Mosaic Variegated Aneuploidy Syndrome 2

A number sign (#) is used with this entry because mosaic variegated aneuploidy syndrome-2 (MVA2) is caused by homozygous or compound heterozygous mutation in the CEP57 gene (607951) on chromosome 11q21.

Description

Mosaic variegated aneuploidy syndrome is an autosomal recessive disorder characterized by poor growth and variable phenotypic manifestations, such as facial dysmorphism and congenital heart defects, associated with mosaic aneuploidies resulting from defects in cell division (summary by Snape et al., 2011).

See also MVA1 (257300), caused by mutation in the BUB1B gene (602860) on chromosome 15q15.

Clinical Features

Lane et al. (2002) reported a 12-year-old boy with poor growth, short stature, microcephaly, mild cognitive defects, and mildly dysmorphic facial features. Cytogenetic analysis found 24% hyperdiploid chromosome numbers during metaphase, consistent with MVA. He had subclinical ventricular septal defect, subaortic stenosis, and aortic valve regurgitation from birth. He also had some unusual features, including subnormal response to growth hormone, delayed bone age, bony lytic lesions of the skull thought to be epidermoid cysts, hypothyroidism, rhizomelic shortening, and hearing impairment. Dysmorphic features became apparent at age 12 years and included a narrow head, frontal whorl hair pattern, bulbous nose, microretrognathia, a long face, epicanthal folds, and low-set ears. He died at age 15 years of sleep apnea (Snape et al., 2011).

Garcia-Castillo et al. (2008) reported 2 Mexican sibs, born of unrelated parents, with poor growth and mildly dysmorphic facial features whose cultured lymphocytes had approximately 50% aneuploidies involving all chromosome pairs during metaphase. The 4-year-old boy showed poor growth with short stature, triangular face, dolichocephaly, occipital prominence, frontal bossing, inverted epicanthal folds, downslanted palpebral fissures, small nose, micrognathia, low-set ears, a cafe-au-lait spot, and clinodactyly. He also had transient hypothyroidism. His younger sister had intrauterine growth retardation, subsequent poor growth, and craniofacial dysmorphisms similar to her brother. Follow-up report of these sibs by Snape et al. (2011) noted that neither patient had developmental delay, abnormal brain imaging, major organ system involvement, or malignancy, consistent with a milder phenotype compared to MVA1. Cellular studies of both patients showed random aneuploidies as well as structural chromosomal abnormalities in about 15% of cells. Only the girl had about 14% premature chromatid separation; studies of parental chromosomes were normal.

Snape et al. (2011) reported another male infant, born of consanguineous Caucasian parents, with MVA2. He had low birth weight, growth retardation, and mild dysmorphic features, mainly temporal bossing and deep-set eyes with short palpebral fissures. He had several congenital defects, including atrial septal defect, atrioventricular septal defect, aortic coarctation, abnormal lung lobation, duodenal atresia, mild rhizomelic shortening of the upper limbs, and fifth finger clinodactyly. Developmental delay included hypotonia. He died of surgery-related complications at age 3 weeks. Cytogenetic analysis showed random aneuploidy of about 35% of cells with no evidence of premature chromatid separation.

Pinson et al. (2014) described a 4-year-old Moroccan girl, born of consanguineous parents, with mosaic variegated aneuploidy and a previously described mutation in the CEP57 gene (607951.0002). Her clinical features, including growth retardation with relative sparing of the head, mildly delayed development, and rhizomelic shortening of the upper limbs, were similar to those of other reported patients with MVA2. In addition, she presented with craniosynostosis with premature fusion of the sagittal and metopic sutures.

Molecular Genetics

By exome sequencing, Snape et al. (2011) identified compound heterozygous mutations in the CEP57 gene (607951.0001 and 607951.0002) in 2 Mexican sibs with MVA and growth retardation (Garcia-Castillo et al., 2008). Subsequent molecular analysis of 18 patients from 13 families with MVA without mutations in the BUB1B gene identified 2 additional unrelated patients with homozygous truncating mutations in the CEP57 gene. All of the mutations were predicted to result in a loss of function. The findings confirmed the causative role of CEP57 in predisposition to aneuploidy. None of the 4 patients had a malignancy.

In a 4-year-old Moroccan girl with MVA, Pinson et al. (2014) found homozygosity for a previously identified mutation in the CEP27 gene (607951.0002). Her unaffected consanguineous parents were heterozygous for the mutation.