Infantile hypotonia, early childhood-onset obesity,
hypogonadism, and mental retardation.
This 7-year-old boy with obesity, short stature, characteristic shape of
the mouth, acromicria, genua valgum, and hypogonadism has
Prader-Willi Syndrome; Willi-Prader Syndrome.
First described in 1956 by A. Prader, A. Labhart, and H. Willi, all
three Swiss pediatricians and internists, on the basis of observation obtained from nine children
with the tetrad of short stature, mental retardation, severe obesity, and small hands and feet.
In 1961, muscle hypotonia in infancy was added to the phenotype. Diabetes mellitus usually
develops in childhood.
In the United States, most cases are sporadic in
occurrence. Rate of prevalence is reported to be 1:16,062 live births by
Burd et al., whereas Butler et al. reports a prevalence of 1:25,000 live
births. Internationally, the reported prevalence range from 1:8,000 in
rural Sweden to 1:16,000 in western Japan.
Syndrome results from the loss of the paternal
copy of chromosome 15q11.2-13. It is described as a microdeletion/disomy
disorder. However, most cases arise sporadically. More than 70% of
patients have a deletion of the paternal copy. Approximately 25% of
patients have maternal uniparental disomy for chromosome 15. The remainder
present with translocation or other structural aberration in chromosome 15.
Reduction in lung volumes, including expiratory
reserve volume, vital capacity, and functional residual capacity; closing
capacity is increased, leading to airway closure in the dependent areas of
the lung and V/Q mismatch; reduced chest and diaphragmatic excursions;
decreased alveolar ventilation; diminished sensitivity of the respiratory
center to hypoxia and hypercarbia—all contributing to hypoxia and
hypercarbia. Intermittent upper airway obstruction and hypoxia during sleep
with resultant chronic sleep deprivation and daytime somnolence; severe and
chronic hypoxia leading to polycythemia, pulmonary hypertension, right
ventricular hypertrophy, and failure.
Neonatal hypotonia is one hallmark feature of this
disorder and is a valuable clue to initiate diagnostic testing. Clinical
features; biochemical (polycythemia, hypoxia, hypercarbia); lung function
tests (reduced lung volumes including total lung capacity, functional
residual capacity, vital capacity, and expiratory reserve volume); ECG
(right axis deviation); chest radiograph or echocardiography (cardiomegaly);
sleep studies (obstructive sleep apnea).
The syndrome is biphasic; initially the picture
is one of hypotonia and later changes to hyperphagia leading to obesity.
Antenatal: delayed onset and reduced fetal activity during pregnancy; often breech
presentation at birth.
Neonatal and infancy: low birth weight, infantile hypotonia (“floppy
infant”), neonatal asphyxia, poor feeding, and failure to thrive; gross motor
developmental delay, weak cry and cough, hypogonadism with genital hypoplasia. Neonates
may require tube feeding for 3 to 4 months, although this usually improves
by 6 months and by 12 to 18 months, uncontrollable hyperphagia occurs.
Childhood: endocrine (polyphagia, insatiable hunger, hypoglycemia, rapid weight gain