Mosaic variegated aneuploidy without microcephaly: Implications for cytogenetic diagnosis

Mosaic variegated aneuploidy (MVA) is a rare condition characterized by multiple trisomies, rarely monosomies, and a non-specific phenotype including microcephaly, growth and mental retardation, mild malformations, and an increased risk of malignancy. We describe a patient with MVA in whom trisomy 19 mosaicism was originally suspected. The patient was the product of an uncomplicated term pregnancy and delivery. Significant findings were mental retardation, obesity, mild epicanthal folds, tapering fingers, relatively small hands and feet, alternating exotropia, nasal speech limited to short phrases, and generalized hypotonia. There is no family history for birth defects, mental retardation, or consanguinity. The initial peripheral blood chromosome study showed trisomy 19 in 4 of 31 metaphase cells. Because mosaic trisomy 19 is rare, the study was extended to 100 cells, wherein two cells with trisomy 8 were identified. A second blood karyotype was obtained and found to be 47,XX,+8[3]/47,XX,+19[3]/47,XX, +18[2]/ 47,XX,+9[1]/46,XX[91]. Skin fibroblast chromosome studies revealed a 46,XX karyotype in 120 cells examined. There was no evidence of premature centromere separation. Mutations in the BUB1B gene that encodes a key mitotic spindle checkpoint protein have been described in MVA; however, no mutations of this gene were identified in our patient. This case illustrates the importance of considering other possibilities when confronted with an extremely rare diagnosis such as mosaic trisomy 19. In addition, it shows the importance of not simply interpreting a low percentage of multiple aneuploidies as cell culture artifact, because an additional work-up to rule out MVA may be warranted since this diagnosis is associated with an increased risk of malignancy.