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Background Osteosclerotic metaphyseal dysplasia (OSMD) is a unique form of osteopetrosis characterised by severe osteosclerosis localised to the bone ends. The mode of inheritance is autosomal recessive. Its genetic basis is not known. Objective To identify the disease gene for OSMD. Methods and results By whole exome sequencing in a boy with OSMD, we identified a homozygous 7 bp deletion (c.5938_5944delGAGTGGT) in the LRRK1 gene. His skeletal phenotype recapitulated that seen in the Lrrk1-deficient mouse. The shared skeletal hallmarks included severe sclerosis in the undermodelled metaphyses and epiphyseal margins of the tubular bones, costal ends, vertebral endplates and margins of the flat bones. The deletion is predicted to result in an elongated LRRK1 protein (p.E1980Afs*66) that lacks a part of its WD40 domains. In vitro functional studies using osteoclasts from Lrrk1-deficient mice showed that the deletion was a loss of function mutation. Genetic analysis of LRRK1 in two unrelated patients with OSMD suggested that OSMD is a genetically heterogeneous condition. Conclusions This is the first study to identify the causative gene of OSMD. Our study provides evidence that LRRK1 plays a critical role in the regulation of bone mass in humans.

Tibial hemimelia is a rare congenital anomaly characterized by deficiency of the tibia with relatively intact fibula. Tibial hemimelia is identified as a solitary disorder, or a part of more complex malformation syndromes. Although the majority of cases with tibial hemimelia are sporadic, affected families with possible autosomal dominant or autosomal recessive inheritance have been reported. Here we report a pair of sibs, 6- and 2-year-old Japanese boys, with tibial hemimelia born to unrelated, phenotypically normal parents. The type of tibial hemimelia and associated malformations of hands and feet was quite different between the brothers. The elder brother was compatible with the Gollop-Wolfgang complex, and the younger brother with tibial agenesis-ectrodactyly syndrome. Screening of mutation by direct sequencing of candidate genes including Sonic hedgehog, HOXD-11, and HOXD-12 was unable to identify a disease-causing mutation.

Mutations in the gene encoding cartilage oligomeric matrix protein ( COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). More than 40 mutations have been identified; however, genotype-phenotype relationships are not well delineated. Further, mutations other than in-frame insertion/deletions and substitutions have not been found, and currently known mutations are clustered within relatively small regions. Here we report the identification of nine novel and three recurrent COMP mutations in PSACH and MED patients. These include two novel types of mutations; the first, a gross deletion spanning an exon-intron junction, causes an exon deletion. The second, a frameshift mutation that results in a truncation of the C-terminal domain, is the first known truncating mutation in the COMP gene. The remaining mutations, other than a novel exon 18 mutation, affected highly conserved aspartate or cysteine residues in the calmodulin-like repeat (CLR) region. Genotype-phenotype analysis revealed a correlation between the position and type of mutations and the severity of short stature. Mutations in the seventh CLR produced more severe short stature compared with mutations elsewhere in the CLRs ( P=0.0003) and elsewhere in the COMP gene ( P=0.0007). Patients carrying mutations within the five-aspartates repeat (aa 469-473) in the seventh CLR were extremely short (below -6 SD). Patients with deletion mutations were significantly shorter than those with substitution mutations ( P=0.0024). These findings expand the mutation spectrum of the COMP gene and highlight genotype-phenotype relationships, facilitating improved genetic diagnosis and analysis of COMP function in humans.

