Infant with failure to thrive and hypotonia
Because of the infant’s prolonged feeding times, a swallow study was performed. Penetration (passage of contrast materials into the larynx but not through the vocal cords) was noted in the side position with the nectar consistency, and aspiration (passage of contrast materials below the true vocal cords) was noted in the sitting up position with all consistencies. The results were consistent with a diagnosis of pharyngoesophageal dysphagia.
Because of the patient’s abnormal genitalia, a chromosomal microarray analysis (CMA) was performed. Results showed a class II deletion in the Angelman syndrome (AS)/Prader-Willi syndrome (PWS) critical region on the proximal long arm of chromosome 15—a finding consistent with either of the 2 conditions. Molecular methylation studies were then recommended in order to differentiate between the 2 disorders. A Southern blot analysis of DNA from the patient utilizing a probe from the AS/PWS critical region revealed a single band of 4.0 Kb, the methylated maternally derived allele, but absence of the paternally derived nonmethylated band at 0.9Kb.
Magnetic resonance imaging (MRI) of the brain with and without contrast was performed and showed a mild paucity of T1-weighted myelin signal in the anterior limbs of the internal capsule and the deep occipital white matter. This suggested delayed or hypomyelination. There also was substantial right parietal, occipital, and left frontal plagiocephaly and mild hypoplasia of the inferior cerebellar vermis.
This patient’s FTT, developmental delay, hypotonia, abnormal swallow study, hypomyelination on the MRI, and a chromosomal microarray with a deletion in the critical region of chromosome 15 suggested either AS or PWS.
Although both AS and PWS have distinct phenotypes later in childhood, their diagnosis in infancy is difficult.8-10 The prevalence of both disorders is similar—about 1 in 10,000—and approximately 20,000 individuals in the United States are affected with each disorder. The following features may raise suspicion for these syndromes and prompt further testing.
Typically, patients with AS have a normal prenatal and birth history, and clinical diagnosis is not considered until after age 1 year.9 Diagnostic clues within the first year of life include hypotonia; feeding difficulties; severe developmental delay with delayed forward progression but no loss of skills; disproportionate growth in head circumference; and seizures with an abnormal electroencephalogram (EEG) pattern. Many of the classically associated signs of AS, such as an easily excitable, happy demeanor with inappropriate and frequent laughter, impaired verbal communication, and ataxic gait are only obvious in older children, making early recognition and diagnosis difficult.9,10
Like AS, PWS is rarely recognized within the first year of life.8-10 There are many different features exhibited in children with PWS, however, the characteristics that are most commonly associated with PWS do not manifest until later in life. The first clue to a diagnosis may be a history of decreased in-utero movement.8,11-14 Recently, there have been several reported cases of PWS being diagnosed in utero based on characteristic ultrasound findings, including decreased fetal movement, polyhydramnios, breech positioning, abnormal growth patterns, and malpositioned hands and feet.14 This constellation of findings on prenatal ultrasound, or any history of decreased fetal movements, warrants further analysis.
Children with PWS exhibit severe hypotonia, feeding problems with FTT, characteristic facial features (such as dolichocephaly, narrow face, almond-shaped eyes, and a small mouth), hypogonadism, and global developmental delay.8,11-13 As they get older, many children with PWS also exhibit temper tantrums and stubborn, compulsive behaviors.13,15 Commonly, children with PWS also have been noted to have a short stature attributed to growth hormone deficiencies. The most stereotypical features of PWS are hyperphagia and food-seeking behavior leading to rapid weight gain and obesity, usually beginning between ages 6 months and 6 years.8,11-15 Because of this later onset, these features are typically not helpful in making a diagnosis before age 1 year.
The main indicator of PWS in children aged younger than 1 year is severe hypotonia and FTT, as these are almost universal findings.8,11-15 These findings, along with a characteristic fetal history, should prompt further workup. A chromosome 5q11-13 deletion, seen via DNA analysis, is diagnostic of PWS.11