Spondyloepiphyseal Dysplasia Research Articles

Total Hip Arthroplasty in Young Adults with Stickler Connective Tissue Disorder: Review of Literature and Case

Connective tissue disorders such as Stickler syndrome cause the premature development of musculoskeletal diseaseresembling spondyloepiphyseal dysplasia, in some cases requiring surgical intervention for premature developmentof osteoarthritis. Total hip arthroplasty is a routine procedure regarded as highly successful in maintaining mobilityin elderly patients. When hip replacement is required in the young, unique challenges are presented to the surgeonincluding efforts to maximize the life of the first prosthesis while also considering that multiple revisions will likelybe necessary. A 17 year old male patient presented with a connective tissue disorder, exhibiting symptoms of Sticklersyndrome. The patient suffered from acute episodes of pain and dysfunction including mechanical clicking andoccasional locking, originally seeking orthopaedic assessment at 14 years old. Total hip arthroplasty was performedafter the patient’s femoral growth plate had fused radiologically and is presented as an option to treat the multifacetedabnormal hip joint caused by Sticklers syndrome. In this way, hip mobility and functionality can be vastlyimproved in young adults with debilitating congenital connective tissue disorders.

Novel compound mutations of SMARCAL1 associated with severe Schimke immuno-osseous dysplasia in a Chinese patient

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive pleiotropic disease caused by mutations in the SMARCAL1 gene. To date there have been no data from the Chinese population. Here, we report the first SIOD case in the Chinese population. No case with gross carpal bone age retardation has been reported previously. The index patient was diagnosed by clinical and laboratory investigations. Mutations analysis of the SMARCAL1 gene and haplotype analysis were performed in the family. Structural predictions of the wild-type and mutant proteins were conducted. Severe SIOD was diagnosed in an 8-year-old boy, who exhibited growth failure, recurrent infection, neutropaenia, spondyloepiphyseal dysplasia, focal segmental glomerulosclerosis, T cell immunodeficiency and facial dysmorphism. Marked carpal bone age retardation was also observed. Sequence analysis of the SMARCAL1 gene revealed two novel mutations: c.3G>A (p.Met1?) and c.1682G>A (p.Arg561His) in the boy. Haplotype analysis and mutation detection showed that the father is the carrier of c.3G>A (p.Met1?) and the mother is the carrier of c.1682G>A (p.Arg561His). The paternal mutation, c.3G>A (p.Met1?), is predicted to introduce a new open reading frame, resulting in truncation of 103 amino acids at the N-terminus. The maternal mutation occurred in the SNF2-related domain involved in ATP hydrolyzation and DNA binding and is predicted to alter the local spatial structure of the protein. We report the first SIOD patient from China, who exhibited gross carpal bone age retardation and carried two novel mutations, c.3G>A (p.Met1?) and c.1682G>A (p.Arg561His), in the SMARCAL1 gene.

Avoiding Transmitting Identified Mutations to Offspring Using Preimplantation Genetic Diagnosis

Preimplantation genetic diagnosis has been used to decrease or avoid the risk of transmitting identified mutations to offspring. A 29-year-old woman with spondyloepiphyseal dysplasia congenita and her 30-year-old husband with Marfan syndrome underwent in vitro fertilization with preimplantation genetic diagnosis. Two mutation-negative embryos were transferred into a gestational carrier, who became pregnant with twins and delivered two clinically normal neonates. Statistically, this couple would be predicted to have a 75% chance of producing an affected embryo. Using preimplantation genetic diagnosis, two dually unaffected embryos were selected and transferred. This experience expands the use of preimplantation genetic diagnosis to cases with multiple autosomal dominant single-gene disorders.

Interaction of Sedlin with PAM14

Sedlin is an evolutionarily conserved and ubiquitously expressed protein that is encoded by the gene SEDL. Mutations in the latter are known to be causative for spondyloepiphyseal dysplasia tarda. However, the mechanism underlying this remains unclear. We have previously shown that Sedlin interacts with the intracellular chloride channel proteins CLIC1 and CLIC2 in the cytoplasm. In this report we show that Sedlin is also physically associated with protein associated with MRG 14 kDa (PAM14), a nuclear protein that interacts with the transcription factor MORF4-related gene on chromosome 15 (MRG15). This was suggested by yeast two-hybrid screening and was confirmed with GST pull-down and immunoprecipitation assays. Moreover, we demonstrate that the C-terminus of Sedlin and the N-terminus of PAM14 are critical for their interaction. Together, these results suggest that nucleus-localized Sedlin may play a role in regulation of transcriptional activities of the MRG family of transcription factors via binding to PAM14.

SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA

We report a case of spondyloepiphyseal dysplasia congenita (SED congenita), diagnosed at autopsy of a term infant. Prenatal ultrasound at 20 weeks of gestation had shown shortening of all the fetal long bones, with bowing of the femora and humeri, clubfeet, and small thoracic cage. We discuss the diagnostic features of SED and the main differential diagnoses.

Schimke immunoosseous dysplasia: defining skeletal features

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00431-009-1115-9) contains supplementary material, which is available to authorized users.

Biochemical consequences of sedlin mutations that cause spondyloepiphyseal dysplasia tarda

SEDT (spondyloepiphyseal dysplasia tarda) is a late-onset X-linked recessive skeletal dysplasia caused by mutations in the gene SEDL coding for sedlin. In the present paper, we investigated four missense mutations observed in SEDT and compare biochemical and cellular characteristics relative to the wild-type protein to address the mechanism of disease and to gain insight into the function of the sedlin protein. In situ hybridization and immunohistochemical experiments in mouse growth plates revealed sedlin to be predominantly expressed in proliferating and hypertrophic chondrocytes. Cell culture studies showed that the wild-type protein localized predominantly in the vicinity of the nucleus and the Golgi, with further localization around the cytoplasm, whereas mutation resulted in mislocalization. The D47Y mutant was expressed similarly to the wild-type, but the S73L, F83S and V130D mutants showed particularly low levels of expression that were rescued in the presence of the proteasome inhibitor MG132 (benzyloxycarbonyl-leucylleucylleucinal). Furthermore, whereas the D47Y mutant folded similarly and had similar stability to the wild-type sedlin as shown by CD and fluorescence, the S73L, F83S and V130D mutants all misfolded during expression. Two independent assays showed that the D47Y mutation resulted in an increased affinity for the transport protein particle component Bet3 compared with the wild-type sedlin. Our results suggest that the sedlin mutations S73L, F83S and V130D cause SEDT by sedlin misfolding, whereas the D47Y mutation may influence normal TRAPP (transport protein particle) dynamics.

A novel insertion mutation in the SEDL gene results in X-linked spondyloepiphyseal dysplasia tarda in a large Chinese pedigree

Background Spondyloepiphyseal dysplasia tarda (SEDT) is an X-chromosome linked primary skeletal dysplasia characterized by a disproportionate short-trunked short stature, dysplasia of the large joints and flattened thoracic and lumber vertebral bodies. The objective of this study is to describe a large Chinese SEDT family with a milder phenotype and describe the molecular and clinical findings. Methods Eight affected males of the family were diagnosed with SEDT according to their clinical and radiological features. Direct DNA sequencing of the SEDL gene was performed. RT-PCR experiments on total RNA from blood lymphocytes were performed to confirm the defect on the SEDL gene. A short summary of all currently known SEDL gene mutations is presented. Results DNA sequencing revealed that all the affected males carried an insertion mutation (c.370-371insA) unreported previously, predicted to result in frameshifts and generate a premature stop codon (p.S124fsX127). The identical mutation was also observed in a 10-year old presymptomatic boy of the family. Eight female carriers had the typical sequencing chromatograms of heterozygotes. Conclusions Identification of the novel insertion mutation (c.370-371insA) in this SEDT family enables carrier detection and presymptomatic/prenatal diagnosis, but also the detailed molecular and clinical features will be useful for extending the evidence for genetic and phenotypic heterogeneity in SEDT.

TRAPPC2L is a Novel, Highly Conserved TRAPP‐Interacting Protein

Mutations in the trafficking protein particle complex C2 protein (TRAPPC2), a mammalian ortholog of yeast Trs20p and a component of the trafficking protein particle (TRAPP) vesicle tethering complex, have been linked to the skeletal disorder spondyloepiphyseal dysplasia tarda (SEDT). Intriguingly, the X-linked TRAPPC2 is just one of a complement of Trs20-related genes in humans. Here we characterize TRAPPC2L, a novel, highly conserved TRAPP-interacting protein related to TRAPPC2 and the uncharacterized yeast open reading frame YEL048c. TRAPPC2L and TRAPPC2 genes are found in pairs across species and show broad and overlapping expression, suggesting they are functionally distinct, a notion supported by yeast complementation studies and biochemical characterization. RNA interference-mediated knockdown of either TRAPPC2L or TRAPPC2 in HeLa cells leads to fragmentation of the Golgi, implicating both proteins in Golgi dynamics. Gradient fractionation of cellular membranes indicates that TRAPPC2L is found with a portion of cellular TRAPP on very low-density membranes whereas the remainder of TRAPP, but not TRAPPC2L, is found associated with Golgi markers. YEL048c displays genetic interactions with TRAPP II-encoding genes and the gene product co-fractionates with and interacts with yeast TRAPP II. Taken together these results indicate that TRAPPC2L and its yeast ortholog YEL048c are novel TRAPP-interacting proteins that may modulate the function of the TRAPP II complex.