Background Limb malformations are rare disorders with high genetic heterogeneity. Although multiple genes/loci have been identified in limb malformations, underlying genetic factors still remain to be determined in most patients. Methods This study consisted of 51 Japanese families with split-hand/foot malformation (SHFM), SHFM with long bone deficiency (SHFLD) usually affecting the tibia, or Gollop-Wolfgang complex (GWC) characterized by SHFM and femoral bifurcation. Genetic studies included genomewide array comparative genomic hybridization and exome sequencing, together with standard molecular analyses. Results We identified duplications/triplications of a 210,050 bp segment containing BHLHA9 in 29 SHFM patients, 11 SHFLD patients, two GWC patients, and 22 clinically normal relatives from 27 of the 51 families examined, as well as in 2 of 1,000 Japanese controls. Families with SHFLD- and/or GWC-positive patients were more frequent in triplications than in duplications. The fusion point was identical in all the duplications/triplications and was associated with a 4 bp microhomology. There was no sequence homology around the two breakpoints, whereas rearrangement-associated motifs were abundant around one breakpoint. The rs3951819-D17S1174 haplotype patterns were variable on the duplicated/triplicated segments. No discernible genetic alteration specific to patients was detected within or around BHLHA9, in the known causative SHFM genes, or in the exome. Conclusions These results indicate that BHLHA9 overdosage constitutes the most frequent susceptibility factor, with a dosage effect, for a range of limb malformations at least in Japan. Notably, this is the first study revealing the underlying genetic factor for the development of GWC, and demonstrating the presence of triplications involving BHLHA9. It is inferred that a Japanese founder duplication was generated through a replication-based mechanism and underwent subsequent triplication and haplotype modification through recombination-based mechanisms, and that the duplications/triplications with various haplotypes were widely spread in Japan primarily via clinically normal carriers and identified via manifesting patients. Furthermore, genotype-phenotype analyses of patients reported in this study and the previous studies imply that clinical variability is ascribed to multiple factors including the size of duplications/triplications as a critical factor. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0125-5) contains supplementary material, which is available to authorized users.

Chondrodysplasia punctata (CDP) is a heterogeneous group of skeletal dysplasias characterized by stippled epiphyses. A subtype of CDP, X-linked dominant chondrodysplasia punctata (CDPX2), known also as Conradi-Hunermann-Happle syndrome, is a rare skeletal dysplasia characterized by short stature, craniofacial defects, cataracts, ichthyosis, coarse hair, and alopecia. The cause of CDPX2 was unknown until recent identification of mutations in the gene encoding Delta(8),Delta(7) sterol isomerase emopamil-binding protein (EBP). Twelve different EBP mutations have been reported in 14 patients with CDPX2 or unclassified CDP, but with no evidence of correlation between phenotype and nature of the mutation. To characterize additional mutations and investigate possible phenotype-genotype correlation, we sequenced the entire EBP gene in 8 Japanese individuals with CDP; 5 of them presented with a CDPX2 phenotypes. We found EBP mutations in all 5 CDPX2 individuals, but none in non-CDPX2 individuals. Three of these CDPX2 individuals carried novel nonsense mutations in EBPand the other two, separate missense mutations that had been reported also in different ethnic groups. Our results, combined with previous information, suggest all EBP mutations that produce truncated proteins result in typical CDPX2, whereas the phenotypes resulted from missense mutations are not always typical for CDPX2. Patients with nonsense mutations showed abnormal sterol profiles consistent with a defect in Delta(8), Delta(7) sterol isomerase. X-inactivation patterns of the patients showed no skewing, an observation that supports the assumption that inactivation of the EBP gene occurs at random in affected individuals.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are common skeletal dysplasias with impaired enchondral ossification and premature degenerative joint disease. The two disorders were in the past considered to be distinct clinical entities; however, recent studies have proven that both diseases can result from mutations of the gene encoding cartilage oligomeric matrix protein (COMP). To characterize further COMP mutations and investigate phenotype-genotype relationships, we screened this gene in 15 patients with PSACH or MED by directly sequencing polymerase chain reaction products from genomic DNA. We identified ten mutations involving conserved residues among the eight calmodulin-like repeats of the gene product: seven were novel missense mutations in exons 9, 10, 11, 13 or 14, and the other three resulted from deletion of one of the five GAC repeats in exon 13. We have found that the GAC repeats in the 7th calmodulin-like repeat in exon 13 represent a hot-spot for mutation, and that mutations in the 7th calmodulin-like repeat produce severe PSACH phenotypes while mutations elsewhere in the gene exhibit mild PSACH or MED phenotypes. These genotype-phenotype correlations may facilitate molecular diagnosis and classification of PSACH and MED, and provide insight into the relationship between structure and function of the COMP gene product.

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.

