Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder characterized by hypothalamic-pituitary dysfunction. The main clinical features consist of neonatal hypotonia, distinctive facial features, delayed overall development with mental deficiency, behavioral abnormalities, poor growth in infancy followed by overeating with severe obesity, short stature, and hypogonadism. Recently, patients with PWS have been diagnosed at an earlier age, especially in the neonatal period. In addition, early interventions such as commencement of growth hormone therapy and dietary programs, have received attention in PWS treatment. Since early diagnosis is now possible based on both clinical symptoms and signs and on molecular genetic criteria, early dietary intervention and early growth hormone therapy during the first two years may improve neurodevelopment, increase muscle mass, and reduce obesity. Our aim in this review is to document the characteristics of infants with PWS and to provide a recent update regarding early management.

SLIDE NOTES

Interesting fact: Angelman’s Syndrome is a mirror image of PWS where deletions and duplications occur on the mother’s 15 chromosome - manifests as a different syndrome

Slide 2.

 C.T is a 12 year old Aboriginal girl, born in 2003.  

At birth, her mother was surprised by her unusual features, poor responses and fair hair, skin and blue eyes.

C.T. was born with Prader-Willi syndrome (PWS). PWS is caused by genetic changes on an "unstable" region of chromosome 15 that affects the regulation of gene expression. It is a condition that occurs in about one in every 15,000 to 25,000 births; affects males and females equally.

Slide .3

There are two distinct phenotypic stages of PWS;

First stage –present at birth and lasting until 2/3 years of age;

Second stage – developing about 2/3 until around 8 years of age.

While some research suggests other intermediate and later stages, this is not yet generally accepted or fully researched.

(Gunay-Aygun, Schwartz, Heger, O'Riordan & Cassidy 2001; Whittington & Holland, 2010).

Slide 4

At birth C.T.;

weighed less than average newborns;

was severely hypotonic, with a weak sucking reflex;

cried quietly and sporadically;  

had distinctive facial features — dolichocephalic head shape, almond-shaped eyes, small mouth with thin upper lip and down-turned corners;

have a hypopigmentation presentation

Slide 5

C.T. required nasogastric intubation to supplement feeding.

At home, C.T. ‘failed to thrive’; she was unable to suckle effectively, slept for significant periods (including through  feed times) and rarely cried.  

Her hypotonia worsened and it was noticed that she had also developed strabismus. Strabismus is a vision condition where one’s eyes are not able to properly align under normal conditions

Her mother was unable to properly care for C.T. and she was placed into foster care at 12 months of age.

Slide 6

With extensive support by her carers and professionals, C.T.’s condition improved    over the following 12 months and she  started to gain weight and develop.

Although delayed in meeting her developmental milestones, at 24 months    she was sitting up, crawling and       beginning to walk.

Slide 7

During the following 12 months, her condition gradually changed.  The hypotonia improved and she was communicating and interacting with the family. However new concerns were now evident.  She was;

overweight and unable to feel satisfied with a normal intake of food;

Overeating (if not monitored) and constantly food-seeking;

continuing to experience sleep problems, including daytime sleepiness;

demonstrating behavioural issues, including obsessive-compulsive symptoms, skin picking and difficulty controlling emotions (especially anger).

Showing signs of a speech impediment;

Demonstrating a high tolerance for pain and inability to vomit (even after gorging on food).

Hypogonadism is a medical term which describes a diminished functional activity of the gonads – the testes and ovaries in males and females, respectively – that may result in diminished sex hormone biosynthesis. In layman's terms, it is sometimes called "interrupted stage 1 puberty"

Slide 8

It became evident to the carers and professionals that C.T.’s condition was something much more than pre and post natal neglect by her mother.

C.T. was finally diagnosed, through clinical and diagnostic testing,  with PWS.

Clinical assessment confirmed that in addition to the symptoms already noticed, there was also evident of;

low metabolism;

intellectual disabilities;

short stature, small hands and feet;

scoliosis (Curvature of the spine)

hypogonadism and likelihood of interrupted puberty and infertility in later life

Slide 9

Diagnostic testing: As a result of the clinical findings C.T. was referred for genetic testing.

DNA methylation analysis confirms diagnosis of PWS. FISH and DNA techniques can identify the specific genetic cause and associated recurrence risk.

The genetic error that leads to Prader-Willi syndrome occurs at random, usually around the time of conception or during early fetal development. The syndrome is usually not hereditary.

Fluorescence in situ hybridization (FISH) provides researchers with a way to visualize and map the genetic material in an individual's cells, including specific genes or portions of genes. This may be used for understanding a variety of chromosomal abnormalities and other genetic mutations.

FISH is useful, for example, to help a researcher or clinician identify where a particular gene falls within an individual's chromosomes. The first step is to prepare short sequences of single-stranded DNA that match a portion of the gene the researcher is looking for. These are called probes. The next step is to label these probes by attaching one of a number of colors of fluorescent dye.

DNA is composed of two strands of complementary molecules that bind to each other like chemical magnets. Since the researchers' probes are single-stranded, they are able to bind to the complementary strand of DNA, wherever it may reside on a person's chromosomes. When a probe binds to a chromosome, its fluorescent tag provides a way for researchers to see its location.