Spondylocarpotarsal Synostosis Syndrome

Mendelian MONDO:0010094 Pathograph 14 Skeletal Dysplasia

Spondylocarpotarsal synostosis syndrome is a rare skeletal dysplasia most often modeled here as classic autosomal recessive FLNB-related SCT, with disproportionate short stature, progressive vertebral fusion, scoliosis, and carpal/tarsal synostosis. Biallelic FLNB loss-of-function should be separated diagnostically from monoallelic FLNB gain-of-function disorders and from MYH3/RFLNA-related SCT-like phenotypes.

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1
Inheritance
4
Pathophys.
16
Phenotypes
14
Pathograph
1
Genes
5
Treatments
2
References
1
Deep Research
👪

Inheritance

1
Autosomal Recessive HP:0000007
SCTSS is inherited in an autosomal recessive manner and is typically caused by biallelic loss-of-function FLNB variants.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33407338 SUPPORT Human Clinical
"BACKGROUND: Loss 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..."
This directly supports recessive inheritance and the core autosomal recessive SCT phenotype.
PMID:17635842 SUPPORT Human Clinical
"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."
This independently supports autosomal recessive inheritance and hallmark clinical features.
⚙

Pathophysiology

4
FLNB Loss-of-Function with Filamin B Deficiency
Biallelic FLNB loss-of-function variants lead to absent or markedly reduced functional filamin B, disrupting skeletal developmental programs.
Chondrocyte link
skeletal system morphogenesis link cartilage development link
Downstream
Derepressed TGF-beta/BMP Disc Ossification Loss of filamin B removes attenuation of TGF-beta/BMP signaling in intervertebral disc cells.
Show evidence (2 references)
PMID:17635842 SUPPORT In Vitro
"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."
This directly links SCT pathogenesis to filamin B deficiency from FLNB truncating variants.
PMID:29566257 SUPPORT Human Clinical
"Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far."
This supports loss-of-function FLNB as the established molecular mechanism.
Derepressed TGF-beta/BMP Disc Ossification
In FLNB deficiency, annulus fibrosus cells undergo abnormal fate conversion toward hypertrophic chondrocyte-like cells with increased TGF-beta Smad2/3 and BMP-p38 signaling, producing disc degeneration and endochondral-like ossification that drives progressive vertebral fusions.
Annulus fibrosus-like fibroblast link Hypertrophic chondrocyte-like cell link
TGF-beta receptor signaling link ↑ INCREASED BMP signaling pathway link ↑ INCREASED endochondral-like ossification of intervertebral discs link ↑ INCREASED
Downstream
Progressive Vertebral and Carpal Joint Fusion Derepressed signaling and disc ossification promote progressive intervertebral fusion.
Show evidence (2 references)
PMID:27019229 SUPPORT Model Organism
"We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf."
Flnb knockout mouse discs show annulus fibrosus cell fate conversion with increased TGF-beta/BMP signaling, linking FLNB loss to the signaling mechanism requested by the review.
PMID:27019229 SUPPORT Model Organism
"This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue."
This supports the disc-ossification step that mechanistically connects altered FLNB signaling to vertebral fusion.
Impaired FLNB Dimerization and Protein Stability
Certain truncating FLNB variants impair dimer formation and reduce protein stability, reinforcing a loss-of-function molecular mechanism.
Chondrocyte link
skeletal system morphogenesis link
Show evidence (2 references)
PMID:28145000 SUPPORT In Vitro
"The mutant p.S2542Lfs* 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells."
This provides direct in vitro evidence of impaired FLNB dimerization.
PMID:28145000 SUPPORT In Vitro
"The p.S2542Lfs* 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus."
This supports decreased FLNB protein stability and mislocalization.
Progressive Vertebral and Carpal Joint Fusion
FLNB deficiency drives progressive vertebral and carpal joint fusion, consistent with failure of joint maintenance processes and antenatal-onset fusion biology.
Chondrocyte link
embryonic skeletal joint development link ossification link
Show evidence (2 references)
PMID:17635842 SUPPORT Model Organism
"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."
This supports progressive fusion as a key disease process in FLNB deficiency.
PMID:17635842 SUPPORT Model Organism
"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."
This supports a joint-maintenance failure mechanism with early fusion onset.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spondylocarpotarsal Synostosis Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

