Spondylocarpotarsal Synostosis Syndrome Research Articles

A novel variant in the FLNB gene associated with spondylocarpotarsal synostosis syndrome.

Genetic disorders involved in skeleton system arise due to the disturbance in skeletal development, growth and homeostasis. Filamin B is an actin binding protein which is large dimeric protein which cross link actin cytoskeleton filaments into dynamic structure. A single nucleotide changes in the FLNB gene causes spondylocarpotarsal synostosis syndrome, a rare bone disorder due to which the fusion of carpels and tarsals synostosis occurred along with fused vertebrae. In the current study we investigated a family residing in north-western areas of Pakistan. The whole exome sequencing of proband was performed followed by Sanger sequencing of all family members of the subject to validate the variant segregation within the family. Bioinformatics tools were utilized to assess the pathogenicity of the variant. Whole Exome Sequencing revealed a novel variant (NM_001457: c.209C>T and p.Pro70Leu) in the FLNB gene which was homozygous missense mutation in the FLNB gene. The variant was further validated and visualized by Sanger sequencing and protein structure studies respectively as mentioned before. The findings have highlighted the importance of the molecular diagnosis in SCT (spondylocarpotarsal synostosis syndrome) for genetic risk counselling in consanguineous families.

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.

Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

BackgroundLoss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height.Case presentationWe describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature.ConclusionOur report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

MYH3-associated distal arthrogryposis zebrafish model is normalized with para-aminoblebbistatin.

Distal arthrogryposis (DA) is group of syndromes characterized by congenital joint contractures. Treatment development is hindered by the lack of vertebrate models. Here, we describe a zebrafish model in which a common MYH3 missense mutation (R672H) was introduced into the orthologous zebrafish gene smyhc1 (slow myosin heavy chain 1) (R673H). We simultaneously created a smyhc1 null allele (smyhc1 −), which allowed us to compare the effects of both mutant alleles on muscle and bone development, and model the closely related disorder, spondylocarpotarsal synostosis syndrome. Heterozygous smyhc1 R673H/+ embryos developed notochord kinks that progressed to scoliosis with vertebral fusions; motor deficits accompanied the disorganized and shortened slow‐twitch skeletal muscle myofibers. Increased dosage of the mutant allele in both homozygous smyhc1 R673H/R673H and transheterozygous smyhc1 R673H/− embryos exacerbated the notochord and muscle abnormalities, causing early lethality. Treatment of smyhc1 R673H/R673H embryos with the myosin ATPase inhibitor, para‐aminoblebbistatin, which decreases actin–myosin affinity, normalized the notochord phenotype. Our zebrafish model of MYH3‐associated DA2A provides insight into pathogenic mechanisms and suggests a beneficial therapeutic role for myosin inhibitors in treating disabling contractures.

Identification of a homozygous frameshift variant in RFLNA in a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome.

Spondylocarpotarsal synostosis syndrome, a rare syndromic skeletal disorder characterized by disrupted vertebral segmentation with vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis, has been associated with biallelic truncating mutations in the filamin B gene or monoallelic mutations in the myosin heavy chain 3 gene. We herein report the case of a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome who had a homozygous frameshift mutation in the refilin A gene (RFLNA) [c.241delC, p.(Leu81Cysfs*111)], which encodes one of the filamin-binding proteins. Refilins, filamins, and myosins play critical roles in forming perinuclear actin caps, which change the nuclear morphology during cell migration and differentiation. The present study implies that RFLNA is an additional causative gene for spondylocarpotarsal synostosis syndrome in humans and a defect in forming actin bundles and perinuclear actin caps may be a critical mechanism for the development of spondylocarpotarsal synostosis syndrome.

Spondylocarpotarsal synostosis syndrome: “Bat wings” spinal fusions and “ladybug” carpal coalitions

Spondylocarpotarsal synostosis syndrome: “Bat wings” spinal fusions and “ladybug” carpal coalitions

Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3

Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3, encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype. Initial whole-exome sequencing (WES) showed that all five were heterozygous for one of two independent splice-site variants in MYH3. Despite evidence indicating that three of the five individuals shared two allelic haplotypes encompassing MYH3, no second variant could be located in the WES datasets. Subsequent genome sequencing of these three individuals demonstrated a variant altering a 5' UTR splice donor site (rs557849165 in MYH3) not represented by exome-capture platforms. When the cohort was expanded to 16 SCTS-affected individuals without FLNB mutations, nine had truncating mutations transmitted by unaffected parents, and six inherited the rs557849165 variant in trans, an observation at odds with the population allele frequency for this variant. The rs557849165 variant disrupts splicing in the 5' UTR but is still permissive of MYH3 translational initiation, albeit with reduced efficiency. Although some MYH3 variants cause dominant SCTS, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. These observations make genetic diagnosis challenging in the context of simplex presentations of the disorder.

Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies.

Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs* 82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs* 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs* 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB.

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.

