Mosaic variegated aneuploidy syndrome

Mosaic variegated aneuploidy syndrome (MVA syndrome), also known as mosaic variegated aneuploidy or premature chromatid separation syndrome, is a rare autosomal recessive disorder characterized by mosaic aneuploidies — meaning that a significant proportion of cells in the body have an abnormal number of chromosomes. This chromosomal instability predominantly involves gains or losses of whole chromosomes (typically affecting more than 25% of cells) and results from defects in the mitotic spindle assembly checkpoint. MVA syndrome is most commonly caused by biallelic pathogenic variants in the BUB1B gene (MVA1), though variants in CEP57 (MVA2) and TRIP13 (MVA3) have also been identified. The condition typically presents at birth or in early infancy with intrauterine growth restriction, microcephaly, and characteristic facial features. Affected individuals frequently develop a range of serious complications including intellectual disability, seizures, eye abnormalities (such as cataracts or microphthalmia), and congenital anomalies of the brain, kidneys, and other organs. A hallmark feature of MVA syndrome is a significantly increased predisposition to cancer in childhood, particularly Wilms tumor, rhabdomyosarcoma, and leukemia. Some patients also develop Dandy-Walker malformation or other posterior fossa abnormalities. The prognosis for MVA syndrome is generally poor, with many affected children dying in infancy or early childhood due to cancer or complications of their congenital anomalies. There is no specific curative treatment for the underlying chromosomal instability. Management is supportive and multidisciplinary, focusing on surveillance for malignancies, treatment of cancers when they arise, management of seizures, developmental support, and addressing individual organ-specific complications. Genetic counseling is recommended for affected families given the recessive inheritance pattern.

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