De novo heterozygous variants in KIF5B cause kyphomelic dysplasia.

Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.

Body knowledge in children with spina bifida.

BACKGROUND: Patients with spina bifida suffer from motor paralysis and sensory disturbance, secondary deformation of the lower extremities, and development of decubitus ulcers. A deep understanding of one's body, such as identifying the names, functions, relationships, homology (e.g. upper and lower limbs) and relative position of body parts, may prevent secondary disorders. The awareness of the body and its characteristics in children with spina bifida has not been fully elucidated. This study aimed to investigate how children with spina bifida perceive their bodies, especially their paralyzed parts and related or homologous ones. METHODS: Participants included 36 children with spina bifida and 14 control children, aged 5-11 years. They were asked to draw self-portraits, and to answer questions about the names of body parts. The number of drawn body parts in the pictures and the correct response rates to the questions were quantified and compared between children with spina bifida and control children. RESULTS: Children with spina bifida drew fewer hands, legs, and feet than control children. In the verbal tests, children with spina bifida had a lower correct response rate than control children on questions concerning the upper limbs, hands, trunk, and feet. CONCLUSIONS: Children with spina bifida have diminished visuospatial and lexical-semantic body knowledge of the paralyzed parts and related organs.

Visual attention to their own paralytic limbs in children with spina bifida: Measurement of gaze direction using eye tracking.

BACKGROUND: Patients with spina bifida experience sensory and motor paralysis and complications in the form of deformation and skin problems of the lower limbs. Enhancing their awareness of the paralysed lesions could be helpful for these patients to prevent secondary disorders. This study sought to investigate to what extent children with spina bifida are visually aware of their body parts and, in particular, to their paralysed lesions. METHODS: Participants included children with spina bifida (n = 10) and typically developing control children (n = 10) between the ages of 5 and 11 years. All participants were shown still images of themselves on a monitor after which their gaze direction was measured using an eye tracker, with or without providing an instruction to direct their attention to their limbs. The gaze direction data were analyzed and compared between children with spina bifida and the control children. RESULTS: Children with spina bifida paid visual attention to their bodies in a manner similar to that of control children. Prompts to direct their attention to their limbs were effective in both groups; however, the degree of efficacy in children with spina bifida was inferior to that in control children. CONCLUSIONS: Promotion of visual awareness to their paralytic parts could be a reasonable and effective method for children with spina bifida to improve their understanding and recognition of their body and prevent associated skin problems.

Identification of novel LFNG mutations in spondylocostal dysostosis.

Spondylocostal dysostosis (SCDO) is a heterogeneous group of skeletal disorders characterized by multiple segmentation defects involving vertebrae and ribs. Seven disease genes have been reported as causal genes for SCDO: DLL3, MESP2, TBX6, HES7, RIPPLY2, DMRT2, and LFNG. Here we report a Japanese SCDO case with multiple severe vertebral anomalies from cervical to sacral spine. The patient was a compound heterozygote for c.372delG (p.K124Nfs*) and c.601G>A (p.D201N) variants of LFNG, which encodes a glycosyltransferase (O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase). The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. This is the second report of LFNG mutations in SCDO.

The Pavlik harness in the treatment of developmentally dislocated hips: results of Japanese multicenter studies in 1994 and 2008.

BACKGROUND: It has already been more than 50 years since the Pavlik harness was introduced in Japan, and today the Pavlik harness is widely recognized as the standard initial treatment modality for developmental dysplasia of the hip. We performed a multicenter nationwide questionnaire study concerning the results of Pavlik harness treatment twice in 1994 and 2008. METHODS: In 1994 and in 2008, we sent questionnaires to 12 institutes in Japan specializing mainly in pediatric orthopedics. We compare the results of these two studies and discuss differences in reduction rates, incidence of avascular necrosis in the femoral epiphysis and the percentage of joints with acceptable morphology (Severin grade I + II/total) at skeletal maturity. We statistically assessed these results to see whether there were changes in the treatment outcomes over this 14-year period. RESULTS: Reduction of the dislocated hips was obtained by the Pavlik harness in 80.2% (1990/2481 hips; 1994) and 81.9% (1248/1523 hips; 2008). The incidences of avascular necrosis of the proximal femoral epiphysis in the dysplastic hips were 14.3% (119/835 hips; 1994) and 11.5% (76/663 hips; 2008). The type of avascular necrosis in hips from the 2008 study was determined according to the classification of Kalamchi and MacEwen: 24/69 hips (34.8%) were classified as group I; 20/69 hips (29.0%) as group II; 11/69 hips (15.9%) as group Ill; 14/69 hips (20.3%) as group IV. The percentages of hips with acceptable outcomes at skeletal maturity discerned from Severin X-ray changes (grade I + II/total) were 72.3% (604/835 hips; 1994) and 77.7% (488/628 hips; 2008). CONCLUSION: Reduction rates and the incidence of avascular necrosis in 2008 were statistically similar to the results in 1994. The rate of acceptable outcome (Severin grade I + II/total) in 2008 was statistically higher than that of 1994.

Surgical Treatment of Chondrodysplasia Punctata Tibial-Metacarpal Type Until Skeletal Maturity: A Case Report.

