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Mosaic variegated aneuploidy syndrome
Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal anomaly characterized by multiple mosaic aneuploidies that leads to a variety of phenotypic abnormalities and cancer predisposition.
ORPHA:1052Classification level: Disorder
To date, 41 cases of MVA have been described in the literature.
The most common clinical features are growth retardation of prenatal onset, microcephaly, developmental delay, structural central nervous system and ophthalmological anomalies (e.g. cataract, corneal opacities, microphthalmia and glaucoma), and mild dysmorphic features, including triangular facies, micrognathia, and epicanthic folds. Additional features include oligohydramnios, ventricular dilatation, Dandy-Walker malformation, fetal ascites, and increased nuchal translucency. Cancer occurs in approximately 1/3 of individuals. Wilms tumor, rhabdomyosarcoma, acute lymphoblastic leukemia, and granulosa cell malignant tumor of the ovary (see these terms) all occur before the age of 5 years. In one individual, carcinoma of the ampulla of Vater and of the colon occurred in adulthood.
MVA is due to defective cell division, leading to aberrant disjunction of chromosomes during mitosis. This results in a high proportion (>10%) of aneuploid cells. Mutations of the BUB1B and CEP57 genes have been identified in individuals with MVA. BUB1B encodes BUBR1, a key protein in the mitotic spindle checkpoint. CEP57 is a centrosomal protein involved in nucleating and stabilizing microtubules. Individuals with BUB1B mutations have a high incidence of cancer (approximately 75%). No individual with a CEP57 mutation has thus far been diagnosed with cancer.
Diagnosis of MVA is based on cytogenetic analysis showing variable aneuploidy.
Aneuploidy can be a feature of chromosomal instability syndromes including Roberts syndrome, ataxia telangiectasia, xeroderma pigmentosum, Bloom syndrome, Werner syndrome and Nijmegen breakage syndrome. Microcephaly with chromosome instability can occur in Fanconi anemia (see these terms).
Prenatal karyotype can be undertaken by chorionic villus sampling or amniocentesis. This allows prenatal diagnosis of familial recurrence or investigation of abnormal sonographic findings consistent with MVA.
MVA is inherited in an autosomal recessive manner. The parents of an affected child are obligate carriers. Recurrence risk to siblings is 25%. Carrier testing for at-risk family members of individuals with biallelic BUB1B or CEP57 mutations is possible.
Management and treatment
Clinical management depends on the affected individual's specific needs (e.g.: growth hormone therapy for the treatment of growth failure). Cases with a cytogenetic confirmation of MVA syndrome and/or demonstrated BUB1B mutations should be offered Wilms tumor surveillance with renal ultrasonography every three to four months until five years.
Prognosis is related to the nature of the malformations and the risk of malignancy.