Early clinical features of Angelman Syndrome in infants with chromosomal deletion of 15g11-q13

Abstract

Angelman Syndrome (AS) is characterized by severe developmental handicap, broad based and ataxic gait, communication disorder with affected children remaining largely pre-verbal, seizure disorders and episodes of spontaneous laughter. Clinical diagnosis may be difficult below age 2, as the clinical phenotype becomes more distinctive in early childhood. We report 2 infants (aged 4 months and 1 week) with chromosomal anomalies involving chromosome 15q11-13 who were subsequently diagnosed to have Angelman syndrome by fluorescent in situ hybridization (FISH) and methylation analysis. Both patients had cleft palate, feeding difficulty, fair skin and hair color compared to siblings, hypertonia since birth and small for gestational age. Patient one also had prominent nose, U-shaped cleft palate with micrognatnia, consistent with Robin sequence, tapering fingers, bilateral inguinal hernias, hypogonadism and failure to thrive. FISH did not identify a deletion of the critical region associated with VCFS/DiGeorge syndrome. High resolution karyotype revealed a deletion of chromosome 15: 46, XY, del(15)(q11.2q13). Methylaltion test confirmed the deleted fragment was of maternal origin. Maternal karyotype is pending. Patient two had a rare chromosomal rearrangement as an unusual etiology of Angelman Syndrome. This baby had 46, XY, -15, + der(16), t(15;16)(q13;q13) mat, resulting in duplication 16p and Angelman Syndrome. FISH confirmed that the breakpoint was in the 15q11-q13 region. He presented with dysmorphic features including hypertelorism, cleft soft palate, malformed ears, campto-clinodactaly and hypospadias. Severe intractable seizures began by day 2. Family history revealed that this translocalion appeared to be inherited over 4 generations from the proband's maternal great grandmother. It was recognized in the literature, poor feeding and hypotonia are the early clinical signs of Angelman syndrome. Of note, both our patients were hypertonic and both with cleft palate which was initially thought to be the cause of poor feeding. Our patients may provide information for clinical suspicion in infants with Angelman Syndrome from chromosomal anomalies.