CASE: An infant boy with chondrodysplasia punctata tibial-metacarpal type (CDP-TM) was followed up till skeletal maturity. The patient underwent surgeries for bilateral patellar dislocations at the age of 9 years of age, left leg length discrepancy at 12 years, and atlantoaxial subluxation at 14 years. At the final follow-up at 18 years, he had no complaints or limitation of his daily life activities. CONCLUSION: CDP-TM may require multiple orthopedic surgeries such as patellofemoral instability, limb length discrepancy, and upper cervical dysplasia until skeletal maturity, and should be followed in order to identify them early.

The relationship between atlas hypoplasia and os odontoideum in children with Down syndrome: a preliminary case report.

The purpose of this study was to evaluate the relationship of os odontoideum and the size of atlas among children with Down syndrome. Understanding the risk of developing myelopathy in asymptomatic cases is important in children with Down syndrome. Children with os odontoideum are considered to be at high risk of developing myelopathy because of instability; however, in cases that are complicated by atlas hypoplasia, the risk remains the same, regardless of instability. This retrospective case-control study assessed atlas hypoplasia in children with Down syndrome with or without os odontoideum. We retrospectively assessed the records of 59 patients (36 males and 23 females) with Down syndrome who underwent spinal X-ray evaluations at our hospital. The average age at examination was 5.0 years (range, 4-7). We evaluated the following radiologically: the presence of os odontoideum; atlas-dens interval; space available for the spinal cord at the atlas level (C1SAC); instability index; sagittal atlas diameter (SAD) as an index of atlas hypoplasia and C5 level SAC (C5SAC), adjusted for child growth. Os odontoideum was present in seven cases (12%). Between the groups with and without os odontoideum, there was no significant difference in age (mean, 5.2 vs. 5.0 years) or male/female ratio (57 vs. 62% males). The SAD/C5SAC (mean, 1.6 vs. 1.9) was significantly smaller in the group with os odontoideum than in those without os odontoideum. The instability index was not significantly different between the two groups. Children with Down syndrome and os odontoideum have small SAD. Evaluations for atlas hypoplasia are necessary.

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 >or=10 degrees was seen compared with Taniguchi group II. CONCLUSIONS: Several characteristic factors of ankle valgus in MCE seem to predict progression.

Osteochondral destruction in the hand following bee stings: a case report of an infant.

We report an infant who developed arthritis with osteochondral destruction in a hand after being stung by bees. The clinical findings resembled those reported as "beekeeper's arthropathy", but the radiological findings were more severe. Histology of the resected specimen revealed fibrous granulation tissue with infiltration of inflammation cells.

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.

Education and related support from medical specialists for Japanese patients with major skeletal dysplasias.

BACKGROUND: Skeletal dysplasias manifest various clinical symptoms. Age at onset, severity, and progression of symptoms differ even among individuals with the same diagnosis. Though necessary support in education is presumed to differ among patients with different disorders, few articles report on education in patients with skeletal dysplasias. OBJECTIVE: To clarify what types of schools children with major skeletal dysplasias attend, what kind of support they needed at schools, and how the advice on such support was conveyed from medical specialists to schools. METHODS: Questionnaire study on patients with achondroplasia or hypochondroplasia (A/HCH), and osteogenesis imperfecta (OI). RESULTS: In A/HCH childhood locomotion ability was high and most patients had received general education, irrespective of their generation. Children with OI showed a lower level of locomotion ability; only about half of them had received general education. In selecting schools, the patients received advice from pediatricians, physiatrists, and orthopedic surgeons. The degree of necessity and content of support at the schools differed between A/HCH and OI. Remodeling of the lavatory, washbasin, and chair and support during swimming lessons were common in A/HCH patients. Support in school for OI patients was more frequent and included propelling wheelchairs, assisting in the use of the bathroom, and remodeling the lavatory. Most children were restricted from participating in physical education classes. CONCLUSIONS: Locomotion ability and the necessary support at school differed between A/HCH and OI. Support and advice from medical specialists who recognize disability of patients with skeletal dysplasias may improve patients' participation and education in schools.

The ACVR1 617G>A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and presents progressive extra-skeletal ossification. The 617G>A (R206H) mutation in the activin receptor type IA (ACVR1) gene has been identified in all examined individuals with FOP of various ethnic groups, including Caucasian and Chinese descents. Here, we examined three Japanese patients with FOP for ACVR1 mutations. We identified the 617G>A mutation in all three patients. Our results suggest that the mutation in the ACVR1 gene is common and recurrent in the global population.

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 >or=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 >or=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.

Slipped capital femoral epiphysis following contralateral infantile Blount's disease.

Slipped capital femoral epiphysis (SCFE) and Blount's disease are reported to have a common etiology, but there is only one report describing two cases in which adolescent Blount's disease coexisted with SCFE. In this article, we describe a case of SCFE following contralateral infantile Blount's disease in an 11-year-old boy. This report is the first known case of SCFE associated with infantile Blount's disease. In this patient, pelvic tilt caused by leg length discrepancy associated with infantile Blount's disease and possible general weakness of the growth plate may be related to the occurrence of SCFE.