16
Ear 1
Hearing Impairment Hearing impairment (HP:0000365)
Show evidence (2 references)
PMID:18470895 SUPPORT Human Clinical
"Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations."
This review supports hearing impairment as a variable manifestation and shows that both sensorineural and mixed forms occur.
PMID:18257094 SUPPORT Human Clinical
"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."
This adds direct evidence that conductive hearing loss can also occur in SCTSS.
Head and Neck 3
Short Neck Short neck (HP:0000470)
Show evidence (1 reference)
PMID:37781000 SUPPORT Human Clinical
"Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula."
This supports short neck as part of the variable axial skeletal phenotype.
Enamel Hypoplasia Enamel hypoplasia (HP:0006297)
Show evidence (2 references)
PMID:18470895 SUPPORT Human Clinical
"Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations."
This review supports dental enamel hypoplasia as a variable manifestation of SCTSS.
PMID:37781000 SUPPORT Human Clinical
"Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia."
This independently supports enamel hypoplasia as part of the SCTSS phenotype spectrum.
Cleft Palate Cleft palate (HP:0000175)
Show evidence (2 references)
PMID:18470895 SUPPORT Human Clinical
"Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations."
This review supports cleft palate as a variable manifestation of SCTSS.
PMID:37781000 SUPPORT Human Clinical
"Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia."
This independently supports cleft palate in the reported phenotype spectrum.
Limbs 5
Carpal Synostosis Carpal synostosis (HP:0009702)
Show evidence (1 reference)
PMID:29566257 SUPPORT Human Clinical
"Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones."
This supports carpal fusion/synostosis as a core phenotype.
Delayed Ossification of Carpal Bones Delayed ossification of carpal bones (HP:0001216)
Show evidence (2 references)
PMID:39086440 SUPPORT Human Clinical
"All cases presented with spinal fusion with variable severity and location, carpal bones coalition, and also delay in carpal ossification."
This cohort directly supports delayed ossification of the carpal bones.
PMID:18257094 SUPPORT Human Clinical
"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."
This independently supports delayed carpal ossification in a molecularly confirmed case.
Tarsal Synostosis Tarsal synostosis (HP:0008368)
Show evidence (1 reference)
PMID:29566257 SUPPORT Human Clinical
"Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones."
This directly supports tarsal synostosis.
Clinodactyly Clinodactyly (HP:0030084)
Show evidence (2 references)
PMID:18470895 SUPPORT Human Clinical
"Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations."
This review supports clinodactyly as a variable manifestation of SCTSS.
PMID:39086440 SUPPORT Human Clinical
"Other findings included clinodactyly, joint limitation without bone fusion, neurosensorial hearing loss, and ophthalmological compromise."
This independently supports clinodactyly in a modern molecular cohort.
Pes Planus Pes planus (HP:0001763)
Show evidence (1 reference)
PMID:18257094 SUPPORT Human Clinical
"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."
This supports pes planus as part of the variable skeletal phenotype.
Musculoskeletal 4
Vertebral Fusion Vertebral fusion (HP:0002948)
Show evidence (1 reference)
PMID:18470895 SUPPORT Human Clinical
"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."
This review directly supports vertebral fusion as a defining human phenotype.
Scoliosis Scoliosis (HP:0002650)
Show evidence (1 reference)
PMID:28145000 SUPPORT Human Clinical
"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."
This directly supports scoliosis as a core clinical feature.
Hyperlordosis Hyperlordosis (HP:0003307)
Show evidence (1 reference)
PMID:28145000 SUPPORT Human Clinical
"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."
This supports lordotic spinal deformity in SCTSS.
Joint Stiffness Joint stiffness (HP:0001387)
Show evidence (2 references)
PMID:37781000 SUPPORT Human Clinical
"Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia."
This supports joint stiffness as a recurrent but variable phenotype.
PMID:39086440 SUPPORT Human Clinical
"Other findings included clinodactyly, joint limitation without bone fusion, neurosensorial hearing loss, and ophthalmological compromise."
This independently supports joint limitation in the SCTSS phenotype spectrum.
Growth 1
Short Stature Short stature (HP:0004322)
Show evidence (1 reference)
PMID:29566257 SUPPORT Human Clinical
"Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones."
This directly supports disproportionate short stature.
Other 2
Block Vertebrae Block vertebrae (HP:0003305)
Show evidence (1 reference)
PMID:10766994 SUPPORT Human Clinical
"Spondylocarpotarsal synostosis syndrome is a recently delineated autosomal recessive condition comprising short stature with short trunk, failure of normal spine segmentation resulting in block vertebrae and fusion of posterior elements, carpal and/or tarsal coalition, scoliosis, lordosis, pes..."
This directly supports block vertebrae as part of the characteristic spinal phenotype.
Round Face Round face (HP:0000311)
Show evidence (1 reference)
PMID:39086440 SUPPORT Human Clinical
"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."
This supports round face as a recurring mild facial feature in a pediatric SCTSS cohort.
🧬

