ANTXR2 – Juvenile Hyaline Fibromatosis

Biallelic pathogenic variants in ANTXR2 cause autosomal recessive juvenile hyaline fibromatosis (Juvenile Hyaline Fibromatosis), characterized by subcutaneous nodules, gingival fibromatosis, flexion contractures, and osteolytic lesions. Over 84 unrelated cases across multiple populations have been documented since the initial identification of CMG2/ANTXR2 mutations in 2003, with segregation consistent with recessive inheritance and concordant functional studies establishing loss of receptor function ([PMID:30176098]).

Genetic evidence includes more than 30 distinct pathogenic variants reported in exons 1–17, comprising truncating, missense, and frameshift alleles. A representative variant is c.658G>T (p.Glu220Ter), which abrogates the transmembrane domain and leads to absence of functional protein ([PMID:12973667]). Segregation analysis in affected sibships confirms autosomal recessive inheritance with two affected siblings in one family ([PMID:16104968]).

Functional assays demonstrate that loss-of-function mutations in ANTXR2 disrupt extracellular matrix interactions of endothelial and fibroblast cells. Site-directed mutants (e.g., p.Gly105Asp, p.Leu329Arg) impair CMG2 folding and cellular adhesion, while proteasome inhibition can rescue certain ectodomain variants to the cell surface ([PMID:12973667], [PMID:21328543]). Electron microscopy of patient fibroblasts shows accumulation of unregulated collagen VI, linking receptor deficiency to hyaline material deposition.

Clinically, patients present in early childhood with gingival hyperplasia (HP:0000169), subcutaneous nodules (HP:0001482), painful joint contractures, and bone lesions. Imaging reveals iso- to hypointense nodular lesions on MRI and CT correlating with histopathology ([PMID:36101737]). Gingivectomy and supportive periodontal care reduce hyperplasia and improve oral hygiene over long-term follow-up ([PMID:16104968]).

Juvenile hyaline fibromatosis and infantile systemic hyalinosis form a spectrum (hyaline fibromatosis syndrome) wherein clinical severity correlates with mutation type and location. Early molecular diagnosis via targeted sequencing enables presymptomatic detection, genetic counseling, and prenatal testing in at-risk families ([PMID:28103792]; [PMID:25186005]).

Integration of robust genetic and functional data over two decades supports a Definitive gene–disease association. Key take-home: molecular testing of ANTXR2 is essential for diagnosis, prognosis, and management of juvenile hyaline fibromatosis.

References

• Human mutation • 2018 • Hyaline fibromatosis syndrome: Clinical update and phenotype-genotype correlations PMID:30176098
• American journal of human genetics • 2003 • Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis PMID:12973667
• EMBO molecular medicine • 2011 • Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors PMID:21328543
• BJR case reports • 2022 • Imaging manifestations of juvenile hyaline fibromatosis: a case report and literature review PMID:36101737
• Journal of clinical periodontology • 2005 • Periodontal treatment of two siblings with juvenile hyaline fibromatosis PMID:16104968
• Journal of medical case reports • 2014 • Hyaline fibromatosis syndrome with mutation c.1074delT of the CMG2 gene: a case report PMID:25186005
• BMC genetics • 2017 • Diagnosis implications of the whole genome sequencing in a large Lebanese family with hyaline fibromatosis syndrome PMID:28103792

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