Urolithiasis in a child with Spondylocarpotarsal Synostosis Syndrome: A Co-Incidence

Spondylocarpotarsal synostosis syndrome (SSS) is an autosomal recessive condition which is characterized by short stature, a carpotarsal coalition and a vertebral fusion, but without any rib anomaly. We are presenting a 7- year- old boy, who had uroliathiasis with the spondylocarpotarsal synostosis syndrome. This association, to the best of our knowledge, has not been reported so far.

The Earliest Case of Spondylocarpotarsal Synostosis Syndrome (Roman Age-2nd Century ad )

Spondylocarpotarsal synostosis syndrome (SCT) is a rare genetic disease. It was described for the first time during the 1970s. The most relevant pathognomonic skeletal changes are vertebral malsegmentation and the fusion of the carpal and tarsal bones. This last implication can be absent in some cases. We have investigated a case of SCT in a female of about 40–45 years of age, dated to the 2nd century ad. This discovery is important for two reasons: first, SCT is not a recent disease but rather one with a very long history; second, the clinical picture of the skeletal changes (malsegmentation of some elements of the spine, fusion of carpal bones) seems not to have varied in the last 2000 years. Furthermore, the age of the Roman female shows medium–long survival in patients suffering from SCT, even in the absence of medical treatment. Copyright © 2011 John Wiley & Sons, Ltd.

Fetal alcohol syndrome: a phenocopy of spondylocarpotarsal synostosis syndrome?

Vassel, Jennifera b; Rupps, Rosemariea b; Krakow, Deborahf; Puvanachandra, Narmand; Gardiner, Jane A.d; Lazeo, Sharon R.e; Boerkoel, Cornelius F.a b c Author Information

Postnatal growth retardation, facial dysmorphism, spondylocarpal synostosis, cardiac defect, and inner ear malformation (cardiospondylocarpofacial syndrome?)—A distinct syndrome?

We report on two unrelated cases born to nonconsanguineous parents with a similar clinical presentation: hypotonia since the neonatal period, severe failure to thrive, postnatal growth retardation, facial dysmorphism, congenital cardiac defects (septal defect and non progressive multiple valve dysplasia), shortened extremities, carpal/tarsal and extensive vertebral synostosis, delayed carpal bone age, deafness, and inner ear malformations. Presently, both patients present with normal psychomotor development. Additional abnormal findings include extra oral frenulum, nasal speech, and vesico-ureteral reflux. Molecular analysis in one patient excluded the Noggin gene and Filamin B (FLNB) was excluded in the other patient. Although some features are similar to spondylocarpotarsal synostosis syndrome, the exclusion of FLNB and this constellation of findings suggest a new entity, closely similar to an autosomal dominant condition reported by Forney et al. 1966 in a unique family. Identification of similarly affected patients should aid in the further elucidation of this syndrome.

Disease-associated Substitutions in the Filamin B Actin Binding Domain Confer Enhanced Actin Binding Affinity in the Absence of Major Structural Disturbance: Insights from the Crystal Structures of Filamin B Actin Binding Domains

Missense mutations in filamin B (FLNB) are associated with the autosomal dominant atelosteogenesis (AO) and the Larsen group of skeletal malformation disorders. These mutations cluster in particular FLNB protein domains and act in a presumptive gain-of-function mechanism. In contrast the loss-of-function disorder, spondylocarpotarsal synostosis syndrome, is characterised by the complete absence of FLNB. One cluster of AO missense mutations is found within the second of two calponin homology (CH) domains that create a functional actin-binding domain (ABD). This N-terminal ABD is required for filamin F–actin crosslinking activity, a crucial aspect of filamin's role of integrating cell-signalling events with cellular scaffolding and mechanoprotection. This study characterises the wild type FLNB ABD and investigates the effects of two disease-associated mutations on the structure and function of the FLNB ABD that could explain a gain-of-function mechanism for the AO diseases. We have determined high-resolution X-ray crystal structures of the human filamin B wild type ABD, plus W148R and M202V mutants. All three structures display the classic compact monomeric conformation for the ABD with the CH1 and CH2 domains in close contact. The conservation of tertiary structure in the presence of these mutations shows that the compact ABD conformation is stable to the sequence substitutions. In solution the mutant ABDs display reduced melting temperatures (by 6–7 °C) as determined by differential scanning fluorimetry. Characterisation of the wild type and mutant ABD F-actin binding activities via co-sedimentation assays shows that the mutant FLNB ABDs have increased F-actin binding affinities, with dissociation constants of 2.0 μM (W148R) and 0.56 μM (M202V), compared to the wild type ABD Kd of 7.0 μM. The increased F-actin binding affinity of the mutants presents a biochemical mechanism that differentiates the autosomal dominant gain-of-function FLNB disorders from those that arise through the complete loss of FLNB protein.