Objective To evaluate the incidence of complications of intrathecal baclofen (ITB) therapy for spasticity in Japan, where a unique training course and nationwide registration are required. Materials and Methods An analysis of complications was performed in all patients who underwent ITB in Japan from 2005 to 2011. Prior to surgery, all the doctors involved took a one-day training course, which included hands-on training. Surgical techniques that avoided complications were emphasized. Results A total of 406 pumps were implanted in 400 patients (277 men, 123 women) having severe spasticity. Because this study is currently in progress, among the 400 patients, 78.3% (313/400) had finished a one-year observation follow-up. There were 369 adult and 31 juvenile (under 17 years old) patients, including 12 patients under nine years old. All-cause adverse events were seen in 148 patients (37%), and 93 (23.3%) of these were regarded as severe. Catheter problems were observed in 34 (8.5%) patients: catheter migration in 25 (6.3%), breakage in 6 (1.5%), obstruction in 2 (0.5%), kinking in 1 (0.3%), and dislodgement in 1 (0.3%). Pump trouble was observed in seven (1.8%) patients: alarm abnormality in one (0.3%), memory error in one (0.3%), delayed recovery in one (0.3%), rotation in one (0.3%), malfunction in one (0.3%), and abnormal infusion rate in two (0.6%). Device-related and surgical wound infection occurred in 12 patients (3%), and nine were regarded as severe. Leakage or subcutaneous accumulation of the cerebrospinal fluid was seen in 13 patients (3.3%). Conclusion The requirement of taking of a training course before starting ITB seemed to reduce complications. Although there were surgery-related complications, the rate of complications in Japan appeared to be lower than those reported in larger series of ITB. However, whether the reported rates can be primarily ascribed to a mandatory training course requires further investigations.

Two infants who had multiple joint dislocations, unusual facies, and bony abnormalities, typical of the syndrome first reported by Larsen et al. (J. Pediatr., 37 (1950) 574–581) are described. This report expands Larsen's syndrome to include the following findings of temporal bone pathology. Case 1 (one year and 8 months old) showed dislocation of the malleus and incus, an abnormal foot plate, mesenchyme remaining in the attic and mesotympanum, poor development of the mastoid air cells, and poor development of the labyrinth. Case 2 (3 years and 6 months old) showed dislocation of the malleus and incus, mesenchyme remaining in the attic and mesotympanum, and an abnormal stapes. These histological findings suggest that a maldevelopment similar to that which occurs in the skeletal system occurs in the temporal bones as well as in the face and extremities including many joints.

Eleven children with spastic cerebral palsy (CP) who could walk underwent exercise at the anaerobic threshold (AT) point. The subjects exercised for 20 minutes per session, twice a week for a period ranging from 6 to 20 weeks. The subjects were divided into two groups. The leg exercise group contained six CP children who exercised on a cycle ergometer with average attendance of 1.8 days a week. The other five CP children constituted the arm exercise group and exercised using an arm cranking ergometer with average attendance of 1.5 days per week. After the exercise period, the oxygen uptake (VO2) at the AT point increased significantly in the children in the leg exercise group. On the other hand, the VO2 at the AT point did not change in children in the arm exercise group. These results demonstrate that cycle ergometer exercise at the AT point is effective in improving the physical endurance of children with CP. In contrast, arm exercises for children with CP seem to have little effect on increasing physical endurance.

Kumakura N, Takayanagi M, Hasegawa T, Ihara K, Yano H, Kimizuka M. Self-assessed secondary difficulties among paralytic poliomyelitis and spinal cord injury survivors in Japan. Arch Phys Med Rehabil 2002;83:1245-51. Objective: To determine the time course of secondary worsening of difficulties (SWD) experienced by postpolio and spinal cord injury (SCI) subjects in the general population. Design: Self-report survey. Setting: Multicenter study in general community in Japan. Participants: A total of 662 postpolio and 736 SCI subjects who had had contact with some rehabilitation facility. Interventions: Not applicable. Main Outcome Measures: Respondents completed a questionnaire about demographic factors, physical complaints, activities of daily living (ADLs), social participation, and a visual analog scale of time course for difficulties (VAST-D) devised for the present study in which the subjects drew a single curve to indicate the lifetime course of disability as they perceived it. Results: Signs of SWD in all extremities of the polio patients and in the upper extremities of the SCI subjects were visually shown by the VAST-D. Additionally, the prevalence of postpolio syndrome and SWD in the SCI group was estimated to be 55.3% and 45.1%, respectively. Conclusions: SWD was visually shown by the VAST-D in polio and SCI subjects. © 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

