Mosaic Variegated Aneuploidy Syndrome 1

A number sign (#) is used with this entry because of evidence that mosaic variegated aneuploidy syndrome-1 (MVA1) is caused by homozygous or compound heterozygous mutation in the BUB1B gene (602860), which encodes a key protein in the mitotic spindle checkpoint, on chromosome 15q15.

See also premature chromatid separation (PCS; 176430), which can be caused by heterozygous mutation in the BUB1B gene. PCS is inherited as an autosomal dominant trait without phenotypic consequences.

Description

Mosaic variegated aneuploidy is an autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. The proportion of aneuploid cells varies but is usually more than 25% and is substantially greater than in normal individuals. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor, and leukemia reported in several cases (summary by Hanks et al., 2004).

Genetic Heterogeneity of Mosaic Variegated Aneuploidy Syndrome

See also MVA2 (614114), caused by mutation in the CEP57 gene (607951) on chromosome 11q21, and MVA3 (617598), caused by mutation in the TRIP13 gene (604507) on chromosome 5p15.

Nomenclature

As noted by Kajii and Ikeuchi (2004), 'premature chromatid separation (PCS)' is sometimes incorrectly referred to as 'premature centromere division (PCD).' PCD is a distinct entity; see 212790. Several references listed in this entry (e.g., Scheres et al. (1986); Flejter et al. (1998); Kawame et al. (1999); Limwongse et al. (1999); Plaja et al. (2001); Mehes et al. (2002)) have incorrectly used the designation PCD when referring to PCS. To avoid confusion, we have changed the designation to PCS in our discussion of these references.

Clinical Features

Scheres et al. (1986) and Unteregger et al. (1987) reported a 29-year-old woman with mental retardation and microcephaly. Cell culture studies showed various aneuploidies in 15% of her cells. Premature chromatid separation was observed in approximately 60% of the metaphases. The authors hypothesized nondisjunction as the mechanism of aneuploidy.

Tolmie et al. (1988) described male and female infants with chromosomal mosaicism, severe microcephaly and mental retardation, and growth retardation. The authors suggested an inherited mutation affecting some aspect of the mitotic process. Papi et al. (1989) described male and female sibs, born in 1957 and 1966, respectively, to third-cousin parents, who presented with mental retardation, microcephaly, short stature, juvenile-onset limb-girdle muscular dystrophy, and multiple chromosome mosaicism in lymphocytes and fibroblasts. Different aneuploidies, mostly trisomies, were found in 15 to 20% of the cells; trisomies for chromosome 8 and chromosome 7 predominated in lymphocytes and fibroblasts, respectively. Monosomies were rare. Papi et al. (1989) suggested autosomal recessive inheritance of a mutation in a protein involved in mitosis, possibly a protein simultaneously involved in spindle apparatus and muscle function.

Miller et al. (1990) described a boy with mental retardation, facial dysmorphism and combined immunodeficiency. Trisomies and monosomies of most autosomes and gonosomal aberrations were found separately or in combination in most of the proband's lymphocytes and fibroblasts. The chromosome number varied from 44 to 50. A high proportion of metaphases showed PCS or had the appearance of 'C-anaphases' (C = colchicine or colcemid, a mitotic spindle inhibitor; i.e., colchicine-arrested anaphases).

Warburton et al. (1991) reported a 17-year-old girl with severe microcephaly and mental retardation in whom karyotype analyses of PHA-stimulated lymphocytes, cultured skin fibroblasts, direct and cultured bone marrow, and EBV-transformed lymphoblasts all showed at least 10% of cells with trisomy, which could be for many different chromosomes. All trisomies except 5, 10, 13, 14, and 17 were observed. Tissue-specific differences in the predominant trisomy were observed. The findings were found repeatedly over a 3-year period. Warburton et al. (1991) proposed the term 'mosaic variegated aneuploidy' to describe cases with these cytogenetic findings.

Kajii et al. (1998) observed premature chromatid separation in 67 to 87.5% of repeated cultures of peripheral blood lymphocytes from 2 unrelated infants with MVA. Also noted was a variety of mosaic aneuploidies, especially trisomies, double trisomies, and monosomies (mosaic variegated aneuploidy). Both infants showed pre- and postnatal growth retardation, profound developmental retardation, uncontrolled seizures, severe microcephaly, hypoplasia of the brain, Dandy-Walker anomaly (220200), abnormal facial appearance, and bilateral cataract. Patient 1, a girl, also had a cleft palate, multiple renal cysts, and Wilms tumor of the left kidney. Patient 2, a boy, had ambiguous external genitalia. Both infants died under 2 years of age. In the 2 families, their parents and 3 other members showed 2.5 to 47% lymphocytes with total PCS but without mosaic variegated aneuploidy or phenotypic abnormalities. Another 10 relatives showed 0 to 1% cells with total PCS and so were judged negative for the total PCS trait. It was deduced that the total PCS trait in the 2 families was transmitted in an autosomal dominant fashion and that the 2 affected infants were homozygous for the trait.

