ANTXR2 – Infantile Systemic Hyalinosis

Infantile systemic hyalinosis (ISH) is a severe autosomal recessive connective tissue disorder caused by biallelic mutations in ANTXR2, leading to widespread hyaline deposits in skin, mucosa, gastrointestinal tract, and internal organs. Clinically, affected infants present in the first year of life with painful joint contractures, gingival overgrowth, subcutaneous nodules, intractable diarrhea, failure to thrive, osteopenia, recurrent infections and hyperpigmented skin patches ([PMID:15725249]).

Genetic evidence supports a definitive gene–disease relationship: over 116 probands from more than 20 unrelated families harbor pathogenic ANTXR2 variants, notably recurrent frameshift alleles such as c.1073dup (p.Ala359fs) and initiation‐codon mutations, with autosomal recessive segregation confirmed in consanguineous kindreds ([PMID:35726349]; [PMID:27753005]). Segregation analysis in multi‐sibling and founder cohorts demonstrated concordant genotype–phenotype correlation in at least four families.

The variant spectrum includes >40 distinct ANTXR2 mutations: missense alterations within the vWA domain, splice‐site and frameshift mutations predominantly in exons 1–12, and gross deletions. A common hotspot, c.1073dup (p.Ala359fs), has been reported in multiple ethnic groups, indicating a founder or mutationally susceptible site ([PMID:15725249]).

Functional studies reveal that ANTXR2 loss‐of‐function impairs extracellular matrix homeostasis: patient fibroblasts show ER retention of mutant CMG2, failure to bind collagen VI, and abnormal hyaline accumulation in tissues. Rescue of select missense mutants by proteasome inhibition and abnormal collagen deposition in patient‐derived intestinal organoids underscore the pathogenic mechanism of disrupted CMG2 signaling ([PMID:12973667]; [PMID:33147779]).

No conflicting or refuting studies have been reported. The cumulative genetic and experimental data meet ClinGen criteria for a definitive association.

Key Take-home: Biallelic ANTXR2 pathogenic variants cause autosomal recessive ISH with a consistent clinical and ultrastructural phenotype, facilitating molecular diagnosis, genetic counseling, prenatal testing, and guiding supportive management.

References

• Clinical and experimental dermatology • 2005 • Capillary morphogenesis gene-2 mutation in infantile systemic hyalinosis: ultrastructural study and mutation analysis in a Taiwanese infant. PMID:15725249
• 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
• Indian journal of pediatrics • 2016 • Infantile Systemic Hyalinosis: Novel Founder Mutation in the Initiation Codon among "Malis (Farmers)" in Jodhpur. PMID:27753005
• Molecular genetics & genomic medicine • 2022 • Hyaline fibromatosis syndrome with a novel 4.41-kb deletion in ANTXR2 gene: A case report and literature review. PMID:35726349
• International journal of molecular sciences • 2020 • Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy. PMID:33147779

Evidence Based Scoring (AI generated)