A tandem duplication of chromosome 21 in a newborn showing a phenotype inconsistent with Down syndrome

Chromosome 21 is a highly studied chromosome and it is involvedfrequently in meiotic and post-zygotic non-disjunction eventscausing Down syndrome. Rare structural rearrangements due tomis-segregation of translocations have defined a Down syndromecritical region (DCR) responsible for the Down syndrome pheno-type[Barnicoatetal.,1996;Wiseman etal.,2009].Chromosome21duplications are more rare events leading to chromosomal trisomyandhavehelpedfacilitateabetterphenotype–karyotypecorrelation[Korenberg et al., 1994; Egashira et al., 2008]. We report here a caseshowingpathologicalfeaturesassociatedwithatandemduplicationof part of 21q, not involving the DCR.The patient was the first child born to unrelated healthy Cauca-sian parents. The pregnancy was uncomplicated until 34 weeks ofgestation, when ultrasound showed microcephaly and cerebellarhypoplasia. Birth was at 37 weeks of gestation without any compli-cation. The patient showed Apgar scores of 6, 8, 9 at 1, 5, 10min,respectively, and the umbilicalpH was7.4. Birth weight, length andheadcircumferencewere3,040g(50thcentile),49cm(50thcentile)and 30.5cm (<3rd centile), respectively.Clinical evaluation revealed dysmorphic features includingmicrophthalmia with severe visual loss, downslanting palpebralfissures, bulbous nasal tip, anteverted nostrils, and microstomia(Fig. 1A). ECG and echocardiography were normal.Signs of encephalopathy were present prevalently in the lefthemisphere.Brain magneticresonanceimaginghighlighted corpuscallosum complete agenesia, enlarged lateral ventricles, especiallyon the left, near trigone and the occipital lobe (Fig. 1A). Cerebellarvermis had poor development showing only the most rostralportion while cerebellar hemispheres and encephalic trunk werehypoplastic.Ophthalmologicevaluationshowedpalepapillaontheright, with only temporal zone involvement on the left. Otoacusticemission, kidneys, liver, urinary tract, spleen, and pancreas werenormal.At2yearsofage,thechildfailedtothrivewithpoorgrowth,psychomotor, and cognitive delay.Patient’s karyotype showed a tandem duplication of part of21q11.2-21.3. Parents were normal indicating that the duplicationwas de novo, and a paternal QFQ variant on the duplicatedchromosome 21 determined the origin. FISH analysis with theprobe covering DCR showed one signal on each chromosome 21indicating lack of DCR involvement. FISH with the WCP21 probeconfirmedthechromosome21originoftheduplicatedregionand2BACsmappingon21q11.2(RP11-106K13BACclone,nt15205277-15205811) and 21q21.1 (RP11-242C13 BAC clone, nt15546175-