Genetic Associations

1
FLNB Biallelic Truncating Variants (Causative)
Show evidence (4 references)
PMID:17635842 SUPPORT Human Clinical
"SCT results from homozygosity or compound heterozygosity for nonsense mutations in FLNB."
This directly supports biallelic FLNB nonsense variants as causative.
PMID:29566257 SUPPORT Human Clinical
"Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition."
This supports truncating FLNB variants as a defining molecular feature.
PMID:39086440 SUPPORT Human Clinical
"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."
This provides additional cohort-level evidence for truncating biallelic FLNB variants.
+ 1 more reference
💊

Treatments

5
Cervical Spine Evaluation and Stabilization
Action: surgical procedure MAXO:0000004
Located in: vertebral column UBERON:0001130
Cervical spine instability and cord-compression risk should be actively assessed, especially before anesthesia or major procedures. Asymptomatic infants with instability may require posterior arthrodesis, and myelopathic signs warrant urgent spine/neurosurgical evaluation for decompression and circumferential stabilization.
Target Phenotypes: Cervical spine instability ↗ Vertebral fusion ↗
Show evidence (3 references)
PMID:10766994 SUPPORT Human Clinical
"This brings the number of well-documented cases of spondylocar- potarsal synostosis to 19, and is the first documenting cervical spine instability. Careful evaluation for this complication should be considered in other cases."
This SCT-specific report supports careful cervical-instability evaluation.
PMID:20301736 SUPPORT Other
"Cervical spine instability in asymptomatic infants can be successfully managed with posterior arthrodesis. Function can be stabilized (if not improved) in infants with myelopathic signs by a combination of anterior decompression and circumferential arthrodesis."
GeneReviews directly supports surgical stabilization and decompression strategies for cervical instability.
url:https://www.ncbi.nlm.nih.gov/books/NBK2534/ SUPPORT Other
"Evaluate cervical spine for instability prior to general anesthesia."
The full GeneReviews evaluation table adds the pre-anesthesia cervical spine safety step requested in the review.
Orthopedic Spine and Scoliosis Surveillance
Action: supportive care MAXO:0000950
Orthopedic follow-up should track progressive vertebral fusion, scoliosis or lordosis, clubfoot or pes planus, and functional impact over growth. Imaging and referral intensity should reflect progression, pain, neurologic signs, and operative planning needs.
Target Phenotypes: Scoliosis ↗ Vertebral fusion ↗ Pes planus ↗
Show evidence (2 references)
PMID:20301736 SUPPORT Other
"Scoliosis and clubfeet are managed in a routine manner."
GeneReviews supports orthopedic management for spinal curvature and clubfoot manifestations.
PMID:20301736 SUPPORT Other
"Surveillance: Annual orthopedic evaluation for progressive scoliosis; feeding and growth assessment for those with cleft palate by a multidisciplinary team; annual audiologic and dental evaluations."
GeneReviews identifies annual orthopedic surveillance for progressive scoliosis as a core monitoring priority.
Physical Therapy and Mobility Support
Action: physical therapy MAXO:0000011
Physical therapy, range-of-motion support, gait assessment, and adaptive mobility planning are appropriate when joint stiffness, pes planus, spinal deformity, or pain limits activity.
Target Phenotypes: Joint stiffness ↗ Pes planus ↗
Show evidence (1 reference)
PMID:10766994 SUPPORT Human Clinical
"Spondylocarpotarsal synostosis syndrome is a recently delineated autosomal recessive condition comprising short stature with short trunk, failure of normal spine segmentation resulting in block vertebrae and fusion of posterior elements, carpal and/or tarsal coalition, scoliosis, lordosis, pes..."
The SCT phenotype includes pes planus and decreased range of motion, supporting targeted mobility and range-of-motion management.
Audiologic, Craniofacial, and Dental Management
Action: supportive care MAXO:0000950
Hearing loss, cleft palate, and enamel hypoplasia should prompt audiology, craniofacial/feeding, dental, and orthodontic care as needed, with annual hearing and dental surveillance.
Target Phenotypes: Hearing impairment ↗ Cleft palate ↗ Enamel hypoplasia ↗
Show evidence (2 references)
PMID:20301736 SUPPORT Other
"When possible, cleft palate and hearing loss are best managed by multidisciplinary teams."
GeneReviews supports multidisciplinary craniofacial and hearing-loss care.
PMID:20301736 SUPPORT Other
"Surveillance: Annual orthopedic evaluation for progressive scoliosis; feeding and growth assessment for those with cleft palate by a multidisciplinary team; annual audiologic and dental evaluations."
GeneReviews supports annual audiologic and dental evaluation and feeding/growth assessment when cleft palate is present.
Genetic Counseling
Action: genetic counseling MAXO:0000079
Genetic counseling should cover autosomal recessive FLNB-SCT recurrence risk, parental carrier testing, heterozygote testing for at-risk relatives, and prenatal or preimplantation testing once familial variants are known. Counseling should also explain the distinction from autosomal dominant FLNB gain-of-function disorders and MYH3-related SCT-like disease.
Show evidence (2 references)
PMID:20301736 SUPPORT Other
"FLNB-SCT is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FLNB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one..."
GeneReviews supports autosomal recessive recurrence-risk counseling for FLNB-SCT families.
PMID:20301736 SUPPORT Other
"Once the FLNB pathogenic variant(s) have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
GeneReviews supports familial-variant testing and reproductive testing options once the causative variants are known.
{ }

