Larsen Syndrome (FLNB): Mechanistic Summary
Genetics and inheritance
Larsen syndrome is an autosomal dominant skeletal dysplasia most commonly caused by heterozygous missense or small in-frame deletion variants in FLNB (PMID:16801345; PMID:27048506). Mutation distribution is non-random, with hotspot clustering in the actin-binding domain and filamin repeat regions (PMID:16648377; PMID:16801345; PMID:27048506).
Pathophysiology
FLNB encodes filamin B, an actin-crosslinking cytoskeletal protein. Disease-associated dominant variants generally preserve protein expression and act via gain-of-function mechanisms rather than null alleles (PMID:19505475; PMID:27048506; PMID:22190451). Experimental work shows increased F-actin binding affinity for key mutant actin-binding-domain constructs (PMID:19505475), and mutation-specific cytoplasmic actin-filamin focal accumulations that correlate with severity for ABD variants (PMID:22190451). Model data further support disturbed chondrocyte maturation and endochondral skeletal development pathways (PMID:17510210).
Hallmark phenotype profile
Core clinical features include congenital large-joint dislocations and characteristic craniofacial dysmorphism (PMID:16801345; PMID:27048506). Classical facial descriptions include prominent forehead, depressed nasal bridge, and hypertelorism, with associated equinovarus/valgus foot deformity (PMID:11837607). Frequently reported FLNB-associated findings include supernumerary carpal/tarsal elements and broad spatulate distal phalanges (PMID:16801345). Cervical spine involvement is clinically critical; cervical kyphosis is repeatedly reported as a high-risk manifestation with potential for neurologic compromise (PMID:17202879; PMID:8609132; PMID:18377309).
Diagnosis and management implications
Diagnostic confirmation combines clinical and radiographic pattern recognition with targeted molecular testing of FLNB (PMID:16801345; PMID:27048506). Because cervical deformity may be occult early and can progress to severe neurologic risk, early cervical imaging surveillance and timely orthopedic/neurosurgical stabilization are emphasized in the literature (PMID:17202879; PMID:8609132).