Kazuharu Takikawa

Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family

Background Mutations in TRPV4, a gene that encodes a Ca2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. Objectives and methods To examine TRPV4 mutation spectrum and phenotype−genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. Results TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. Conclusion The TRPV4 mutation spectrum in MD and SMDK, which showed genotype−phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Stature and severity in multiple epiphyseal dysplasia

We investigated the stature and radiological findings in 15 patients with multiple epiphyseal dysplasia (MED). They were divided into normal-stature and short-stature groups according to their body height after 4 or 5 years of age. Their stature was not related to the involvement of the spine or epiphyses of long tubular bones except for the distal radius. Proximal phalanges and metacarpi were shorter in the short-stature group than in the normal-stature group, indicating that stature in MED had some relationship to the involvement of the wrist and hand. However, some patients in the normal-stature group showed involvement of distal radial epiphyses, and some patients in the short-stature group did not have stubby fingers. There are thus no clear-cut criteria to differentiate between the severe Fairbank type and the milder Ribbing type of MED.

Spine and rib abnormalities and stature in spondylocostal dysostosis.

Study Design. A retrospective study of radiographic and clinical findings of spondylocostal dysostosis. Objective. To determine the features of spondylocostal dysostosis diagnosed using consistent diagnostic criteria. Summary of Background Data. To our knowledge, no clear definition of spondylocostal dysostosis exists, and little information is available regarding its clinical or radiographic features. Methods. We defined spondylocostal dysostosis as a congenital spinal disorder consisting of ≥2 vertebral anomalies associated with rib anomalies, without crab-like chest. For 30 patients, including 12 males and 18 females, who met these criteria, we evaluated vertebral and rib anomalies, birth and present body height, and associated anomalies. There were only 2 familial cases. Results. Features of spondylocostal dysostosis were: (1) anomalies involved the thoracic region in all cases; many also involved the cervical spine; (2) most patients had ≥4 vertebral anomalies; (3) frequent vertebral anomalies were butterfly vertebra, hemivertebra, complete block, and unilateral bar, which were associated with both rib absence and fusion; (4) short stature was not always present at birth; and (5) complete block was 1 factor identified as being related to short stature after 12 years of age. Conclusion. Several features of sporadic spondylocostal dysostosis disorder were determined, including new findings related to body height.

Characteristic factors of ankle valgus with multiple cartilaginous exostoses.

Background: Ankle valgus is one of the most common deformities in multiple cartilaginous exostoses (MCEs). However, the characteristic factors of ankle valgus are not well known. Methods: To determine the characteristic factors of ankle valgus in MCE, we investigated 62 ankles in 33 patients (23 males, 10 females) with no history of surgical treatment of ankles with MCE. Mean age at investigation was 11 years 4 months (range, 2 years 7 months-17 years 1 month). We evaluated Taniguchi classification, tibiotalar angle (ankle valgus), site of exostoses in the distal tibia and distal fibula, fibular shortening (Malhotra classification), and correlations between these factors. Results: According to Taniguchi classification, patients were classified as group II (n = 8), group III (n = 18), or unknown (n = 7). Mean tibiotalar angle was 5.1 degrees (range, −4 to 20 degrees) in males and −0.8 degrees (range, −5 to 7 degrees) in females. Significant differences in ankle valgus were found between sexes within the same age group, and ankle valgus progressed with age in males. Ankles with involvement of both lateral distal tibia and medial distal fibula showed significantly more severe ankle valgus than ankles with involvement of the lateral distal tibia alone or no involvement. In Malhotra classification, all except 1 ankle showed station 0 in females. All cases of station II or III involved males and degree of fibular shortening correlated with ankle valgus in males. Taniguchi group III was associated with more frequent involvement of both lateral distal tibia and medial distal fibula in males, and greater frequency of both fibular shortening and ankle valgus with ≥10 degrees was seen compared with Taniguchi group II. Conclusions: Several characteristic factors of ankle valgus in MCE seem to predict progression. Level of Relevance: Level 4, Prognostic Study.

Recurrent salmonella osteomyelitis of both hands in a child with no signs of haemoglobinopathy: follow‐up until 19 years of age

Salmonella osteomyelitis is rare in children and usually occurs in conjunction with haemoglobinopathies. We followed a girl with recurrent salmonella osteomyelitis of both hands from infancy until she was 19 years of age. She was not affected by sickle cell disease, which sometimes accompanies acute swelling of hands and feet, and is known as hand‐foot syndrome.

Distinctive skeletal phenotype in high bone mass osteogenesis imperfecta due to a COL1A2 cleavage site mutation.

Distinctive Skeletal Phenotype in High Bone Mass Osteogenesis Imperfecta Due to a COL1A2 Cleavage Site Mutation Gen Nishimura,* Masahiro Nakajima, Kazuharu Takikawa, Nobuhiko Haga, and Shiro Ikegawa Department of Pediatric Imaging, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan Department of Orthopedics, Shizuoka Children’s Hospital, Shizuoka, Japan Department of Rehabilitation Medicine, University of Tokyo, Tokyo, Japan