Source YAML

click to show 
name: Spondylocarpotarsal Synostosis Syndrome
creation_date: '2026-03-04T20:22:00Z'
updated_date: '2026-04-19T07:27:31Z'
category: Mendelian
description: >
  Spondylocarpotarsal synostosis syndrome is a rare skeletal dysplasia most
  often modeled here as classic autosomal recessive FLNB-related SCT, with
  disproportionate short stature, progressive vertebral fusion, scoliosis, and
  carpal/tarsal synostosis. Biallelic FLNB loss-of-function should be separated
  diagnostically from monoallelic FLNB gain-of-function disorders and from
  MYH3/RFLNA-related SCT-like phenotypes.
disease_term:
  preferred_term: spondylocarpotarsal synostosis syndrome
  term:
    id: MONDO:0010094
    label: spondylocarpotarsal synostosis syndrome
parents:
- Skeletal Dysplasia
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    SCTSS is inherited in an autosomal recessive manner and is typically caused by
    biallelic loss-of-function FLNB variants.
  evidence:
  - reference: PMID:33407338
    reference_title: "Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BACKGROUND: Loss 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.
    explanation: >-
      This directly supports recessive inheritance and the core autosomal recessive SCT phenotype.
  - reference: PMID:17635842
    reference_title: "Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This independently supports autosomal recessive inheritance and hallmark clinical features.
prevalence:
- population: Published literature cohorts worldwide
  percentage: approximately 25 historically reported patients
  notes: >-
    No population-based prevalence studies were identified in PubMed abstracts.
    The best available epidemiology remains literature-based case counting: a
    2008 review summarized 25 reported patients, and a 2018 molecular series
    noted nine previously reported FLNB-positive families before adding 10 more
    affected individuals from seven new families.
  evidence:
  - reference: PMID:18470895
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This review gives a clear historical case-count benchmark for the extreme
      rarity of spondylocarpotarsal synostosis syndrome.
  - reference: PMID:29566257
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far. We report clinical features of 10 additional patients from 7 families with spondylocarpotarsal synostosis syndrome due to 7 novel deleterious variants in FLNB, thus expanding the clinical and molecular repertoire of spondylocarpotarsal synostosis syndrome.
    explanation: >-
      This later molecular series confirms that published epidemiology remained
      limited to a very small number of families and case reports.
pathophysiology:
- name: FLNB Loss-of-Function with Filamin B Deficiency
  description: >
    Biallelic FLNB loss-of-function variants lead to absent or markedly reduced
    functional filamin B, disrupting skeletal developmental programs.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: skeletal system morphogenesis
    term:
      id: GO:0048705
      label: skeletal system morphogenesis
  - preferred_term: cartilage development
    term:
      id: GO:0051216
      label: cartilage development
  evidence:
  - reference: PMID:17635842
    reference_title: "Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      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.
    explanation: >-
      This directly links SCT pathogenesis to filamin B deficiency from FLNB truncating variants.
  - reference: PMID:29566257
    reference_title: "Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic loss-of-function variants in FLNB are known to cause spondylocarpotarsal synostosis syndrome and 9 families and 9 pathogenic variants have been reported so far.
    explanation: >-
      This supports loss-of-function FLNB as the established molecular mechanism.
  downstream:
  - target: Derepressed TGF-beta/BMP Disc Ossification
    description: >
      Loss of filamin B removes attenuation of TGF-beta/BMP signaling in
      intervertebral disc cells.
    causal_link_type: DIRECT
- name: Derepressed TGF-beta/BMP Disc Ossification
  description: >
    In FLNB deficiency, annulus fibrosus cells undergo abnormal fate conversion
    toward hypertrophic chondrocyte-like cells with increased TGF-beta Smad2/3
    and BMP-p38 signaling, producing disc degeneration and endochondral-like
    ossification that drives progressive vertebral fusions.
  cell_types:
  - preferred_term: Annulus fibrosus-like fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Hypertrophic chondrocyte-like cell
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: INCREASED
  - preferred_term: endochondral-like ossification of intervertebral discs
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: INCREASED
  evidence:
  - reference: PMID:27019229
    reference_title: "TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf.
    explanation: >-
      Flnb knockout mouse discs show annulus fibrosus cell fate conversion with
      increased TGF-beta/BMP signaling, linking FLNB loss to the signaling
      mechanism requested by the review.
  - reference: PMID:27019229
    reference_title: "TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue.
    explanation: >-
      This supports the disc-ossification step that mechanistically connects
      altered FLNB signaling to vertebral fusion.
  downstream:
  - target: Progressive Vertebral and Carpal Joint Fusion
    description: >
      Derepressed signaling and disc ossification promote progressive
      intervertebral fusion.
    causal_link_type: DIRECT
- name: Impaired FLNB Dimerization and Protein Stability
  description: >
    Certain truncating FLNB variants impair dimer formation and reduce protein
    stability, reinforcing a loss-of-function molecular mechanism.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: skeletal system morphogenesis
    term:
      id: GO:0048705
      label: skeletal system morphogenesis
  evidence:
  - reference: PMID:28145000
    reference_title: "Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant p.S2542Lfs* 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells.
    explanation: >-
      This provides direct in vitro evidence of impaired FLNB dimerization.
  - reference: PMID:28145000
    reference_title: "Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The p.S2542Lfs* 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus.
    explanation: >-
      This supports decreased FLNB protein stability and mislocalization.
- name: Progressive Vertebral and Carpal Joint Fusion
  description: >
    FLNB deficiency drives progressive vertebral and carpal joint fusion,
