Infantile Hyaline Fibromatosis Syndrome (also known as IHFS or Inherited Systemic Hyalinosis or ANTXR2-Related Hyaline Fibromatosis Syndrome) is a genetic condition characterized by deposition of hyaline in the skin, muscle, and viscera. IHFS is inherited in an autosomal recessive manner and characterized by mutations in the ANTXR2 (Anthrax Toxin Receptor 2) gene, resulting in the abnormal deposition of hyaline material in skin and organs. Symptoms can subsequently develop in multiple organ systems including rheumatological (progressive joint contractures), musculoskeletal (severe motor disability), immunological (increased susceptibility to infections), dermatological (thick, rough skin, hyperpigmented macules, nodules, and papules), and gastrointestinal (failure to thrive, nausea, vomiting, protein-losing enteropathy, failure to thrive). Complications from these can result in lifelong debilitation and early death. Per FDA definition, it meets criterion for an ultra-rare condition, affecting fewer than 1 in 1,000,000 births throughout the United States and with fewer than 100 total cases reported worldwide.

Here we present the case of a 4-month-old with a complicated medical history including painful extremity contractures, global developmental delay, neck hemangioma, and feeding intolerance who initially presented to our institution for abdominal distension. The multi-systemic, progressively worsening nature of her symptoms prompted consultation to inpatient pediatric genetics. Per their recommendation, rapid whole-genome sequencing (rWGS) was performed through Rady Children’s Hospital Institute for Genomic Medicine® in San Diego with the help of the Fabric GEM artificial intelligence (AI) tool. This revealed a homozygous pathogenic variant c.652T>C; P.Cys218Arg in the ANTXR2 gene consistent with IHFS.

This case was significant not only for its extreme rarity, but also its early manifestation of symptoms, wide range of affected body systems, and severity of symptoms, which together present a fascinating diagnostic dilemma for future clinicians that should be taken into consideration. It also highlights the increasing utility of AI-assisted rapid whole-exome sequencing as a diagnostic tool for medically complex patients with hitherto unknown multisystemic hereditary conditions.