Tarsal Fusion Research Articles

A severe case of cardiospondylocarpofacial syndrome with a novel MAP3K7 variant

Cardiospondylocarpofacial syndrome (CSCFS) is a congenital malformation characterized by growth retardation, facial features, short toes with carpal and tarsal fusion, extensive posterior neck vertebral fusion, congenital heart disease, and deafness. Here, we report a severe case of CSCFS with a novel variant, p.Thr187Ile, in MAP3K7. Thr187 is the main phosphorylation site for TGF-beta-activated kinase 1 encoded by MAP3K7, and this variant may cause significant abnormalities in downstream signaling.

Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome.

Spondylocarpotarsal synostosis syndrome (SCT) is a very rare skeletal dysplasia characterized by vertebral, carpal, and tarsal fusion; growth retardation; and mild dysmorphic facial features. Variants in FLNB, MYH3, and RFLNA have been implicated in this dysplasia. We report the clinical and radiological follow-up of seven SCT pediatric cases associated with biallelic FLNB variants, from four Argentinian families. The seven cases share previously described facial characteristics: round facies, large eyes, and wide based nose; all of them had variable height deficit, in one case noted early in life. Other findings included clinodactyly, joint limitation without bone fusion, neurosensorial hearing loss, and ophthalmological compromise. All cases presented with spinal fusion with variable severity and location, carpal bones coalition, and also delay in carpal ossification. The heterozygous carrier parents had normal height values to -2.5 score standard deviation, without skeletal defects detected. Three different FLNB variants, one nonsense and two frameshift, were detected, all of which were predicted to result in a truncated protein or are degraded by nonsense mediated decay. All cases had at least one copy of the nonsense variant, c.1128C> G; p. (Tyr376*), suggesting the presence of a common ancestor.

Intervertebral disc degeneration is rescued by TGF\u03b2/BMP signaling modulation in an ex vivo filamin B mouse model

Spondylocarpotarsal syndrome (SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B (FLNB). Utilizing a FLNB knockout mouse, we showed that the vertebral fusions in SCT evolved from intervertebral disc (IVD) degeneration and ossification of the annulus fibrosus (AF), eventually leading to full trabecular bone formation. This resulted from alterations in the TGFβ/BMP signaling pathway that included increased canonical TGFβ and noncanonical BMP signaling. In this study, the role of FLNB in the TGFβ/BMP pathway was elucidated using in vitro, in vivo, and ex vivo treatment methodologies. The data demonstrated that FLNB interacts with inhibitory Smads 6 and 7 (i-Smads) to regulate TGFβ/BMP signaling and that loss of FLNB produces increased TGFβ receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFβ/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFβ/BMP pathway activity restored Flnb−/− IVD morphology. These most effective improvements resulted from specific inhibition of TGFβ and p38 signaling activation. FLNB acts as a bridge for TGFβ/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFβ/BMP signaling that maintains the IVD. These findings further our understanding of IVD biology and reveal new molecular targets for disc degeneration as well as congenital vertebral fusion disorders.

Rare heterozygous GDF6 variants in patients with renal anomalies

Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.

Tarsal fusion for pes equinovarus deformity improves gait capacity in chronic stroke patients

BackgroundGait impairments are common and disabling in chronic stroke patients. Pes equinovarus deformity is one of the primary motor deficits underlying reduced gait capacity after stroke. It predisposes to stance-phase instability and subsequent ankle sprain or falls. This instability is most pronounced when walking barefoot. Tarsal fusion is a recommended treatment option for varus deformity, but scientific evidence is sparse. We therefore evaluated whether a tarsal fusion improved barefoot walking capacity in chronic stroke patients with pes equinovarus deformity.MethodsTen patients with a pes equinovarus deformity secondary to supratentorial stroke underwent surgical correction involving a tarsal fusion of one or more joints. Instrumented gait analysis was performed pre- and postoperatively using a repeated-measures design. Primary outcome measure was gait speed.ResultsWalking speed significantly improved by 32% after surgery (0.38 m/s ± 0.20 to 0.50 m/s ± 0.17, p = 0.007). Significant improvement was also observed when looking at cadence (p = 0.028), stride length (p = 0.016), and paretic step length (p = 0.005). Step length on the nonparetic side did not change. Peak ankle moment increased significantly on the nonparetic side (p = 0.021), but not on the paretic side (p = 0.580). In addition, functional ambulation scores increased significantly (p = 0.008), as did satisfaction with gait performance (p = 0.017).ConclusionsTarsal fusion for equinovarus deformity in chronic stroke patients improves gait capacity, and the degree of improvement is of clinical relevance. Our results suggest that the improved gait capacity may be related to better prepositioning and loading of the paretic foot, leading to larger paretic step length and nonparetic ankle kinetics.

