Prader-Willi Syndrome

The presentation of Prader-Willi syndrome depends upon the age of the patient.

In fetal life:

• Reduced fetal movements and abnormal position
• Polyhydramnios 
• Requirement for caesarean section

In neonates and children:

• Feeding difficulties (poor suckling reflex)
• Delayed developmental motor milestones
• Delayed onset of speech
• Thick saliva
• Weak cry
• Excessive sleeping
• Hypotonia [2]
• Lethargy
• Short stature
• Light colored hair
• Small hands and feet
• Skin hypopigmentation 
• Strabismus
• Scoliosis
• Hypopituitarism
• Kyphosis
• Cryptorchidism
• Failure of development of secondary sexual characteristics and delayed puberty
• Cognitive impairment
• Mental retardation
• Persistent hunger feeling
• Acquired obesity (secondary to overeating)

In adults:

• Infertility
• Hypogonadism
• Learning difficulties
• Physical appearance typical of PWS
• Gastrointestinal abnormalities
• High threshold for pain
• Behavioral problems (temper tantrums, obsessive–compulsive disorder (OCD), etc.)
• Psychosis
• Secondarily acquired diseases (cor pulmonale, diabetes mellitus)

Diagnosis is established with the help of the following investigations.

• Prenatal DNA testing for gene abnormalities
• Southern blotting for DNA methylation patterns
• Polymerase chain reaction (PCR)
• Parental DNA sampling for disomy
• Fluorescent in situ hybridization (FISH)
• Chorionic villus sampling and amniocentesis
• Screening tests for serum insulin like growth factor-1 (IGF-1), growth hormone levels and glycosylated hemoglobin
• Thyroid function tests
• Magnetic Resonance Imaging (MRI) in case of (hypopituitarism)
• Serial dual energy x-ray absorptiometry (DEXA) scanning (osteoporosis)
• X-ray of the chest
• Abdominal ultrasonography
• Computerized Tomography (CT) scans

There is no cure for Prader-Willi syndrome as it is a gene defect. The treatment is done for the management of acute symptoms of the disease [3]. It consists of the following.

• Symptomatic management of the following conditions is done to minimize morbidity.
  
  • Obesity [4] [5] [6]
  • Hypogonadism [7]
  • Hypopituitarism
  • Behavioral problems [8]
  • Hypotonia
  • Ophthalmologic abnormalities

• Growth hormone therapy helps improve the skeletal and muscle defects of Prader-Willi syndrome, in particular hypotonia [9][10].
• Vitamin D supplementation in these patients is associated with good results.
• Surgical management of respiratory difficulties may be indicated if the symptoms are severe. Tracheostomy may need to be done.
  
  

The condition is associated with development of secondary disorders like diabetes mellitus which can lead to comorbidities. Gastric and respiratory problems may lead to death. The overall prognosis is poor.

The syndrome arises due to deletion of genes on the chromosome 15 in the region 15q11-13 along with gene imprinting in maternal chromosomes [1]. Mutations or translocation of the genes may also give rise to Prader-Willi syndrome.

Prader-Willi syndrome occurs in about 1 in 10,000 to 1 in 25,000 newborns. The occurrence of this disease is sporadic. It affects male and females equally. No gender, racial or ethnic predisposition has been found.

The syndrome is not heritable as this is an acquired anomaly of the embryonic life. However, rare genetic changes in Prader-Willi syndrome can be passed on. Recurrence of the syndrome in siblings is uncommon.

Deletion of genes on the chromosome 15 in the region 15q11-13 leads to this abnormality. The underlying gene defect can occur by any of the three pathways:

• Deletion of genes in the paternal chromosomes.
• Genomic imprinting (and resultant silencing) of corresponding genes in the maternal chromosomal set.
• Uniparental disomy (UPD) can be another of the mechanisms of gene defects.

These genes usually code for certain small nucleolar RNAs (snoRNAs) which have regulatory as well as other functions.
Loss of SNORD116 gene cluster and OCA2 genes is common in Prader-Willi syndrome. This leads to hypopigmentation of skin and hair that is associated with the disorder.

Hypothalamic dysfunction underlies most of the symptoms of Prader-Willi syndrome, leading to disturbances of sleep-wake cycles, sexual characteristics, hunger and satiety, pain and temperature sensations.

The following measures should be adopted in order to minimize the morbidity from Prader-Willi syndrome.

