MOSAIC VARIEGATED ANEUPLOIDY SYNDROME 1 AND 2
The term mosaic variegated aneuploidy (MVA) was first used by Warburton and colleagues to describe a rare clinical entity associated with specific cytogenetic findings in cell lines (Warburton et al. 1991). The clinical picture is severe microcephaly, growth deficiency, mild physical abnormalities, and mental retardation. Many other features have been reported. Malignancies have also been found, with myelodysplasia, rhabdomyosarcoma, leukemia, and Wilms Tumours reported. Cytogenetically, the main features are aneuploidy for different chromosomes occurring mosaically; the proportion of cells showing aneuploidy varies considerably, but often more than a quarter of all cells show aneuploidy. Based on these findings, it was postulated that the underlying molecular defect was homozygosity for an autosomal recessive gene mutation that predisposed to mitotic instability. Other cases of affected children whose parents were consanguineous supported this conjecture (Tolmie et al. 1988; Papi et al. 1989). It has been noted that in MVA 3 of 14 reported cases developed a malignancy (Jacquemont et al. 2002). The finding of homozygous mutations in BUB1B (Hanks et al. 2004) confirmed the earlier prediction and are of particular interest because of the associated cancer predisposition. Surprisingly, an adult male with multiple gastrointestinal Tumours, including carcinoma of the ampulla of Vater, stomach, and colon, was found to be homozygous for a BUB1B mutation that created a de novo splice site (Rio Frio et al. 2010). It is likely that the attenuated phenotype observed was attributable to “leaky” splicing and a sufficient amount of functional normal BUBR1 protein being present.
BUB1B encodes BUBR1, a protein that is essential for mitosis. BUBR1 regulates the mitotic spindle. Somatic mutations in BUB1B are rare in most cancers studied thus far, but have been identified (Cahill et al. 1998), and genes that regulate mitosis are likely to have an important role in cancer (Lengauer et al. 1997). The question of whether cancers can arise solely from chromosomal instability has been debated (Rajagopalan et al. 2003; Sieber et al. 2003a, b). The recent findings in mosaic variegated aneuploidy and in clonal mosaicism (from genome sequencing studies) (Jacobs et al. 2012) support the notion that aneuploidy is a sufficient cause of carcinogenesis and perhaps suggest a bigger role for aneuploidy in cancer predisposition.
Screening for cancer in patients with MVA is challenging, particularly in view of its rarity and very variable penetrance, and no studies of surveillance in individuals with this condition have been reported. In view of the identification of mutations in another gene in a variation of MVA, the original syndrome has been termed by some MVA1.
Mosaic Variegated Aneuploidy Syndrome 2
A variant of MVA, currently referred to as MVA2 (MVA syndrome type 2), is caused by biallelic mutations in the gene encoding the centrosome protein CEP57, but no individuals with biallelic mutations in this gene have been reported to have been diagnosed with cancer (Snape et al. 2011), although so far, only 4 such cases have been reported overall.