    consistent with failure of joint maintenance processes and antenatal-onset
    fusion biology.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: embryonic skeletal joint development
    term:
      id: GO:0072498
      label: embryonic skeletal joint development
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
  evidence:
  - reference: PMID:17635842
    reference_title: "Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      This supports progressive fusion as a key disease process in FLNB deficiency.
  - reference: PMID:17635842
    reference_title: "Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      This supports a joint-maintenance failure mechanism with early fusion onset.
genetic:
- name: FLNB Biallelic Truncating Variants
  association: Causative
  gene_term:
    preferred_term: FLNB
    term:
      id: hgnc:3755
      label: FLNB
  notes: >
    Biallelic truncating FLNB variants are the major cause of classic recessive
    FLNB-SCT. This loss-of-function mechanism is distinct from monoallelic
    gain-of-function FLNB disorders such as Larsen syndrome and
    atelosteogenesis, while clinically overlapping SCT phenotypes can also
    involve other genes such as MYH3 and RFLNA.
  evidence:
  - reference: PMID:17635842
    reference_title: "Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCT results from homozygosity or compound heterozygosity for nonsense mutations in FLNB.
    explanation: >-
      This directly supports biallelic FLNB nonsense variants as causative.
  - reference: PMID:29566257
    reference_title: "Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition.
    explanation: >-
      This supports truncating FLNB variants as a defining molecular feature.
  - reference: PMID:39086440
    reference_title: "Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This provides additional cohort-level evidence for truncating biallelic FLNB variants.
  - reference: PMID:14991055
    reference_title: "Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721).
    explanation: >-
      This foundational FLNB paper supports both the biallelic truncating
      FLNB-SCT mechanism and its distinction from dominant FLNB missense
      skeletal dysplasias.
phenotypes:
- name: Short Stature
  description: >
    Disproportionate short stature is a core growth phenotype in SCTSS.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:29566257
    reference_title: "Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones.
    explanation: >-
      This directly supports disproportionate short stature.
- name: Short Neck
  description: >
    A short neck has been reported in some affected individuals with FLNB-related
    SCTSS.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: PMID:37781000
    reference_title: "A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula.
    explanation: >-
      This supports short neck as part of the variable axial skeletal phenotype.
- name: Vertebral Fusion
  description: >
    Vertebral fusion is a defining axial skeletal abnormality in SCTSS.
  phenotype_term:
    preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  evidence:
  - reference: PMID:18470895
    reference_title: "Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This review directly supports vertebral fusion as a defining human phenotype.
- name: Block Vertebrae
  description: >
    Block vertebrae are part of the radiographic spinal involvement in SCTSS.
  phenotype_term:
    preferred_term: Block vertebrae
    term:
      id: HP:0003305
      label: Block vertebrae
  evidence:
  - reference: PMID:10766994
    reference_title: "Spondylocarpotarsal synostosis syndrome and cervical instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylocarpotarsal synostosis syndrome is a recently delineated autosomal recessive condition comprising short stature with short trunk, failure of normal spine segmentation resulting in block vertebrae and fusion of posterior elements, carpal and/or tarsal coalition, scoliosis, lordosis, pes planus, dental enamel hypoplasia, decreased range of motion or dislocation of the elbow, renal anomalies, and hearing loss.
    explanation: >-
      This directly supports block vertebrae as part of the characteristic spinal phenotype.
- name: Carpal Synostosis
  description: >
    Carpal coalition or synostosis is a characteristic appendicular imaging finding.
  phenotype_term:
    preferred_term: Carpal synostosis
    term:
      id: HP:0009702
      label: Carpal synostosis
  evidence:
  - reference: PMID:29566257
    reference_title: "Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones.
    explanation: >-
      This supports carpal fusion/synostosis as a core phenotype.
- name: Delayed Ossification of Carpal Bones
  description: >
    Delayed carpal ossification has been reported in some molecularly confirmed
    cases.
  phenotype_term:
    preferred_term: Delayed ossification of carpal bones
    term:
      id: HP:0001216
      label: Delayed ossification of carpal bones
  evidence:
  - reference: PMID:39086440
    reference_title: "Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases presented with spinal fusion with variable severity and location, carpal bones coalition, and also delay in carpal ossification.
    explanation: >-
      This cohort directly supports delayed ossification of the carpal bones.
  - reference: PMID:18257094
    reference_title: "Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This independently supports delayed carpal ossification in a molecularly confirmed case.
- name: Tarsal Synostosis
  description: >
    Tarsal coalition or synostosis is a recurrent lower-limb skeletal feature.
  phenotype_term:
    preferred_term: Tarsal synostosis
    term:
      id: HP:0008368
      label: Tarsal synostosis
  evidence:
  - reference: PMID:29566257
    reference_title: "Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylocarpotarsal synostosis syndrome is characterized by disproportionate short stature, vertebral anomalies and fusion of carpal and tarsal bones.
    explanation: >-
      This directly supports tarsal synostosis.
- name: Scoliosis
  description: >
    Scoliosis is part of the characteristic vertebral deformity pattern in SCTSS.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:28145000
    reference_title: "Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This directly supports scoliosis as a core clinical feature.
- name: Hyperlordosis
  description: >
    Increased spinal lordosis is part of the vertebral deformity spectrum.
  phenotype_term:
    preferred_term: Hyperlordosis
    term:
      id: HP:0003307
      label: Hyperlordosis
  evidence:
  - reference: PMID:28145000
    reference_title: "Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This supports lordotic spinal deformity in SCTSS.
- name: Hearing Impairment
  description: >
    Hearing loss is variably reported and may be conductive, mixed, or sensorineural.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:18470895
    reference_title: "Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations.
    explanation: >-
      This review supports hearing impairment as a variable manifestation and shows that both sensorineural and mixed forms occur.
  - reference: PMID:18257094
    reference_title: "Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This adds direct evidence that conductive hearing loss can also occur in SCTSS.
- name: Joint Stiffness
  description: >
    Joint stiffness or limitation without bone fusion is a variable musculoskeletal
    feature.
  phenotype_term:
    preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  evidence:
  - reference: PMID:37781000
    reference_title: "A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia.
    explanation: >-
      This supports joint stiffness as a recurrent but variable phenotype.
  - reference: PMID:39086440
    reference_title: "Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings included clinodactyly, joint limitation without bone fusion, neurosensorial hearing loss, and ophthalmological compromise.
    explanation: >-
      This independently supports joint limitation in the SCTSS phenotype spectrum.
- name: Clinodactyly
  description: >
    Clinodactyly is a variable appendicular skeletal feature in SCTSS.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:18470895
    reference_title: "Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations.
    explanation: >-
      This review supports clinodactyly as a variable manifestation of SCTSS.
  - reference: PMID:39086440
    reference_title: "Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings included clinodactyly, joint limitation without bone fusion, neurosensorial hearing loss, and ophthalmological compromise.
    explanation: >-
      This independently supports clinodactyly in a modern molecular cohort.
- name: Pes Planus
  description: >
    Pes planus has been reported in some affected individuals with SCTSS.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:18257094
    reference_title: "Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This supports pes planus as part of the variable skeletal phenotype.
- name: Enamel Hypoplasia
  description: >
    Dental enamel hypoplasia is a recurrent but variable extra-axial feature.
  phenotype_term:
    preferred_term: Dental enamel hypoplasia
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  evidence:
  - reference: PMID:18470895
    reference_title: "Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations.
    explanation: >-
      This review supports dental enamel hypoplasia as a variable manifestation of SCTSS.
  - reference: PMID:37781000
    reference_title: "A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia.
    explanation: >-
      This independently supports enamel hypoplasia as part of the SCTSS phenotype spectrum.
- name: Cleft Palate
  description: >
    Cleft palate is reported in a subset of SCTSS cases.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:18470895
    reference_title: "Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations.
    explanation: >-
      This review supports cleft palate as a variable manifestation of SCTSS.
  - reference: PMID:37781000
    reference_title: "A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia.
    explanation: >-
      This independently supports cleft palate in the reported phenotype spectrum.
- name: Round Face
  description: >
    Round face has been reported as a mild craniofacial feature in some cohorts.
  phenotype_term:
    preferred_term: Round face
    term:
      id: HP:0000311
      label: Round face
  evidence:
  - reference: PMID:39086440
    reference_title: "Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This supports round face as a recurring mild facial feature in a pediatric SCTSS cohort.
diagnosis:
- name: Clinical-Radiographic Pattern with FLNB Exome Confirmation
  description: >
    Diagnosis is established using characteristic clinical-radiographic findings
    including disproportionate short trunk/short stature, vertebral fusion or
    segmentation-like defects across cervical, thoracic, or lumbar spine,
    scoliosis progression, and carpal/tarsal coalition. Molecular testing should
    confirm biallelic FLNB loss-of-function variants, include copy-number-sensitive
    methods for intragenic deletions, and distinguish classic FLNB-SCT from
    MYH3/RFLNA-related SCT-like disorders and dominant FLNB gain-of-function
    disorders.
  evidence:
  - reference: PMID:29566257
    reference_title: "Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our report validates key clinical (fused thoracic vertebrae and carpal and tarsal coalition) and molecular (truncating variants in FLNB) characteristics of this condition.
    explanation: >-
      This supports the combined radiographic and molecular diagnostic framework.
  - reference: PMID:33407338
    reference_title: "Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family.
    explanation: >-
      This supports exome-based molecular confirmation and segregation testing.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of FLNB-SCT is established in a proband by identification of biallelic loss-of-function pathogenic variants in FLNB by molecular genetic testing."
    explanation: >-
      GeneReviews baseline: spondylocarpotarsal synostosis (FLNB-SCT) is
      confirmed by biallelic loss-of-function FLNB variants.
  - reference: PMID:33916386
    reference_title: "Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases highlight the need for copy number sensitive methods to be utilized in order to be comprehensive in the search for a molecular diagnosis in individuals with a clinical diagnosis of SCT.
    explanation: >-
      This supports adding deletion/duplication or other copy-number-sensitive
      FLNB testing to the diagnostic workup.
  - reference: PMID:28145000
    reference_title: "Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively.
    explanation: >-
      This supports diagnostic separation of autosomal recessive FLNB-SCT from
      dominant MYH3-related SCT-like disease.
treatments:
- name: Cervical Spine Evaluation and Stabilization
  description: >
    Cervical spine instability and cord-compression risk should be actively