A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGF\u03b2 signaling and cause autosomal dominant spondylocarpotarsal synostosis

Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin. Cells transfected with the MYH3 missense mutations had reduced TGFβ signaling, revealing a regulatory role for embryonic myosin in the TGFβ signaling pathway. In wild-type mice, there was persistent postnatal expression of embryonic myosin in the small muscles joining the neural arches of the spine suggesting that loss of myosin function in these muscles contribute to the disease. Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions.

Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome.

Spondylocarpotarsal synostosis syndrome (SCT) is a rare Mendelian disorder (OMIM #272460) characterized by prenatal vertebral fusion, scoliosis, short stature and carpal and tarsal synostosis. SCT is typically known as an autosomal recessive disease caused by variants in the FLNB gene. The genetic basis of the rarer cases of vertical transmissions remains unknown. In two independent families with symptoms related to autosomal dominant SCT, we identified - by exome sequencing - two protein-altering variants in the embryonic myosin heavy chain 3 (MYH3) gene. As MYH3 variants are also associated with distal arthrogryposis (DA1, DA2A, DA2B) and autosomal dominant multiple pterygium syndromes (MPS), the present study expands the phenotypic spectrum of MYH3 variants to autosomal dominant SCT. Vertebral, carpal and tarsal fusions observed in both families further confirm that MYH3 plays a key role in skeletal development.

Diagnostics in tarsal fusion: The theory and practise in The Netherlands

A review of reactions of quaternary salts of 2,3-dimethylquinoxaline, especially those leading to indigoid or quinoid chromogens, is combined with the presentation of recent results. Part III includes the synthesis of a novel indigoid dye together with a new route to hydrindines. On heating the title salt with thiophenols in all probability the 2,2'-dimer was isolated. This is related, as a parent compound, to the cationic dyes 24 described in Part II, but could not be obtained by conventional methods. 1H NMR and mass spectra are presented and reaction mechanism is discussed.Die vorliegende Serie verknüpft einen Rückblick auf Arbeiten im Chinoxalin-und Farbstoffgebiet mit bisher unveröffentlichten Ergebnissen.Im Teil III wird einerseits eine durch Erhitzen mit Thiophenol im neutralen aprotonischen Solvens induzierte Dimerisierung des 1-Methyl-chinoxalinium-Ions beschrieben. Wahrscheinlichstes Produkt ist hier 4-Methyl-3-(4-methyl-3,4-dihydro-chinoxalinio-3-yliden)-3,4-dihydrochin-oxalinium-bis-perchlorat 45, reaktives Agens höchstwahrscheinlich ein kationisches Ylid. Das basenempfindliche Dikation addiert Thiophenol, wenn man der Reaktionslösung vor der Aufarbeitung ein tertiäres Amin zusetzt. Versuche, die korrespondierende indigoide Farbbase freizusetzen, blieben erfolglos. Gleiches gilt für einen alternativen Syntheseweg, der durch die bekannte baseninduzierte Umwandlung anderer heterocyclischer Quartärsalze vorgezeichnet schien.Mit 1,3,3-Trimethyl-2-methyliden-3H-indolenin reagiert 1-Methyl-chin-oxalinium-toluolsulfonat andererseits zum erwarteten Monomethincyanin. Die Umsetzung mit quartären Salzen des 2,3-Dimethylchinoxalins eröffnete hingegen einen neuen Zugang zu asymmetrisch substituierten 5,12-Di-hydrochinoxalino[2,3-b] phenazinen, die in höchst überraschender Weise anstelle der postulierten zwitterionischen Produkte anfallen. Auf analogem Wege wurde 14-Phenyl-7-methyl-chinoxalino[2,3-g]pyrido[2,3-b]chinoxalin gewonnen.Die Produkte werden durch UV/Vis-Spektren, Elementaranalyse und soweit möglich durch 1H NMR- und/oder Massenspektren charakterisiert.