In cytogenetic studies of 2 sisters with mild microcephaly, growth retardation, and mild errors of morphogenesis, Flejter et al. (1998) identified an unusual combination of multiple trisomies, most often involving chromosomes 8 and 18 either together as sole trisomies or in combination with other chromosomes. Since neither sib had phenotypic anomalies associated with trisomy 8 or trisomy 18 mosaicism, the trisomies were thought not to have occurred during embryogenesis but later, possibly due to a predisposition to mitotic instability. To determine if the observed chromosome instability may be related to centromere function, the metaphase cells were characterized by immunofluorescence of the centromere protein CENP-E (117143). Hybridization of CENP-E antibodies, in combination with in situ hybridization of a chromosome 8 or 18 alpha-satellite probe, showed hybridization to chromosomes 8 and 18 in both normal and aneuploid cells from each patient. These findings indicated that the chromosomes in each child contained functional and active centromeres. Combined with previous reported, the studies supported the notion that a recessive mitotic mutant may be responsible for the chromosome mosaicism and for the resulting clinical phenotype. Both sibs showed areas of hypo- and hyperpigmentation of the skin over the torso front and back. Mental retardation was not a feature in this family.

Limwongse et al. (1999) reported a 7-year-old boy with mosaic variegated aneuploidy who developed embryonal rhabdomyosarcoma of the soft palate. This was said to have been the eleventh reported case of MVA. Clinical findings shared similarities to those previously described, including microcephaly and growth retardation as the 2 most common abnormalities. Notably, mental retardation and seizures were not present in the patient reported by Limwongse et al. (1999). Results of serial cytogenetic analyses performed on somatic and neoplastic tissues were reviewed and compared with those of other previously reported patients. The authors thought that mosaic variegated aneuploidy was causally related to the development of rhabdomyosarcoma in their patient. This was the first report of a patient with MVA who developed cancer.

Kawame et al. (1999) described a Japanese male infant with multiple congenital anomalies and mosaic variegated aneuploidy. Clinical features included prenatal-onset growth retardation, microcephaly, dysmorphic face, seizures, hypotonia, feeding difficulty, and developmental delay. In addition, he developed bilateral Wilms tumors. Neuroradiologic examination showed Dandy-Walker malformation and hypoplasia of the cerebral hemispheres and pons. Multiple cytogenetic analysis revealed various multiple numerical aneuploidies in blood lymphocytes, fibroblasts, and bone marrow cells, together with premature chromatid separation. Peripheral blood chromosome analysis in his parents also showed PCS, but no aneuploid cells. Kawame et al. (1999) suggested that the clinical phenotype and multiple aneuploidies of the patient was a consequence of the homozygous PCS trait inherited from his parents. Comparison with previously reported cases suggested that MVA with PCS is a clinically recognizable syndrome with the major clinical features including mental retardation, microcephaly, structural brain anomalies, and possibly cancer predisposition. Matsuura et al. (2000) analyzed skin fibroblast cells from 2 unrelated Japanese male infants with MVA and chromosome instability. One of the patients had been reported by Kawame et al. (1999). Both infants had severe growth and developmental retardation, microcephaly, and Dandy-Walker anomaly, and both developed Wilms tumor. One died at age 5 months and the other at age 3 years. Laboratory studies of cultured cells showed total PCS and MVA, and the cells did not arrest in metaphase after treatment with colcemid. Further studies showed that the colcemid-treated cells entered G1 and S phases without sister chromatid segregation and cytokinesis. Preparations of short-term colcemid-treated cells contained those cells with chromosomes in total PCS and all or clusters of them encapsulated by nuclear membranes. Cell cycle studies demonstrated the accumulation of cells with a DNA content of 8C.

Plaja et al. (2001) studied 3 patients with MVA related to PCS, showed that the phenomenon is expressed in vivo, and found that PCS is a cancer-prone disorder. One of their patients was the first in whom this condition was recognized (Scheres et al., 1986; Unteregger et al., 1987). The patient was a mentally retarded girl with microcephaly, short stature, and primary amenorrhea. Premature chromatid separation was found when she was 29 years old. Comparison of the 3 patients with 8 other PCS patients indicated that the phenotype is most frequently comprised of microcephaly, CNS anomalies with migration defects, mental retardation, pre- and postnatal growth retardation, flat and broad nasal bridge, apparently low-set ears, eye and skin abnormalities, and ambiguous genitalia in male patients. Wilms tumor was observed in 3 patients, rhabdomyosarcoma in 2 others, and acute leukemia in yet another. FISH studies indicated that random aneuploidies occurred in uncultured blood and buccal smear cells.