R992C (p.R1192C) Substitution in Collagen II Alters the Structure of Mutant Molecules and Induces the Unfolded Protein Response

We investigated the molecular bases of spondyloepiphyseal dysplasia (SED) associated with the R992C (p.R1192C) substitution in collagen II. At the protein level, we analyzed the structure and integrity of mutant molecules, and at the cellular level, we specifically studied the effects of the presence of the R992C collagen II on the biological processes taking place in host cells. Our studies demonstrated that mutant collagen II molecules were characterized by altered electrophoretic mobility, relatively low thermostability, the presence of atypical disulfide bonds, and slow rates of secretion into the extracellular space. Analyses of cellular responses to the presence of the mutant molecules showed that excessive accumulation of thermolabile collagen II was associated with the activation of an "unfolded protein response" and an increase in apoptosis of host cells. Collectively, these data suggest that molecular mechanisms of SED may be driven not only by structural changes in the architecture of extracellular collagenous matrices, but also by intracellular processes activated by the presence of mutant collagen II molecules.

Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke‐immuno‐osseous dysplasia

SIOD is a multisystem disorder caused by a mutant chromatin remodelling protein. The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF. Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft. However, with respect to the underlying immune disorder and the increased susceptibility to life threatening infections, the question of the optimal immunosuppressive therapy after renal transplantation remains unresolved. Under conventional immunosuppressive regimens some SIOD patients have developed severe disseminated cutaneous papilloma virus infections or EBV associated lymphoproliferative disease. We present several cases of children with SIOD (four of five had SMARCAL1 mutations) and monotherapy maintenance immunosuppression after renal transplantation and compare them with 13 patients from the SIOD registry. We have found that post-renal transplantation immunosuppressive monotherapy results in a good outcome with a reduced number of severe infections. Due to the underlying immunodeficiency in SIOD, limited immunosuppression may be possible without increasing the risk of acute or chronic rejection.

Omani‐type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3

We describe a family with progressive skeletal dysplasia and severe spinal involvement, short stature, premature arthrosis and joint contractures diagnosed as spondyloepiphyseal dysplasia Omani type. Mutation analysis in CHST3, the gene encoding for the chondroitin 6-O-sulfotransferase-1 (C6ST-1), revealed a homozygous missense mutation (T141M) in exon 3 in all three affected members of the family. Using recombinant C6ST-1, we showed that the identified missense mutation results in a reduction of C6ST-1 activity to 24-29% of the wild type protein. In addition to the previously noted skeletal features, affected members of this family also had cardiac involvement including mitral, tricuspid and/or aortic regurgitations and type E brachydactyly.

A novel RNA-splicing mutation in TRAPPC2 gene causing X-linked spondyloepiphyseal dysplasia tarda in a large Chinese family

X-linked spondyloepiphyseal dysplasia tarda (SEDT; OMIM 313400) is a rare osteochondrodysplasia that occurs in affected individuals between 3 and 12 yr of age. Clinical features include short trunk, barrel-shaped chest and disproportionate short stature. Radiological abnormalities may become evident between 10 and 14 yr of age and include platyspondyly with hump-shaped central and posterior portions of the vertebrae, narrow disc spaces and moderate epiphyseal dysplasia of the long bones, which may be associated with osteoarthritis. Female heterozygous carriers are clinically and radiographically normal. SEDT is caused by mutations in the TRAPPC2 gene, (trafficking protein particle complex 2), which spans a genomic region of ∼20 kb in Xp22. In a large Chinese SEDT family, we screened all the six exons of the TRAPPC2 gene and identified a novel RNA-splicing mutation (IVS4+1A>G). We also demonstrated that the mutation induced splice pattern change from AT/AC to GT/AG. As a result, the first seven nucleotides of exon 5 were spliced out from the transcript. The prediction of the amino acid sequence showed that the seven nucleotides deletion of the transcript caused frame shift and led to premature translation termination, causing loss of two alpha helices. The results of our study expand the spectrum of the gene mutations associated with SEDT, and will help further to elucidate the role of this protein in the etiology of this form of osteochondrodysplasia. X-linked spondyloepiphyseal dysplasia tarda mutations in the TRAPPC2 gene previously identified as SEDL gene,