Diagnostics in tarsal fusion: The theory and practise in The Netherlands

This study compares the preferences of Dutch orthopaedic surgeons for different diagnostic modalities in performing tarsal fusions versus consensus, evidence or expert opinion reported in the literature. A literature search of Medline was performed to obtain evidence-based information on various diagnostic tools. In addition, 89 registered Dutch foot and ankle surgeons were sent a questionnaire concerning the diagnostic modalities use in tarsal fusion. Fifty-eight (65%) questionnaires were returned. The experienced surgeons measured outcomes significantly more often than other surgeons. Diagnostic injections were often used, although scant evidence exists in the literature. Postoperative diagnostics mainly consist of X-ray examination, although there is consensus in the literature that computed tomography is more accurate. The study revealed some surprising discrepancies concerning the use of diagnostic imaging in tarsal fusion. More clinical research is needed to identify the most effective diagnostic imaging modalities so as to encourage their wider adoption.

Differential diagnosis of carpal and tarsal ankylosis on dry bones: Example from the catacomb of Saints Peter and Marcellinus (Rome, 1st–3rd century AD)

Bone ankylosis is a pathological feature that may occur in many chronic diseases involving joints. In paleopathology, it is therefore challenging to attribute such a change to a specific condition. Here, we illustrate the differential diagnosis by discussing the lesions observed on an incomplete skeleton from the Roman period, recovered from the catacomb of Saints Peter and Marcellinus (Rome, Italy). The skeleton exhibits several bone changes, including ankylosis on both feet and the left hand. The right tarsal fusion is accompanied by soft tissue ossifications involving the plantar aponeurosis and the tendinous structures connecting the great toe's proximal phalanx and sesamoid bones. The lesions recorded suggest that a spondyloarthropathy is the most likely cause of these extensive fusions.

Tarsal fusion and the formation of the astragalus in Hylonomus lyelli, the earliest amniote, and other early tetrapods

The origin of the amniote astragalus, the enlarged proximal tarsal distal to the tibia and one of the few diagnostic skeletal features of the group (Carroll, 1970; Gauthier et al., 1988), has been ...

Diagnostik und Therapie der Koalitionen und Synostosen bei Kindern und Jugendlichen

The majority of tarsal coalitions are located in the calcaneonavicular and talocalcaneal regions and other locations are rare. Complete early ossified synostoses are found not only in major limb deficiencies but also in otherwise normal feet. Magnetic resonance imaging (MRI) and computed tomography (CT) scans are the most important imaging techniques especially for preoperative planning. Early resection is advisable in calcaneonavicular coalitions as soon as it is detected in childhood and adolescence. Indications for or against resection or limited tarsal fusion are much more difficult in talocalcaneal coalition. The patient's complaints, extension and location of the coalition, additional malalignment and especially patient age are some of the factors that should be considered carefully. Results of surgical resection are not always satisfactory with a long-lasting rehabilitation especially in older children or adolescents and the necessity for secondary procedures can never be ruled out. In cases of malalignment corrective tarsal osteotomy can be considered as a simultaneous or staged procedure. An overview with special emphasis on surgical options is presented with typical examples as well as rare conditions and a review of important literature from recent years is included.

Síndrome de coalición tarso-carpiana: un caso familiar

Tarsal-carpal coalition syndrome (TCC, OMIM #186570) is an autosomal dominant disorder characterised by fusion of the carpals, tarsals, and phalanges, with the short first metacarpals causing brachydactyly and humeroradial fusion. Mutations in the NOG gene have been reported in many families. We describe a family with carpal tarsal fusion seen at a Skeletal Dysplasia Clinic and look at the differential diagnoses.

TAK1 is an essential regulator of BMP signalling in cartilage

TGFβ activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1col2 mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage.

Spondylocarpotarsal synostosis: A rare case of vertebral segmentation defect

Spondylocarpotarsal synostosis (SS) is a disorder of abnormal vertebral segmentation. Clinically manifest as kyphoscoliosis/scoliosis with characteristic radiographic findings vertebral, carpal and tarsal bone fusion. It is inherited as an autosomal recessive disorder. The present study report a case of SS and describe the clinical and radiological manifestations. In addition to classical signs, neuroimaging revealed cervical spine abnormalities, further supporting the importance of spine imaging in such cases.