Kajii et al. (2001) reported 5 infants (2 girls and 3 boys) with MVA and total PCS from 4 families. All demonstrated severe pre- and postnatal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and uncontrolled clonic seizures. Four infants developed Wilms tumors, and 1 showed cystic lesions in both kidneys. All showed variegated mosaic aneuploidy in cultured lymphocytes. Cytogenetic analysis of 2 infants showed 48.5% and 83.2% lymphocytes in total PCS; their parents had 3.5 to 41.7% of their lymphocytes in total PCS. The remaining 3 infants and their parents, whose chromosomes were prepared at other laboratories, tended to show lower frequencies of total PCS. Seven of the 10 reported infants developed proven or probable Wilms tumors. The age at diagnosis of the tumors was younger than usual at 2 to 16 months. The tumors were bilateral in 4 infants and unilateral in 3 infants, and cystic changes were present in 6 infants. Two infants developed botryoid ('like a bunch of grapes') rhabdomyosarcoma. Two of the patients were brothers. Another female patient had 2 older sisters with similar features who had developed seizures and bilateral, well-differentiated polycystic nephroblastoma and died at ages 12 and 16 months, respectively (Nakamura et al. (1981, 1985)). One of these previously born sisters had arhinencephaly, agenesis of the corpus callosum, hypoplasia of the cerebellum, and botryoid sarcoma of the vagina extending to the bladder (Nakamura et al., 1981). Her chromosomes were reportedly normal. The second sister had trisomy 8 in 16% of the cells analyzed (Nakamura et al., 1985). Autopsy showed Dandy-Walker complex, type A, with a large cyst in the posterior fossa connected to the fourth ventricle, defect of the lower cerebellar vermis, and moderate hydrocephalus. The brain was small and pachygyric.

Mehes et al. (2002) reported a 22-month-old girl with nonsyndromic Wilms tumor who was found to have a normal karyotype but premature chromatid separation in 21% of her lymphocyte mitoses. This phenomenon was not found in her parents. PCS was noted in less than 4% of lymphocyte mitoses from 5 other children with Wilms tumor, similar to results obtained from 12 healthy controls.

Jacquemont et al. (2002) stated that 14 cases of MVA syndrome had been reported during the previous 10 years. The phenotype was quite consistent: severe microcephaly, growth deficiency, mild physical anomalies, and mental retardation. They described a boy in whom MVA syndrome was associated with myelodysplasia with a monosomy 7 bone marrow clone (252270). At the age of 3 years, myelodysplasia progressed to acute lymphoblastic leukemia and the patient died soon thereafter. Jacquemont et al. (2002) noted that 3 (21%) of the previously reported 14 patients had developed a malignancy (rhabdomyosarcoma, acute lymphoblastic leukemia, and nephroblastoma).

Callier et al. (2005) tabulated the clinical and cytogenetic findings in 28 reported cases of MVA syndrome. They also reported the first case of MVA syndrome without microcephaly and suggested that microcephaly is not mandatory for the diagnosis of the disorder.

Clinical Variability

Rio Frio et al. (2010) reported a 68-year-old man, born of remotely consanguineous parents, with an atypical phenotype of MVA due to a homozygous mutation in the BUB1B gene (602860.0013). He developed adenocarcinoma of the ampulla of Vater at 34 years of age, followed by adenomatous polyps and multiple primary invasive adenocarcinomas of both the colon and the stomach about 2 decades later. Laboratory studies of patient lymphocytes and fibroblasts showed premature chromatid separation in 57 to 84% of cells and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities. However, the patient had no other features of the mosaic variegated aneuploidy syndrome, such as poor growth, microcephaly, or mental retardation. Although the mutant BUB1B mRNA was found to be targeted by nonsense-mediated mRNA decay, a small amount (10 to 15%) of normal BUB1B was produced and correctly localized to the kinetochores of patient fibroblasts. However, the residual amount of protein was unable to maintain the spindle-assembly checkpoint, and thus the cells completed mitosis without cytokinesis, resulting in aneuploidy in some cells. Further studies of patient cells showed decreased BUB1B interaction with APC (611731). Heterozygous family members had low levels of premature chromatid separation (176430) but were otherwise asymptomatic. The report expanded the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers.

Molecular Genetics

Hanks et al. (2004) hypothesized that mutations in a gene involved in the mitotic spindle checkpoint might underlie MVA. In affected members of 5 of 8 MVA families, they identified biallelic mutations in the BUB1B gene (see, e.g., 602860.0003-602860.0010). Each family carried 1 missense mutation and 1 mutation resulting in premature protein truncation or an absent transcript. Three of the families had previously been reported by Limwongse et al. (1999) and Plaja et al. (2001).

Matsuura et al. (2006) identified heterozygosity for mutations in the BUB1B gene (see, e.g., 602860.0011-602860.0012) in affected members of 7 unrelated Japanese MVA families. Five of the families had previously been reported by Kajii et al. (1998), Kawame et al. (1999), and Kajii et al. (2001). Although a second mutation was not identified in any of the families, the authors identified a haplotype that was associated with decreased levels of the BUB1B transcript and protein, suggesting that allelic variations of gene expression contributed to reduced amounts of the BUB1B protein in affected individuals. Matsuura et al. (2006) concluded that a greater than 50% decrease in BUB1B activity results in abnormal mitotic spindle checkpoint function and MVA syndrome.