Rapid Molecular Prenatal Diagnosis of Spondyloepiphyseal Dysplasia Congenita by PCR-SSP Assay

Heterozygous mutations of COL2A1 gene are responsible for type II collagenopathies. The common skeletal phenotypes include achondrogenesis type II, hypochondrogenesis, Stickler dysplasia, Kniest dysplasia, late onset spondyloepiphyseal dysplasia, and spondyloepiphyseal dysplasia congenita (SEDC). Prevention of SEDC can be achieved by prenatal diagnosis. This study reports the first rapid molecular prenatal diagnosis of SEDC performed in China by polymerase chain reaction sequence-specific primer (PCR-SSP) analysis. The pregnant woman we previously reported with SEDC carried the G to A substitution at nucleotide 1510 in exon 23 of COL2A1 gene, which caused a change from glycine to serine at codon 504 (G504S). By the time the woman got pregnant again, she had terminated two pregnancies and still had no child. In the first pregnancy, the molecular mutation of the family was not yet identified, and therefore prenatal diagnosis was unable to be performed by DNA analysis. In the second pregnancy, G504S mutation was found from fetal DNA. At the time of her third pregnancy, the woman and her husband became extremely worried about the potential SEDC for the fetus. For this reason, a quick and reliable molecular prenatal diagnosis of SEDC was performed by a PCR-SSP on an amniocyte sample collected at the 14th week of pregnancy. No mutation of the fetal DNA was identified. The result was obtained within 24 h after the sample was collected. The technique could be applied in confirmatory diagnosis and prenatal diagnosis for the affected family.

Progressive acetabular dysplasia in a boy with mucopolysaccharoidosis type IV A (Morquio syndrome): a case report.

BackgroundMorquio syndrome is an autosomal recessive lysosomal storage disorder, a mucopolysaccharidosis (PMS), characterized by abnormal metabolism of glycosaminoglycans. Major treatable concerns in patients with MPS type IV involve C1 to C2 instability, genu valgum, and hip subluxation. All patients demonstrate characteristic acetabular dysplasia and failure of ossification of the superolateral femoral head.Case presentationWe report on a 6-year-old boy whose prime presentation was a waddling gait associated with pain since early childhood. Radiographic documentation showed progressive acetabulo-femoral dysplasia associated with additional skeletal deformities. Laboratory investigations showed increased urinary keratan sulfate and reduced leukocyte enzymatic activity of N-Acetyl-Galaktosamin-6-sulfate-sulfatase. Mucopolysaccharoidosis type IV A (Morquio syndrome) has been identified.ConclusionPatients with Morquio syndrome usually appear normal at birth but exhibit growth failure and spondyloepiphyseal dysplasia as infants. Most children are brought to a physician for investigation of what the parents perceive as an abnormal appearance by 12 to 18 months of age and thoracic kyphosis is supposed to be the first appearing deformity. In our present patient progressive acetabular dysplasia was the prime orthopaedic presentation causing effectively the development of a painful waddling gait.

Noncanonical and canonical splice sites: a novel mutation at the rare noncanonical splice-donor cut site (IVS4+1A>G) of SEDL causes variable splicing isoforms in X-linked spondyloepiphyseal dysplasia tarda

X-linked spondyloepiphyseal dysplasia tarda can be caused by mutations in the SEDL gene. This study describes an interesting novel mutation (IVS4+1A>G) located exactly at the rare noncanonical AT-AC consensus splicing donor point of SEDL, which regained the canonical GT-AG consensus splicing junction in addition to several other rarer noncanonical splice patterns. The mutation activated several cryptic splice sites and generated the production of seven erroneous splicing isoforms, which we confirmed by sequencing of RT-PCR products and resequencing of cDNA clones. All the practical splice donors/acceptors were further assessed using FSPLICE 1.0 and SPL(M) Platforms to predict potential splice sites in genomic DNA. Subsequently, the expression levels of SEDL among the affected patients, carriers and controls were estimated using real-time quantitative PCR. Expression analyses showed that the expression levels of SEDL in both patients and carriers were decreased. Taken together, these results illustrated how disruption of the AT donor site in a rare AT-AC intron, leading to a canonical GT donor site, resulted in a multitude of aberrant transcripts, thus impairing exon definition. The unexpected splicing patterns resulting from the special mutation provide additional challenges and opportunities for understanding splicing mechanisms and specificity.

