Mesomelic Dysplasia, Kantaputra Type

Description

Kantaputra mesomelic dysplasia (MMDK) is a rare, autosomal dominant skeletal disease characterized by symmetric marked shortening of the upper and lower limbs. The ulnae are very short and the radii are bowed. The distal humerus has a dumbbell shape, whereas the hands are relatively normal but show progressive flexion contractures of the proximal interphalangeal joints. Carpal and tarsal synostoses are observed in some individuals. In the lower limbs, the feet are fixed in plantar flexion with the sole facing backward, causing 'ballerina-like standing.' The prominent distal fibula on the ventral aspect is considered to be the signature finding of the syndrome. The calcaneus is small or missing, and a small fibula and talus as well as fibulocalcaneal synostosis are characteristic features. The tibial bony knot articulates with the proximal end of the fibula (summary by Kantaputra et al., 2010).

See 613681 for discussion of the chromosome 2q31.1 duplication syndrome, which shows cytogenetic and phenotypic overlap with MMDK.

Clinical Features

In a large Thai family, Kantaputra et al. (1992) described a distinct type of mesomelic dysplasia characterized by bilateral, symmetric marked shortening of the ulna and shortening and bowing of the radius. The proximal fibula was unusually short, and synostoses were present between the tibia and fibula and between the small, malformed calcaneus and talus. The prominent calcaneus on the ventral surface of the distal fibula was a characteristic feature. Carpal and tarsal synostoses were present in most affected persons. All affected persons walked on the tips of their toes with the dorsal foot deviated laterally. The average height of affected male adults was 152 cm. There were 15 affected individuals in 3 generations, including a pair of identical twins and many instances of male-to-male transmission.

Mesomelia and synostosis are also cardinal features of the mesomelia-synostoses syndrome (600383).

Kantaputra (2004) provided a follow-up on the family originally described by Kantaputra et al. (1992). In a 21-year-old male (previously examined at age 8 years), the author noted progressively bowed radii, overlapping carpal and tarsal bones, flexion contractures of proximal interphalangeal joints 4 and 5, narrower proximal and distal interphalangeal joints 4 and 5, and fusion of the right tibia with the malformed talus and distal fibula. Large, dumbbell-shaped distal humeri were seen in all affected adults. A 4-year-old member of the family had upper and lower limb abnormalities similar to those of her relatives, but with more flexion contractures of the interphalangeal joints than any other relative. Kantaputra (2004) noted that she had the fibular prominence that seemed to be the most consistent hallmark of the syndrome.

Shears et al. (2004) described a Danish mother and son with mesomelic limb shortening in whom radiologic examination showed severe shortening of the radius and ulna with bowing of the radius and dislocation of the radial head. Multiple carpal and tarsal synostoses were present, and the talus and calcaneum were fused. Sequencing of the HOXD11 gene (142986) in the mother revealed no mutation. Shears et al. (2004) stated that this phenotype was most consistent with Kantaputra-type mesomelic dysplasia. Kantaputra (2004) reviewed the findings and concluded that with less severely affected radii and ulnae, the absence of 'ballerina-like' standing, and the absence of the characteristic fibular prominence, the syndrome described by Shears et al. (2004) represents a distinct entity that is probably allelic to MMDK.

Kwee et al. (2004) reported a grandmother, her 3 children, and 3 grandchildren who had short stature and bilateral symmetric skeletal abnormalities consisting of very short, broad and bowed radii, very short and broad ulnae, mildly short lower legs, short proximal end of fibula, abnormal ankles, abnormal calcaneus, and talus and pes equinus. They had normal craniofacial features, normal intelligence, normal chromosomes, and no mutations or deletions in the SHOX gene (312865). Using markers that have shown linkage with the MMDK locus, Kwee et al. (2004) observed perfect cosegregation with the disease phenotype, but the family was too small to obtain a significant lod score. The authors concluded that these patients represented the third reported family with autosomal dominant mesomelic dysplasia of the Kantaputra type.

Mapping

Because of the location of the breakpoints of a balanced translocation, t(2;8)(q31;p21), in patients from an Italian family with a skeletal dysplasia similar to the Kantaputra type of mesomelic dysplasia, reported by Ventruto et al. (1983), Fujimoto et al. (1998) performed linkage analysis in the Thai family, using 50 CA-repeat markers mapping to the 2q22-q34 and 8p24-p21 regions. The results ruled out linkage of MMDK to marker loci in the 8p24-p21 region, whereas all 9 affected members available for the study shared a haplotype at 4 loci spanning about 22.7 cM in the 2q24-q32 region. The computer-assisted 2-point linkage analysis revealed lod scores greater than 4.2 at theta = 0.0 for all 4 of these loci. Fujimoto et al. (1998) suggested that MMDK may be allelic to dyschondrosteosis (127300). They suggested that the human HOXD genes (see 142987), especially those located at the 5-prime region of the gene cluster, are strong candidates for the site of the mutation responsible for the MMDK phenotype.

Cytogenetics

Cho et al. (2010) reported a Korean family with mesomelic dysplasia caused by a 1.0-Mb duplication at chromosome 2q31.1 (613681) and suggested that the disorder might be allelic to MMDK.

Kantaputra et al. (2010) performed array CGH and identified 2 microduplications on chromosome 2 (2q31.1-q31.2) encompassing approximately 481 kb and 507 kb, separated by a segment of normal copy number. The more centromeric duplication, which extends approximately from position 176506582 to 176986597, encompasses the entire HOXD cluster, as well as the neighboring genes EVX2 (142991) and MTX2 (608555). Kantaputra et al. (2010) confirmed segregation of the duplications with the MDK phenotype by quantitative PCR analysis of a further 9 family members from the Thai family; 8 were affected and 1, who did not carry the duplication, was unaffected. The families reported by Shears et al. (2004) and Kwee et al. (2004) did not have a clinically relevant copy number change within chromosome 2q or elsewhere in the genome. Kantaputra et al. (2010) noted that the breakpoints of the duplication localized to the same region as the previously identified inversion of the mouse mutant ulnaless (Ul), which has a similar phenotype as MDK, as described by Peichel et al. (1997) and Herault et al. (1997). Kantaputra et al. (2010) proposed that MDK is caused by duplications that modify the topography of the locus and as such result in deregulation of HOXD gene expression.

Molecular Genetics

Exclusion Studies

Because they had identified microdeletions on chromosome 8q13 involving the SULF1 (610012) and SLCO5A1 (613543) genes in patients with the mesomelic-synostoses syndrome (600383), Isidor et al. (2010) analyzed SULF1 and SLCO5A1 in 2 patients with the Kantaputra type of mesomelic dysplasia, previously reported by Shears et al. (2004) and Siwicka et al. (2008), respectively, but did not identify any mutations. No deletions or duplications at chromosome 8q13 or elsewhere in the genome were detected by 44K oligonucleotide array.