Kagami-Ogata Syndrome

A number sign (#) is used with this entry because Kagami-Ogata syndrome is an imprinting disorder involving genes within the imprinted region of chromosome 14q32.

Clinical Features

Epigenetic germline modification, or imprinting, leads to functional differences in gene expression throughout development, depending on parental origin. Genomic imprinting is typically revealed when both homologs of a chromosome pair are inherited exclusively from 1 parent. This condition is called uniparental disomy (UPD) and results in either overexpression or absence of a parent-specific transcript. For most chromosomes, no obvious phenotypic effect from UPD has been observed. However, UPD of certain chromosomes leads to clinically recognizable syndromes, and paternal UPD for chromosome 14 is one that causes a distinct disorder (Cotter et al., 1997; Kurosawa et al., 2002; Takada et al., 2000). Human paternal uniparental disomy for chromosome 14, UPD14(pat), presents with skeletal abnormalities, joint contractures, dysmorphic facial features, and developmental delay/mental retardation (Sutton et al., 2003). In humans, consistent radiographic findings include a narrow, bell-shaped thorax with caudal bowing of the anterior ribs, cranial bowing of the posterior ribs, and flaring of the iliac wings without shortening or dysplasia of the long bones. The axial skeleton is predominantly affected. Most reported cases of human parental UPD14 are characterized by inheritance of a Robertsonian translocation from the father, or have a de novo paternal isochromosome, as reviewed by Sutton and Shaffer (2000). Presumably, some of these individuals were trisomic for chromosome 14 at conception.

Uniparental isodisomy of chromosome 14 results in such a severe phenotype that it is often associated with spontaneous miscarriage. The abnormality has been detected in 1 of 81 miscarriages with a normal karyotype (Tsukishiro et al., 2005).

Kagami et al. (2005) reported 3 Japanese patients with paternal isodisomy for chromosome 14, including a 5.5-year-old girl, a male neonate, and a 6.5-year-old girl. Physical features at birth included a hairy forehead, protruding philtrum, micrognathia, small thorax, and abdominal wall defects. Radiographic studies showed a bell-shaped thorax with coat-hanger appearance of the ribs, but the thoracic deformity tended to ameliorate in the older children. Microsatellite analysis indicated full paternal isodisomy for chromosome 14 in younger girl and boy, and segmental paternal isodisomy for chromosome 14 distal to D14S981 at chromosome 14q23.3 in older girl. Methylation specific PCR assay for the differentially methylated region (DMR) of GTL2 (605636) at chromosome 14q32 yielded positive products with methylated primers in all 3 patients. The findings were consistent with the involvement of imprinted genes on chromosome 14q32 as critical components of the phenotype. Kagami et al. (2005) suggested that, if infants with this disorder survive respiratory insufficiency in infancy, they may improve with age.

Mattes et al. (2007) reported a female infant with paternal uniparental isodisomy of chromosome 14 with mosaicism for a supernumerary marker chromosome 14. She had a small thorax with coat-hanger-shaped ribs, kyphoscoliosis, hypoplasia of the maxilla and mandible, a broad nasal bridge with anteverted nares, contractures of the wrists with ulnar deviation bilaterally, diastasis recti, and marked muscle hypotonia. Other unusual features included vertical skin creases under the chin and stippled epiphyses of the humeri. She died at age 5 months due to respiratory infection. Cytogenetic studies showed a mosaic karyotype with 88% of cells showing the bisatellited markers and 12% showing no cytogenetic abnormality. Mattes et al. (2007) suggested that the presence of a supernumerary marker could be an important clue to the presence of UPD.

Nomenclature

The European Network of Imprinting Disorders designated the paternal imprinting disorder on chromosome 14 'Kagami-Ogata syndrome.'

Animal Model

Distal human chromosome 14 is homologous to distal mouse chromosome 12, and both regions contain imprinted genes. Sutton et al. (2003) showed that skeletal defects in UPD14(pat) in the human are recapitulated in the mouse model. Mice with UPD12(pat) have thin ribs with delayed ossification of the sternum, skull, and feet. In both mice and humans, the axial skeleton is predominantly affected. Sutton et al. (2003) hypothesized that there is an imprinted gene (or genes) on human chromosome 14 and mouse chromosome 12 that specifically affects rib/thoracic development and the maturation of ossification centers in the sternum, feet, and skull with little effect on long bone development.