A new case report illustrates the importance of prenatal genetic tests when clinical signs strongly suggest a diagnosis of Prader-Willi syndrome (PWS).
The study, “Possibility of early diagnosis in a fetus affected by Prader-Willi syndrome with maternal hetero-UPD15: A lesson to be learned,” was published in the journal Molecular Medicine Reports.
Difficulties in early diagnosis, treatment, and care contribute to the development of excessive weight, signs of developmental delay, and hypogonadism — impaired function of the gonads — in PWS patients. Despite a worldwide effort, the lack of specificity of PWS manifestations in utero, such as abnormal position of the feet and toes, limits the success of prenatal diagnosis. Also, few studies have addressed prenatal diagnosis of PWS through ultrasound or molecular techniques.
A team from China presented the case of a 1-day-old boy who had a healthy sister age 10. As is characteristic in PWS, he showed polyhydramnios — excessive accumulation of amniotic fluid — and lack of movement during pregnancy.
Considering that the mother was 41 years old, the findings prompted interventional prenatal diagnosis. Amniocentesis was conducted at 24 weeks for genetic analysis; results were normal.
At 30 weeks of gestation, the fetal weight was below the 10th percentile. Eight weeks later, the mother was hospitalized with fetal distress (insufficient amount of oxygen). A cesarean section was performed on the same day because of breech presentation, which occurs when the baby’s legs or buttocks is positioned to descend the birth canal first.
The newborn weighed 2,680 grams/5.9 pounds (5th percentile), was 47 centimeters/18.5 inches long (2.9th percentile), and had a head circumference of 33.5 centimeters/13.1 inches (20.7th percentile). He was admitted to the neonatal intensive care unit immediately after birth with a severely poor suck and hypotonia (low muscle tone). Among other notable features indicative of PWS, he had a narrow forehead, micrognathia (undersized jaw), widely spaced nipples, long and slender fingers, and a weak cry.
The negative results of the genetic analysis made the clinicians consider rare types of PWS.
At one month of age, the boy weighed 3,160 grams (6.9 pounds), was 48.5 centimeters (19 inches) long, and his head circumference was 35.2 centimeters (13.8 inches). He required a gastric tube for feeding, had persistent hypotonia, and had symptoms of upper respiratory infection.
At four months of age, the boy died of recurrent respiratory infections, hypoventilation, and food choking.
A test called DNA methylation analysis was conducted to confirm the PWS diagnosis. The test revealed the absence of the paternal copy of genes located in a specific region of chromosome 15, typical in PWS. Analysis of single nucleotide polymorphisms — differences in a single nucleotide, the building blocks of DNA — in chromosome 15 was consistent with the PWS diagnosis.
Subsequent genetic tests revealed a 100% match between the child and his mother, which indicates maternal heterodisomy — receiving a pair of non-identical chromosomes from the mother only – for the entire chromosome 15 as the cause of PWS.
“This present study indicated that although prenatal signs are not sufficient for a diagnosis to be confirmed, a comprehensive consideration of these signs is important in leading to a diagnosis of suspected PWS, and thus prompts further prenatal investigations using molecular genetic tools,” the team stated.
“If clinical signs strongly suggest PWS, other prenatal molecular genetic investigations, including methylation tests… [and] analysis for uniparental disomy, are recommended as an additional tool to aid diagnosis,” the researchers said.