Spondyloepiphyseal dysplasia tarda: four cases from two families

Spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA) is an autosomal recessively inherited skeletal dysplasia. We present four patients (three patients-a brother and a sister and their third cousin-in a family and one patient in another family) with SEDT-PA. All patients had short stature and stubby hands and feet. Their radiographs revealed typical changes for SEDT-PA including platyspondyly, severe osteopenia and dysplastic bone changes. Physical therapy and exercises were performed to all patients in order to decrease in pain and increase or at least maintain joint motion and mobility. Symptomatic relief was achieved in all patients for about a couple of months. The major clinical importance of this rather rare disorder is its similarity to juvenile idiopathic arthritis which has rather different treatment protocol.

6.4 Spondylo-epiphyseal dysplasia – a physiotherapy approach

6.4 Spondylo-epiphyseal dysplasia – a physiotherapy approach

Coxa Vara in Chondrodysplasia

To better understand anatomical and functional outcomes of coxa vara in chondrodysplasia according to the initial presenting hip morphology, disease type, and impact of surgery. Clinical and radiographic records of 19 children (35 hips) diagnosed with coxa vara and with osteochondrodysplasia were reviewed. We classified the hip radiographic findings into 2 groups: (a) group I, coxa vara with a fragmented and/or nonossified head; and (b) group II, coxa vara with a regular femoral head. Surgical indications in coxa vara included decreased range of hip motion (usually diminished abduction, extension, and internal rotation), coxa vara with progression documented on regular follow-up hip radiographs, and/or severe coxa vara with a Hilgenreiner epiphyseal angle (HEA) of 60 degrees or more. Follow-up was until the completion of growth and, for some patients, into early adulthood. Mean follow-up was 8 years. Twenty-five hips were operated on in 13 patients. In 23 hips, the procedure was a valgus osteotomy fixed by pins and wire. A pelvic extension osteotomy without valgus osteotomy was performed in one patient (2 hips). Coxa vara recurred in 7 hips. In 4 of these hips, repeat surgery with hypervalgus osteotomy was indicated to stop epiphyseal slipping (3 hips) or to improve the arc of motion (1 hip). Functional outcomes were poor in coxa vara associated with poor epiphyseal development (nonossified or fragmented epiphysis) as seen in spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia, Kniest disease, and multiple epiphyseal dysplasia. Coxa vara with physeal instability as observed in spondylometaphyseal dysplasia resulted in deformity recurrence postoperatively during growth. In contrast, outcome was better in cases of coxa vara with nonphyseal/nonepiphyseal involvement, that is, good femoral head morphology, stable physis, and good articular cartilage, as seen in cases of metaphyseal dysplasia and cleidocranial dysplasia. Coxa vara with physeal and epiphyseal involvement and severe impairment of the articular cartilage has a poor prognosis even after reconstructive surgery. In coxa vara with an abnormal physis, there were numerous postsurgical recurrences of the deformity during growth if the physis was not stabilized at the time of valgus osteotomy. In these cases, we should delay osteotomy until an HEA greater than 60 degrees. Coxa vara in which only the metaphysis of the femoral neck is involved, the deformity is milder and often requires no treatment. Indications for surgery in this group are increasing coxa vara, Trendelenburg gait, or an HEA greater than 60 degrees.

Spondyloepiphyseal dysplasia, Omani type: Further definition of the phenotype

Spondyloepiphyseal dysplasia (SED), Omani type (OMIM 608637) is a recessively inherited skeletal dysplasia previously described in two distantly related families from the Republic of Oman. The phenotype consists of short stature, severe kyphoscoliosis, arthritic joints (elbows, wrists, knees), secondary large joint dislocations, rhizomelia, fusion of carpal bones and mild brachydactyly. Affected individuals were homozygous for a missense mutation, R304Q in CHST3 that encodes the enzyme chondroitin 6-O-sulfotransferase-1 (C6ST-1). This enzyme mediates the sulfation of proteoglycans, particularly chondroitin sulfate (CS), in the extracellular matrix of cartilage. Here we describe the identification of a mutation (857T > C predicting the substitution L286P) in CHST3 in a Turkish family and extend the clinical phenotype of SED-Omani type to include congenital joint dislocation, club feet, ventricular septal defect, deafness, metacarpal shortening and accessory carpal ossification centers. Fibroblasts and urine obtained from affected patients demonstrated negligible levels of 6-O-sulfated GalNAc residue in CS. Furthermore, the 6-O-sulfotransferase activity of cloned C6ST-1 into which the L286P mutation had been introduced was dramatically reduced, confirming the pathogenicity of this substitution. These results indicate that the clinical consequences of a deficiency of 6-O-sulfation in CS can be varied and that a clinical spectrum may exist similar to that seen in other skeletal dysplasias characterized by disorders of proteoglycan sulfation.