    assessed, especially before anesthesia or major procedures. Asymptomatic
    infants with instability may require posterior arthrodesis, and myelopathic
    signs warrant urgent spine/neurosurgical evaluation for decompression and
    circumferential stabilization.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
    located_in:
      preferred_term: vertebral column
      term:
        id: UBERON:0001130
        label: vertebral column
  target_phenotypes:
  - preferred_term: Cervical spine instability
    term:
      id: HP:0010646
      label: Cervical spine instability
  - preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  evidence:
  - reference: PMID:10766994
    reference_title: "Spondylocarpotarsal synostosis syndrome and cervical instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This brings the number of well-documented cases of spondylocar- potarsal synostosis to 19, and is the first documenting cervical spine instability. Careful evaluation for this complication should be considered in other cases.
    explanation: >-
      This SCT-specific report supports careful cervical-instability evaluation.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cervical spine instability in asymptomatic infants can be successfully managed with posterior arthrodesis. Function can be stabilized (if not improved) in infants with myelopathic signs by a combination of anterior decompression and circumferential arthrodesis.
    explanation: >-
      GeneReviews directly supports surgical stabilization and decompression
      strategies for cervical instability.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK2534/
    reference_title: FLNB-Related Disorders - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Evaluate cervical spine for instability prior to general anesthesia."
    explanation: >-
      The full GeneReviews evaluation table adds the pre-anesthesia cervical
      spine safety step requested in the review.
- name: Orthopedic Spine and Scoliosis Surveillance
  description: >
    Orthopedic follow-up should track progressive vertebral fusion, scoliosis or
    lordosis, clubfoot or pes planus, and functional impact over growth. Imaging
    and referral intensity should reflect progression, pain, neurologic signs,
    and operative planning needs.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  - preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  - preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Scoliosis and clubfeet are managed in a routine manner.
    explanation: >-
      GeneReviews supports orthopedic management for spinal curvature and
      clubfoot manifestations.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Surveillance: Annual orthopedic evaluation for progressive scoliosis; feeding and growth assessment for those with cleft palate by a multidisciplinary team; annual audiologic and dental evaluations.
    explanation: >-
      GeneReviews identifies annual orthopedic surveillance for progressive
      scoliosis as a core monitoring priority.
- name: Physical Therapy and Mobility Support
  description: >
    Physical therapy, range-of-motion support, gait assessment, and adaptive
    mobility planning are appropriate when joint stiffness, pes planus, spinal
    deformity, or pain limits activity.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  - preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:10766994
    reference_title: "Spondylocarpotarsal synostosis syndrome and cervical instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylocarpotarsal synostosis syndrome is a recently delineated autosomal recessive condition comprising short stature with short trunk, failure of normal spine segmentation resulting in block vertebrae and fusion of posterior elements, carpal and/or tarsal coalition, scoliosis, lordosis, pes planus, dental enamel hypoplasia, decreased range of motion or dislocation of the elbow, renal anomalies, and hearing loss.
    explanation: >-
      The SCT phenotype includes pes planus and decreased range of motion,
      supporting targeted mobility and range-of-motion management.
- name: Audiologic, Craniofacial, and Dental Management
  description: >
    Hearing loss, cleft palate, and enamel hypoplasia should prompt audiology,
    craniofacial/feeding, dental, and orthodontic care as needed, with annual
    hearing and dental surveillance.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  - preferred_term: Enamel hypoplasia
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      When possible, cleft palate and hearing loss are best managed by multidisciplinary teams.
    explanation: >-
      GeneReviews supports multidisciplinary craniofacial and hearing-loss care.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Surveillance: Annual orthopedic evaluation for progressive scoliosis; feeding and growth assessment for those with cleft palate by a multidisciplinary team; annual audiologic and dental evaluations.
    explanation: >-
      GeneReviews supports annual audiologic and dental evaluation and
      feeding/growth assessment when cleft palate is present.
- name: Genetic Counseling
  description: >
    Genetic counseling should cover autosomal recessive FLNB-SCT recurrence risk,
    parental carrier testing, heterozygote testing for at-risk relatives, and
    prenatal or preimplantation testing once familial variants are known. Counseling
    should also explain the distinction from autosomal dominant FLNB gain-of-function
    disorders and MYH3-related SCT-like disease.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNB-SCT is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FLNB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial FLNB pathogenic variants.
    explanation: >-
      GeneReviews supports autosomal recessive recurrence-risk counseling for
      FLNB-SCT families.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Once the FLNB pathogenic variant(s) have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
    explanation: >-
      GeneReviews supports familial-variant testing and reproductive testing
      options once the causative variants are known.
notes: >
  Variants in FLNB, MYH3, and RFLNA have been implicated in SCT phenotypes;
  classic recessive SCTSS is most often associated with biallelic FLNB
  loss-of-function variants.
references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK2534/
  title: FLNB-Related Disorders - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301736
  title: "FLNB-Related Disorders."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