We undertook the anaesthetic management of two children with Hecht-Beals syndrome for orthopaedic surgery under general anaesthesia. Both patients had arachnodactyly, kyphoscoliosis, and multiple congenital joint contractures, but limited mandible excursion was not obvious preoperatively in either, although mental retardation made it difficult for them to cooperate with mouth examination. They had no apparent difficulties with their mouths in daily activities. The anaesthesia records of one patient showed that intubation had been difficult in an earlier procedure. The other patient also had a history of difficult intubation, with slight tearing of the corners of her mouth during an intubation procedure. During slow induction of general anaesthesia with sevoflurane, face mask ventilation was easily performed. We attempted to visualize the larynx under anaesthesia with muscle relaxation, but we were unsuccessful because of the limited mouth opening. After several trials, blind oral intubations were fortunately successful in both patients. There were no postoperative problems with the airway.

Background. Ischial hypoplasia is an extremely rare malformation, both as an isolated anomaly and as a syndromic constituent. Objective. To elucidate the clinical and radiological characteristics in five patients with the combination of ischial hypoplasia and spinal malformations. Materials and methods. The clinical records and radiographs of two females and three males, ranging in age from 3 months to 38 years, were evaluated. Results. Ossification defects of the ischial rami were symmetrical and total in four patients, whereas the right ischial ramus was partly ossified in the other patient. All patients possessed multiple segmental defects of the spine, with rib anomalies of varying severity. One patient characteristically showed multiple rib gaps, resulting in respiratory distress. Severe anomalies of the cervical spine were evident in two patients. Four patients exhibited lumbosacral hypoplasia, which ultimately led to cauda equina syndrome in three older patients. One patient had mild facial dysmorphism and another had a diversity of anomalies, including ichthyosiform skin changes. Four patients were sporadic cases, whereas the other patient was born to consanguineous parents. Conclusions. The combination of anomalies in these patients constitutes a recognisable pattern of malformations but may represent a heterogeneous group of disorders.

A problem in diagnosing pseudoachondroplasia (PSACH) is that the pathognomonic changes of vertebral bodies invariably disappear around the age of 10, and an adult case might subsequently be misdiagnosed as MED, Fairbank type, though the latter is less severe than PSACH. We present a Japanese girl (follow-up, 3-10 years of age) whose epi-metaphyseal involvement of long bones was minimal and whose height was +2 S.D. of standard for PSACH in spite of the typical changes of the vertebral bodies. She might not have been diagnosed only as PSACH but also as MED, Fairbank type, after disappearance of the typical vertebral body changes because of the apparent lack of stubby fingers. Since the overlap of PSACH and MED has recently been discussed from the viewpoint of molecular biology, study of the spectrum of clinical features of PSACH is important.

Retinal detachment is one of the most serious complications of spondyloepiphyseal dysplasia congenita (SEDC). The ocular complication of 12 patients with SEDC was studied. Three patients developed bilateral retinal detachments; five of the six detachments occurred during the period of rapid growth spurt. Our results suggest that patients with SEDC have an increased risk for development of retinal detachment during the period of rapid growth spurt.

Two patients with slowly progressive muscle atrophy limited to only one leg are reported. They had pes equinovarus deformity and muscle weakness in the affected leg but no symptom in the other limbs. Muscle biopsies from the affected leg showed dystrophic changes consisting of variation in muscle fiber size, endomysial fibrosis, and necrotic and regenerating fibers. Dystrophin was normally expressed at the surface membrane of the muscle fibers. These two patients possibly had a variant of distal muscular dystrophy, though a neural influence could not be completely excluded.

The contact area of eight human talocrural joints was measured. After preparation, the talocrural joint was set into the compression machine. Under loading the casting was made by silicon rubber and the pressure distribution was measured by pressure sensor sheet. The contact area was localized at anterior and lateral parts. Under 1,500 N loading, the contact area was 522 mm2 and the maximum pressure was 9.9 MPa. Slight diastasis caused a decrease of the contact area and an increase of pressure.