Autosomal dominant spondylocarpotarsal synostosis syndrome: Phenotypic homogeneity and genetic heterogeneity

Spondylocarpotarsal synostosis syndrome (SCT) (OMIM 272460), originally thought to be a failure of normal spine segmentation, is characterized by progressive fusion of vertebras and associates unsegmented bars, scoliosis, short stature, carpal and tarsal synostosis. Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations. Twenty-five patients have been reported. Thirteen affected individuals were siblings from six families and four of these families were consanguineous. In four of those families, Krakow et al. [Krakow et al. (2004) Nat Genet 36:405-410] found homozygosity or compound heterozygosity for mutations in the gene encoding FLNB. This confirmed autosomal recessive inheritance of the disorder. We report on two new patients (a mother and her son) representing the first case of autosomal dominant inheritance. These patients met the clinical and radiological criteria for SCT and did not present any features which could exclude this diagnosis. Molecular analysis failed to identify mutations in NOG and FLNB. SCT is therefore, genetically heterogeneous. Both dominant and autosomal recessive forms of inheritance should be considered during genetic counseling.

Spondylocarpotarsal synostosis: Long‐term follow‐up of a case due to FLNB mutations

Spondylocarpotarsal synostosis: Long‐term follow‐up of a case due to <i>FLNB</i> mutations

Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father

We report on a 5-year-old boy with spondylocarpotarsal synostosis (SCT) syndrome who presents with disproportionate short stature, thoracic scoliosis, pes planus, dental enamel hypoplasia, unilateral conductive hearing loss and mild facial dysmorphisms. Radiographs showed abnormal segmentation of the spine with block vertebrae and carpal synostosis. In addition to the typical phenotype of SCT syndrome, he showed pronounced delay of carpal bone age and bilateral epiphyseal dysplasia of the proximal femora. The patient's father has mild short stature and unilateral hip dysplasia. Molecular studies of the filamin B gene (FLNB) revealed a homozygous mutation in the index patient while both parents were heterozygous for the mutation. In this report we expand the phenotype of SCT syndrome in a patient with a causal FLNB mutation.

Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome

Spondylocarpotarsal synostosis syndrome (SCT) is an autosomal recessive disease that is characterized by short stature, and fusions of the vertebrae and carpal and tarsal bones. SCT results from homozygosity or compound heterozygosity for nonsense mutations in FLNB. FLNB encodes filamin B, a multifunctional cytoplasmic protein that plays a critical role in skeletal development. Protein extracts derived from cells of SCT patients with nonsense mutations in FLNB did not contain filamin B, demonstrating that SCT results from absence of filamin B. To understand the role of filamin B in skeletal development, an Flnb-/- mouse model was generated. The Flnb-/- mice were phenotypically similar to individuals with SCT as they exhibited short stature and similar skeletal abnormalities. Newborn Flnb-/- mice had fusions between the neural arches of the vertebrae in the cervical and thoracic spine. At postnatal day 60, the vertebral fusions were more widespread and involved the vertebral bodies as well as the neural arches. In addition, fusions were seen in sternum and carpal bones. Analysis of the Flnb-/- mice phenotype showed that an absence of filamin B causes progressive vertebral fusions, which is contrary to the previous hypothesis that SCT results from failure of normal spinal segmentation. These findings suggest that spinal segmentation can occur normally in the absence of filamin B, but the protein is required for maintenance of intervertebral, carpal and sternal joints, and the joint fusion process commences antenatally.

Filamin B represses chondrocyte hypertrophy in a Runx2/Smad3-dependent manner

FILAMIN B, which encodes a cytoplasmic actin binding protein, is mutated in several skeletal dysplasias. To further investigate how an actin binding protein influences skeletogenesis, we generated mice lacking intact Filamin B. As observed in spondylocarpotarsal synostosis syndrome patients, Filamin B mutant mice display ectopic mineralization in many cartilaginous elements. This aberrant mineralization is due to ectopic chondrocyte hypertrophy similar to that seen in mice expressing Runx2 in chondrocytes. Accordingly, removing one copy of Runx2 rescues the Filamin B mutant phenotype, indicating that Filamin B is a regulator of Runx2 function during chondrocyte differentiation. Filamin B binds Smad3, which is known to interact with Runx2. Smad3 phosphorylation is increased in the mutant mice. Thus, Filamin B inhibits Runx2 activity, at least in part, through the Smad3 pathway. Our results uncover the involvement of actin binding proteins during chondrogenesis and provide a molecular basis to a human genetic disease.

Unusual facies, thumb hypoplasia, distinctive spinal fusions and extraspinal mobility limitation, in a pair of monozygotic twins

We report a pair of monozygotic twins with unusual facies and hypoplastic thumbs associated with progressive spinal fusion and joint immobility. The radiographic features were neither consistent with the multiple synostosis syndrome of Herrmann, nor with the spondylocarpotarsal synostosis syndrome. The overall spinal radiographic abnormalities seen in our patients were suggestive of an exceptionally early onset of Forestier disease (anterolateral, perivertebral, ligament ossification), but the thumb hypoplasia and pterygium colli are not seen in that condition. We report what might be a novel genetic entity.