age.

A PWS Profile has been developed as valid questionnaire which is specific to those with PWS and may aid with future research. ²⁷