• Parental genetic counseling should be done.
• Due to poor muscle power, neonates should be handled and picked up carefully.
• Strict dietary control should be observed for prevention of obesity. A balanced diet should be followed. All essential nutrients should be made a part of diet. Access of child to food should be restricted to prevent bouts of overeating and to keep their weight in check.
• Muscle activity like sports should be encouraged to overcome hypotonia and motor problems.
• Steroid therapy should be avoided as it tends to exacerbate the behavioral dysfunction
• Monitoring of children should be done to prevent respiratory and gastric difficulties.
• A strict sleeping routine should be followed to avoid daytime sleepiness and other sleep-related abnormalities.
• Behavioral problems should be handled with patience. If needed, psychiatric help should be sought.
• Parental screening tests should be carried out to assess the risk of recurrence of the disease with further pregnancies.

Prader-Willi syndrome (PWS), also known as Prader-Labhart-Willi syndrome, is a rare genetic disorder that arises due to genetic abnormalities. It is a multiphasic disorder that can lead to obesity in children.

Delayed onset of development is commonly observed in the cases of PWS. Behavioral and cognitive problems are also common in such children along with some degree of intellectual deficit.

Prader-Willi syndrome (PWS) develops as a result of genetic abnormalities due which the child suffers from late speech development, decrease muscle power, insatiable hunger and overeating bouts, obesity, excessive sleeping, weakness and mental retardation. Short stature and short hands and feet are typical of PWS. Growth retardation is common and such children fail to thrive. Puberty is delayed in patients of Prader-Willi syndrome and infertility is common.

Testing should be done to check for gene abnormalities before birth so that appropriate measures can be taken beforehand. The disease is rarely passed onto the next generation and is compatible with life but a lot of abnormalities develop in such patients. Presence of Prader-Willi syndrome in one child does not mean that further pregnancies will result in recurrence of the syndrome.

1. Cassidy SB. Prader-Willi syndrome. Characteristics, management, and etiology. The Alabama journal of medical sciences. Apr 1987;24(2):169-175.
2. Witkowski R, Ullrich E, Pietsch P, et al. [Infant hypotonia, obesity, hypogenitalism and oligophrenia--new viewpoints on the etiology and symptoms of Prader-Willi syndrome]. Psychiatrie, Neurologie, und medizinische Psychologie. May 1985;37(5):255-261.
3. Zipf WB. Prader-Willi syndrome: the care and treatment of infants, children, and adults. Advances in pediatrics. 2004;51:409-434.
4. Altman K, Bondy A, Hirsch G. Behavioral treatment of obesity in patients with Prader-Willi syndrome. Journal of behavioral medicine. Dec 1978;1(4):403-412.
5. De Peppo F, Di Giorgio G, Germani M, et al. BioEnterics intragastric balloon for treatment of morbid obesity in Prader-Willi syndrome: specific risks and benefits. Obesity surgery. Nov 2008;18(11):1443-1449.
6. Scheimann A, Butler MG, Stevenson D, Miller JL, Cuffari C, Klish WJ. "Efficacy of laparoscopic sleeve gastrectomy as a stand-alone technique for children with morbid obesity" and "BioEnterics intragastric balloon for treatment of morbid obesity in Prader-Willi syndrome: specific risks and benefits". Obesity surgery. May 2009;19(5):671-672; author reply 673.
7. Eiholzer U, Grieser J, Schlumpf M, l'Allemand D. Clinical effects of treatment for hypogonadism in male adolescents with Prader-Labhart-Willi syndrome. Hormone research. 2007;68(4):178-184.
8. Benarroch F, Hirsch HJ, Genstil L, Landau YE, Gross-Tsur V. Prader-Willi syndrome: medical prevention and behavioral challenges. Child and adolescent psychiatric clinics of North America. Jul 2007;16(3):695-708.
9. Hoybye C, Hilding A, Jacobsson H, Thoren M. Growth hormone treatment improves body composition in adults with Prader-Willi syndrome. Clinical endocrinology. May 2003;58(5):653-661.
10. Craig ME, Cowell CT, Larsson P, et al. Growth hormone treatment and adverse events in Prader-Willi syndrome: data from KIGS (the Pfizer International Growth Database). Clinical endocrinology. Aug 2006;65(2):178-185.

• Hypogonadism
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