Prader-Willi Syndrome

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What Is Prader-Willi Syndrome?

Prader-Willi syndrome (PWS) is a rare genetic disorder that is caused due to abnormal functioning of specific genes on chromosome 15.The condition is named after Swiss physicians Andrea Prader and Heinrich Willi and Alexis Labhart who described it in detail in 1950s. It is also called as Prader-Labhart-Willi, or Prader-Willi-Fanconi syndrome.

It is characterized by small hands and feet, abnormal growth and body composition (small stature, early-onset childhood obesity), hypotonia (weak muscles) at birth, hypogonadism, insatiable hunger, extreme obesity, and intellectual disability.

Prevalence

PWS affects an estimated 1 in 15,000 - 30,000 people. The prevalence rates differ among studies across countries, mainly due to using different methods for case identification. There is no strong evidence for increased risk in specific countries or gene pools. Both sexes appear to be affected equally.

Etiology and Pathological Process

People normally inherit one copy of chromosome from each parent except those with sex characteristics. Some of these genes are turned on (active) only on the copy that is inherited from a person's father (the paternal copy) which is called as genomic imprinting.

PWS is caused due to abnormality in the expression of genes on Chromosome 15 specifically on the long arm of chromosome 15q11-q13. This abnormality can be caused due to:

1. deletion of the genes on the paternal copy (70-80%)
2. the genes on the maternal copy are turned off (inactive) (20-25%)
3. has two copies of chromosome 15 inherited from the mother instead of one copy from each parent (maternal uniparental disomy) (1%)
4. chromosomal rearrangement called a translocation (<1%)
5. by a mutation or other defect (Imprinting center defects) (1%)

Prader-Willi syndrome is the first human disorder attributed to genomic imprinting.

The PW genes identified are:

1. SNRPN and NDN necdin genes,
2. clusters of snoRNAs: SNORD64, SNORD107, SNORD108 and two copies of SNORD109

There are significant advances in understanding and characterizing the genetic changes associated with PWS that have taken place, though, the exact mechanism by which lack of functional genetic material causes PWS is not understood. Researchers are still studying the normal role of the genetic sequences in the PWS region and how their loss affects multiple other systems in the body.

The genetic changes associated with this disorder present as random events during the formation of reproductive cells or in early embryonic development, with no history of the disorder in the family. Hereditary transmission is also very rarely seen.

Clinical Features

The Clinical Features vary according to the age and individual. The signs and symptoms change over time from childhood to adulthood. The clinical features aid in diagnosis of the PWS and are categorized as major, minor and supportive findings:

In Infants:

Signs and symptoms that may be present include:

- Major Findings:

• Poor muscle tone: poor muscle tone (hypotonia).
• Distinct facial features: almond-shaped eyes, a narrowing of the head at the temples, a turned-down mouth and a thin upper lip.
• Poor sucking reflex: feeding difficulty causing failure to thrive.
• Underdeveloped genitals: Males may have a small penis and scrotum or cryptorchidism. In females, the clitoris and labia may be small.
• Obesity

- Minor Findings:

• Generally poor responsiveness: A baby may seem unusually tired, respond poorly to stimulation, have a hard time waking up or have a weak cry.

Early childhood to adulthood

Features of Prader-Willi syndrome appearing during early childhood remain throughout life, requiring careful management. These features include:

- Major Findings:

• Excessive appetite and overeating (hyperphagia): a constant craving for food, resulting in rapid weight gain, starting around age 2 years. Unusual food-seeking behaviors, such as hoarding food, or eating frozen food or even garbage.
• Hypogonadism: sex organs (testes in men and ovaries in women) produce little or no sex hormones causing incomplete or delayed puberty, and in nearly all cases, infertility. Without treatment, women may not start menstruating until their 30s or may never menstruate, and men may not have much facial hair and their voices may never fully deepen.
• Poor growth and physical development: Underproduction of growth hormone can result in short adult height, low muscle mass and high body fat. Other endocrine problems include: 1) underproduction of thyroid hormone (hypothyroidism). 2) central adrenal insufficiency, which prevents the body from responding appropriately during stress or infections.
• Cognitive impairment: Mild to moderate intellectual disability, such as issues with thinking, reasoning and problem-solving.
• Delayed motor development: delayed motor, cognitive, and language development. The average intelligence quotient of older individuals is in the upper range of mild mental retardation. Learning disabilities may also be present.

- Minor Findings:

• Speech problems: Speech is often delayed. Poor articulation of words may be an ongoing problem into adulthood.
• Behavioral problems: stubborn, angry, controlling or manipulative with frequent temper tantrums They may also develop obsessive-compulsive or repetitive behaviors, or both a well as anxiety and skin picking.
• Sleep disorders: disruptions of the normal sleep cycle and sleep apnea. These disorders can result in excessive daytime sleepiness and worsen behavior problems.
• small hands and feet, short stature.

- Supportive Findings:

• Scoliosis,
• reduced saliva flow, nearsightedness and other vision problems, problems regulating body temperature, a high pain tolerance, hypopigmentation causing hair, eyes and skin to be pale.
• Osteoporosis
• Early Adrenarche

Diagnosis

Early diagnosis and intervention are critical. The diagnosis of PWS is mainly via Genetic Testing and Counselling and supported by Clinical Diagnostic Criteria.

Methods of Genetic testing and counselling:

1. DNA methylation:  only technique which can both confirm and reject the diagnosis of PWS. Gold Standard.
2. High resolution chromosomal analysis (HRCA): along with the fluorescence in situ hybridization (FISH) to detect deletions and translocation of chromosome 15
3. methylation-specific multiplex ligation PCR amplification

Consensus clinical diagnostic criteria have been published and modified to trigger diagnostic testing. The scoring system varies, depending on age due to the variability in presentation of cases. The Major, minor and supportive findings have been reported above.

- In children 3 years of age and younger, only five points are required for diagnosis; four must come from the major group.

- A total score of eight is necessary for the diagnosis in the 3 year to adulthood group with major criteria items comprising five or more points of the total score

Differential Diagnosis

PWS has to be differentially diagnosed with:

1. Craniopharyngioma: DNA methylation will help in differentiating
2. Congenital myotonic dystrophy type 1
3. Spinal muscular atrophy: Molecular genetic testing, EMG/NCV, and/or muscle biopsy required to differentiate these conditions.
4. Angelman syndrome 
5. Fragile X syndrome
6. WAC-related intellectual disability
7. Albright hereditary osteodystrophy
8. Alstrom Syndrome
9. Cohen Syndrome

DNA methylation technique helps to differentially diagnose PWS from the above conditions.

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