Genetic Insights Into Hyaline Fibromatosis Syndrome: A Case Report of an ANTXR2 Mutation Featuring a Rare Variant c.697+1G>A

Hyaline fibromatosis syndrome (HFS) is a rare genetic disorder encompassing juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH), caused by mutations in the anthrax toxin receptor 2 gene (ANTXR2). This condition leads to the accumulation of hyaline plaques in the skin and organs, resulting in symptoms such as skin lesions, joint contractures, and digestive issues, often culminating in early mortality due to infections or diarrhea. By 2005, 20 mutations in ANTXR2 linked to ISH and JHF had been documented, impairing cellular adhesion to the laminin matrix. In this study, we present a case of a 6-month-old Iranian female of western Asian ethnicity, born to consanguineous parents. She exhibited hyperpigmentation of the proximal interphalangeal (PIP) joints, knee flexion contractures, persistent diarrhea, and failure to thrive. Initial assessments suggested arthrogryposis; however, the presence of hyperpigmented nodules and perianal plaques prompted further investigation. Genetic analysis confirmed a homozygous mutation in ANTXR2 and incidental heterozygous mutations in the HEXA and PAH genes. The patient will undergo regular monitoring and may require immunosuppressive therapy and orthopedic interventions. Hyaline fibromatosis syndrome presents unique diagnostic challenges due to its overlap with other conditions like arthrogryposis. While arthrogryposis typically lacks systemic symptoms, HFS is marked by significant pain and systemic manifestations due to hyaline deposits in tissues. The case presented aligns with existing literature regarding HFS characteristics, including joint contractures and skin lesions. The identification of the c.697+1G>A mutation at a splice site within the ANTXR2 gene highlights potential mechanisms contributing to HFS pathology. This finding emphasizes the necessity for comprehensive genetic profiling when diagnosing rare syndromes. Furthermore, low allele frequencies of this variant across population databases underscore its rarity and potential significance in disease manifestation. Hyaline fibromatosis syndrome (HFS) is an uncommon autosomal recessive disorder that is marked by notable clinical features, such as the deposition of hyaline material in various tissues, joint contractures, and systemic complications. The case discussed illustrates the diagnostic challenges associated with HFS, particularly in a young patient who presented with atypical symptoms that initially indicated arthrogryposis. Genetic analysis revealed a homozygous mutation in the ANTXR2 gene, specifically the c.697+1G>A variant, which interferes with normal splicing and results in the absence of functional protein. This observation emphasizes the critical role of genetic testing in the precise diagnosis of rare syndromes and in differentiating them from other hereditary disorders.