FBN2 – Congenital Contractural Arachnodactyly

Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder caused by pathogenic variants in the FBN2 gene, which encodes the extracellular matrix protein fibrillin-2. Patients present with a marfanoid habitus, multiple joint contractures, arachnodactyly, kyphoscoliosis and characteristic crumpled external ears. Genetic linkage and mutation analyses across unrelated families have unequivocally associated FBN2 variants with CCA, distinguishing it from Marfan syndrome linked to FBN1.PMID:7493032 PMID:9199560

Inheritance is strictly autosomal dominant, with both de novo and inherited mutations reported. Mosaicism has been documented, as exemplified by a branch-point mutation detectable in paternal germline cells but absent in blood, underlying two affected siblings and emphasizing recurrent recurrence risk through gonadal mosaicism.PMID:9106527

Case series and linkage in an 18-member pedigree demonstrated full cosegregation of an intronic g-26t transversion causing partial exon skipping, confirming FBN2 as the CCA locus.PMID:9199560

Over 40 distinct pathogenic FBN2 variants have been described in classical CCA, including missense substitutions of conserved cysteine residues (e.g., c.4301G>C (p.Cys1434Ser)), splice-site mutations in introns 28–32, small indels and multiexon deletions. These cluster within exons 23–34, a hotspot corresponding to the neonatal Marfan region in FBN1.PMID:19006240

Segregation data from multiple families support a definitive gene–disease relationship, with at least 18 affected relatives in a single five-generation kindred exhibiting perfect cosegregation of a branch-point mutation and clinical phenotype (affected_relatives = 18).PMID:9199560

Functional studies confirm that splice-site and branch-point mutations result in aberrant fibrillin-2 transcripts with exon skipping, while missense alterations disrupt calcium-binding EGF-like domains and critical disulfide bonds. Fbn2-null mice exhibit syndactyly and muscle weakness, mirroring human musculoskeletal features and demonstrating fibrillin-2’s role in microfibril integrity.PMID:20161761

Prenatal ultrasound reliably detects arthrogryposis multiplex congenita (AMC) features of CCA—clenched fists, contractures and ear malformations—when confirmed by targeted FBN2 sequencing. Genetic counseling should address the 50% transmission risk and the potential for mosaicism in apparently sporadic cases.

Key Take-home: FBN2 testing is clinically actionable for diagnosis, reproductive counseling and management of congenital contractural arachnodactyly.

References

• Nature Genetics • 1995 • Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. PMID:7493032
• American journal of human genetics • 1997 • A rare branch-point mutation is associated with missplicing of fibrillin-2 in a large family with congenital contractural arachnodactyly. PMID:9199560
• Human mutation • 2009 • Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature. PMID:19006240
• American journal of human genetics • 1997 • Parental somatic and germ-line mosaicism for a FBN2 mutation and analysis of FBN2 transcript levels in dermal fibroblasts. PMID:9106527
• PLoS One • 2010 • ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2. PMID:20161761

Evidence Based Scoring (AI generated)