2
url:https://www.ncbi.nlm.nih.gov/books/NBK2534/
FLNB-Related Disorders - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
PMID:20301736
FLNB-Related Disorders.
No top-level findings curated for this source.

Deep Research

1
Manual Pubmed Review ▸
Spondylocarpotarsal Synostosis Syndrome (SCTSS): Mechanistic Summary
n/a 6 citations 2026-03-04T20:48:00Z

Spondylocarpotarsal Synostosis Syndrome (SCTSS): Mechanistic Summary

Genetics and inheritance

SCTSS is primarily an autosomal recessive skeletal dysplasia caused by biallelic loss-of-function variants in FLNB (PMID:33407338; PMID:17635842; PMID:29566257). Truncating variants are common across reported families and can reduce/abolish functional filamin B (PMID:28145000; PMID:29566257; PMID:39086440).

Pathophysiology

FLNB loss-of-function leads to filamin B deficiency and abnormal skeletal development programs affecting vertebral and appendicular joints (PMID:17635842). Functional studies show that certain SCTSS variants impair FLNB dimerization and reduce protein levels, supporting a direct protein dysfunction mechanism (PMID:28145000). Mouse knockout data indicate progressive vertebral fusion due to impaired joint maintenance rather than primary segmentation failure (PMID:17635842).

Hallmark phenotype profile

Core manifestations include disproportionate short stature, vertebral anomalies/fusion, and carpal/tarsal synostosis with frequent scoliosis/lordosis (PMID:28145000; PMID:29566257). Additional variable features include facial dysmorphism, hearing impairment, and delayed carpal ossification in some cohorts (PMID:39086440; PMID:18257094).

Disease heterogeneity context

While FLNB biallelic LOF is the dominant mechanism for classic recessive SCTSS, related SCT phenotypes may involve other genes (e.g., MYH3, RFLNA), supporting locus heterogeneity in clinically overlapping presentations (PMID:39086440; PMID:28145000).

References

  • PMID:17635842
  • PMID:28145000
  • PMID:29566257
  • PMID:33407338
  • PMID:39086440
  • PMID:18257094