Differences Due to PWS Genetic Class, Growth Hormone Use Described

Specific genetic subtypes and growth hormone use both influence the physical characteristics, such as head shape and eye appearance, of people with Prader-Willi syndrome (PWS), a large study indicates.

The study, “Influence of Molecular Classes and Growth Hormone Treatment on Growth and Dysmorphology in Prader‐Willi Syndrome: A Multicenter Study,” was published in the journal Clinical Genetics.

PWS results from the loss of a set of paternal genes located on chromosome 15. Conceptually, this happen through one of three mechanisms: one is deletion, wherein those genes are entirely lacking. Another is uniparental maternal disomy (UPD), wherein an individual inherits two copies of chromosome 15 from their mother, rather than one copy from each parent. The third, which is less common, concerns abnormalities with imprinting, or modifications made to DNA in sperm and egg cells.

PWS is characterized by certain physical abnormalities, such as almond-shaped eye, a narrow forehead, and short stature. Growth hormone (GH) treatment can lessen the impact of the disorder.

Researchers in the U.S. assessed the physical features of PWS patients, and how specific genetic subtypes might alter a GH therapy’s effectiveness.

Data from 355 people with PWS, collected from four U.S.-based centers, were analyzed. Of these patients, 93% were white, 45.1% were male and 59.2% were female, and their average age was 13. PWS was caused by deletions in 61% of patients, by UPD in 36%, and by imprinting abnormalities in 3%.

Compared to patients with UPD, those with deletions were significantly heavier on average. Height and body mass index (BMI), a ratio of weight to height, did not differ significantly between the deletion and UPD groups.

Relative to UPD, those with deletions had significantly smaller head circumferences. They were also significantly more likely to have almond-shaped eyes, a flat occiput (the back of the head), a low anterior hairline, a short fifth finger, fingernail abnormalities, and dental problems.

UPD patients were more likely to have strabismus (when the eyes do not properly align when looking at an object), downward-slanting eyes, and ears at an abnormal angle than were those with deletions.

In the overall group, 81.4% of patients had a history of GH treatment.

The rate of GH use was similar among those with UPD or a deletion. Differences seen in patients starting with GH at younger ages (1 year old or younger) included lesser incidence of abdominal fat and slit-like eyes, and lower incidences of kyphosis (an outward, or hunching, curvature of the spine). Statistically significant differences were not evident when comparing treatment duration among age groups.

As expected, individuals treated with growth hormone were taller, with larger hands and heads.

Among treated patients, those with a deletion were significantly more likely to have scoliosis (sideways curvature of the spine), a flattened occiput, stretch marks, and fairer hair compared to those with UPD. Down-slanting eyes and ears at an abnormal angle were significantly more common in treated UPD patients than those with a deletion.

But among untreated patients, scoliosis was more common in the UPD group and kyphosis in the deletion group.

Significant differences were also noted in comparisons of patients who had never been treated with GH. For example, almond-shaped eyes and dental abnormalities were more common in deletion than UPD patients. Scoliosis was also more common in this UPD group, and kyphosis (an outward, or hunching, curvature of the spine) in the untreated deletion group.

“GH treatment had different influences among the molecular classes [of PWS],” the researchers concluded.

This study’s main strength, according to its researchers, was the large dataset used — in general, having more data available makes it easier to detect statistically significant differences among groups (in this case, different underlying causes of PWS).

Still, the team stressed the need for further research into the effects of GH treatment in people with PWS.