ANTXR2 – Hyaline Fibromatosis Syndrome

Hyaline fibromatosis syndrome (HFS) is a rare autosomal recessive connective tissue disorder caused by bi-allelic pathogenic variants in the anthrax toxin receptor 2 gene (ANTXR2). Clinically, HFS encompasses the spectrum from juvenile hyaline fibromatosis to infantile systemic hyalinosis and is characterized by papulonodular skin lesions, gingival hypertrophy, joint contractures, osteolytic bone lesions and, in severe cases, multisystem hyaline deposition with protein-losing enteropathy and fatal infantile course (PMID:25186005).

Numerous case reports have described homozygous and compound heterozygous ANTXR2 mutations in patients presenting with classic HFS features. For example, a Moroccan patient carried a homozygous c.1074delT (p.Ala359HisfsTer50) variant and his sister was identified presymptomatically via family testing (PMID:25186005). A Chinese patient exhibited compound heterozygous c.470_472del (p.Val157del) and c.1073delC (p.Pro358LeufsTer?) variants (PMID:30152846).

In the largest cohort to date, 19 unrelated index patients harbored ten distinct homozygous ANTXR2 mutations—including three novel frameshift variants—confirming extensive allelic heterogeneity (PMID:31455396). Additional consanguineous and multi-ethnic case series (Lebanese, Turkish, Japanese) further support the recessive inheritance and broad mutational spectrum of ANTXR2 in HFS.

Segregation under an autosomal recessive model is consistently observed, with affected individuals carrying bi-allelic loss-of-function or deleterious missense variants, and unaffected relatives typically heterozygous for single alleles. Early molecular diagnosis enables presymptomatic family screening and informed genetic counseling.

Functional studies elucidate the pathogenic mechanism of ANTXR2 variants. Patient‐derived fibroblasts show abrogated extracellular matrix interactions due to misfolded CMG2 receptor (PMID:12973667). Missense mutations in the ectodomain lead to ER retention and proteasomal degradation, which can be partially rescued by proteasome inhibitors in vitro (PMID:21328543). Duodenal organoids from affected patients demonstrate abnormal collagen VI accumulation underlying protein-losing enteropathy (PMID:33147779).

Collectively, genetic and experimental data support a Strong gene–disease association: bi-allelic ANTXR2 mutations result in loss of CMG2 function, leading to extracellular hyaline deposition across tissues. Molecular confirmation of ANTXR2 variants is critical for definitive diagnosis, prognostication, genetic counseling, and exploration of proteostasis-targeted therapies.

Key Take-home: Bi-allelic ANTXR2 variants cause autosomal recessive Hyaline Fibromatosis Syndrome; early genetic diagnosis directs clinical management and family planning.

References

• Journal of medical case reports • 2014 • Hyaline fibromatosis syndrome with mutation c.1074delT of the CMG2 gene: a case report. PMID:25186005
• Molecular medicine reports • 2018 • Two novel mutations in the ANTXR2 gene in a Chinese patient suffering from hyaline fibromatosis syndrome: A case report. PMID:30152846
• Orphanet journal of rare diseases • 2019 • Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome. PMID:31455396
• 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
• International journal of molecular sciences • 2020 • Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy. PMID:33147779

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