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).