Case Reports: Symptomatic Bilateral Talonavicular Coalition

Congenital talonavicular coalition is reported less frequently than talocalcaneal or calcaneonavicular coalition and represent approximately 1% of all tarsal coalitions. Although reportedly transmitted as an autosomal-dominant disorder, tarsal coalition may be inherited as an autosomal-recessive trait. It has been associated with various orthopaedic anomalies, including symphalangism, clinodactyly, a great toe shorter than the second toe, clubfoot, calcaneonavicular coalition, talocalcaneal coalition, and a ball-and-socket ankle. Patients with talonavicular coalitions are usually asymptomatic and rarely undergo surgical treatment. We report the case of a 24-year-old woman with symptomatic bilateral talonavicular coalitions and previously unreported associated anomalies (nail hypoplasia and metatarsus primus elevatus) and review the relevant literature. The patient underwent surgery (calcaneocuboid joint distraction arthrodesis and a proximal plantar flexion osteotomy with a dorsal open wedge of the first metatarsal). At 1-year followup, she was pain-free with better alignment of both feet and showed radiographic consolidation of the arthrodesis. Although this condition is less likely to be clinically important than other tarsal fusions, it sometimes can be painful enough for the patient to undergo surgery.

Muenke syndrome (FGFR3‐related craniosynostosis): Expansion of the phenotype and review of the literature

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling.

The Noggin null mouse phenotype is strain dependent and haploinsufficiency leads to skeletal defects

Noggin is a secreted peptide that binds and inactivates Bone Morphogenetic Proteins, members of the transforming growth factor beta superfamily of secreted signaling molecules. In vertebrate limbs, Noggin is expressed in condensing cartilage and immature chondrocytes. Inactivation of the Noggin gene has been reported in an inbred 129X1/SvJ mouse genetic background. The null allele was lethal at 18.5 dpc and resulted in severe hyperplasia of the cartilage together with multiple joint fusions. In order to investigate the effect of the genetic background on the phenotypic manifestation of Noggin inactivation, we crossed the Noggin null allele into the outbred CD1 and inbred DBA1 and C57BL/6 mouse strains. We describe here skeletal phenotypes of Noggin null mice, such as accelerated or delayed mineralization of different bones suggestive of a complex tissue response to the perturbations in BMP balances. Additionally, we found that in the absence of Noggin, early specification of myogenic differentiation was unaffected, whereas terminal stages of myogenesis were delayed. Furthermore, we have discovered Noggin haploinsufficiency leading to carpal and tarsal fusions reminiscent of some phenotypes reported for NOGGIN haploinsufficiency in humans.

The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation.

Saethre-Chotzen syndrome (SCS) and Muenke-type mutation (MTM) are complex syndromes with craniosynostosis and skeletal anomalies including syndactyly, carpal and tarsal fusions, and cervical spine abnormalities. In this study, we analysed radiographs of the cervical spine, hands and feet of a large patient population with genetically proven SCS and MTM. The aim was to describe the pattern of skeletal anomalies and to determine whether specific features are present that could help differentiate between the two entities. Radiographs of 43 patients (23 males, 20 females) with SCS (n=35) or MTM (n=8) were evaluated. The median age was 8 years (range 1 month-36 years). All radiographs were reviewed by two radiologists. In the hands and feet, a variety of anomalies such as brachyphalangy, clinodactyly, partial syndactyly, partial carpal or tarsal fusion, and cone-shaped epiphyses were noted. Duplicated distal phalanx of the hallux (n=12/35) and triangular deformity of the epiphysis of the distal phalanx of the hallux (n=10/35) were detected in SCS only; calcaneo-cuboid fusion (n=2/35) was detected in MTM only. In the cervical spine, fusion of vertebral bodies and/or the posterior elements occurred only in patients with SCS. Pathognomonic signs for SCS are the triangular shape of the epiphysis and duplicated distal phalanx of the hallux. Calcaneo-cuboid fusion was detected in MTM only. These signs may be helpful in the differentiation of SCS from MTM.

Nasal cartilage aplasia in a family with facioaudiosymphalangism syndrome

The main clinical features of facioaudiosymphalangism syndrome (FASS) (OMIM *186500) are characterized by a distinct facies with a broad hemicylindrical nose and hypoplasia of alae nasi, proximal symphalangism of the fingers, carpal and tarsal fusion, and progressive conductive deafness. A number of patients, who were mainly reported in the early literature, showed intrafamilial and interfamilial variability. We have found this disorder in 2 members of a family in whom FASS was associated with nasal cartilage aplasia.