Terminal Gain of 12p13.33 and Terminal Loss of 9p24.3, Detected in a Child with Developmental Delay and Growth Issues and Due to a Maternal Unbalanced Rearrangement Between 12p and 9p

Abstract

Down syndrome (DS) is the most common genetic cause of intellectual disability and is most commonly caused by complete trisomy of chromosome 21. Correlations between specific critical regions of chromosome 21 and key DS clinical features are incompletely characterized. Ectrodactyly is not associated with DS. We report a 4-year-old Guatemalan boy with developmental delay, referred to Genetics for evaluation of complex bilateral syndactyly and ectrodactyly. Following surgery, ulnar deviation of index fingers, radial deviation of middle fingers, and fifth finger clinodactyly were present bilaterally, together with variable hypoplasia of middle and terminal phalanges of the index, middle, and ring fingers. His head was small (5 centile), with bitemporal prominence and plagiocephaly. He had upslanting palpebral fissures, protruding ears, flattened midfacial appearance, and bilateral genu varus; no syndactyly or ectrodactyly was observed in the feet. Typical DS features not seen include tongue protrusion, single palmar creases, and hypotonia. DS was not initially suspected and FGFR2 sequencing was normal. Chromosomal SNP microarray (Illumina CytoSNP 850K) supported the mosaic karyotype: 47,XY,+21[3]/47,XY,+r(21)(p11.2q21.1) [3]/46,XY[6], and defined gene content of a ring chromosome 21 derived from 21p11.2-21q21.1, sparing the DS critical region. This is a highly atypical presentation of DS, and to our knowledge there are no reports implicating candidate genes or chromosomal regions on chromosome 21 in ectrodactyly, suggesting the complex mosaic karyotype as the likely cause. The presence of a trisomic cell line and absence of isodisomy of chromosome 21 support trisomy rescue as a plausible mechanism for mosaicism.