Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in <i>FLNB</i>

Salian, Sujith Raj; Shukla, Anju; Shah, Hitesh; Bhat, Sushma N; Bhat, Vineel; Nampoothiri, Sheela; Shenoy, Rajgopal; Phadke, Shubha R.; Hariharan, Sankar Vaikom; Girisha, Katta M.

doi:10.1111/cge.13252

Cited by 12 publications

(12 citation statements)

References 17 publications

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“…SCT caused by pathogenic FLNB variants are rare findings and only a few of these patients have had molecular confirmation, with the largest series reported data for seven families. 3 In this study, three different FLNB variants, one nonsense and two frameshift, were detected in the four families, all of which are predicted to result in a truncated protein or degraded by nonsense mediated decay. Interestingly, all cases had at least one copy of the nonsense variant, c.1128C> G; p. (Tyr376*).…”

Section: Discussionmentioning

confidence: 68%

Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 68%

Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome

et al. 2022

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“…It is important to assess patient stature and lower extremity length and alignment because foot pathology can correlate with other lower extremity problems and global syndromes, such as fibular hemimelia, tarsal-carpal coalition syndrome, and other symphalangism spectrum disorders. [7][8][9][10] The clinician should observe for coronal plane pelvic tilt, asymmetry of muscle bulk, and a compensatory equinus foot position in the setting of a leg length discrepancy.…”

Section: Physical Examinationmentioning

confidence: 99%

Evaluation and Management of Adolescents With a Stiff Flatfoot

Ford

Zide

Riccio

2022

J Am Acad Orthop Surg

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While flatfeet are normal in children, persistence into adolescence with associated pain or asymmetry warrants additional evaluation. Rigidity of a flatfoot deformity, whether a clinical report or evident on examination, should raise suspicion for pathology. The differential diagnosis includes tarsal coalition, neurogenic planovalgus, and peroneal spasticity. History must include pointed inquiry into birth and neurologic histories to probe for a source of central spasticity. Examination must include standing assessment of hindfoot and midfoot alignment. Hindfoot rigidity may be assessed by the double limb heel rise test and manual examination. Radiographs should include standing ankle (anterior-posterior and mortise) and whole foot (anterior-posterior, external rotation oblique, and lateral) images. Magnetic resonance imaging is more sensitive for identifying coalitions and better characterizes adjacent cartilage, subchondral edema, and tendon pathology, yet CT better characterizes the anatomy of a bony coalition. Conservative treatments are pathology-dependent and play a more prominent role in neurogenic or peroneal spastic flatfoot. Surgical management of coalitions is centered on coalition resection coupled with arthrodesis in the case of a talocalcaneal coalition with a dysplastic subtalar joint; concomitant planovalgus reconstruction is considered on a case-by-case basis.

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“…Spondylocarpotarsal synostosis (SCT) is an autosomal recessive skeletal disorder characterized by carpal/tarsal bone and vertebrae fusions, delayed endochondral ossification, and short stature 1 – 6 . The majority of SCT cases result from biallelic nonsense mutations in the gene that encodes filamin B ( FLNB ) 2 , 5 – 7 . SCT is progressive; there is radiographic evidence of mild disc narrowing at birth ultimately advancing to severe spinal scoliosis, kyphosis, and lordosis due to premature vertebral fusions 1 , 2 , 5 , 6 , 8 .…”

Section: Introductionmentioning

confidence: 99%

“…The majority of SCT cases result from biallelic nonsense mutations in the gene that encodes filamin B ( FLNB ) 2 , 5 – 7 . SCT is progressive; there is radiographic evidence of mild disc narrowing at birth ultimately advancing to severe spinal scoliosis, kyphosis, and lordosis due to premature vertebral fusions 1 , 2 , 5 , 6 , 8 .…”

Section: Introductionmentioning

confidence: 99%

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

Zieba¹,

Forlenza²,

Heard³

et al. 2022

Bone Res

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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.

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Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB

Cited by 12 publications

References 17 publications

Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome

Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome

Evaluation and Management of Adolescents With a Stiff Flatfoot

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

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