HFS is a collective term that encompasses infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF), representing different levels of severity within the same disease spectrum.
Affected individuals present with a broad spectrum of symptoms, ranging from mild to life-threatening forms.
• Cutaneous manifestations: Thickened skin, hyperpigmented macules over bony prominences, pearly papules on the face and neck, and perianal masses. Skin nodules may be white-to-pink and progressively increase in over time.
• Musculoskeletal features: Progressive joint contractures, which may begin in utero and lead to severe motor disability. Contractures typically involve the hips, knees, elbows, and wrists.
• Pain and mobility issues: Severe pain with passive movement in infancy or early childhood, often leading to excessive crying.
• Gastrointestinal involvement: Failure to thrive, chronic diarrhea, and protein-losing enteropathy. Malabsorption may result from villous atrophy and lymphangiectasia.
• Craniofacial abnormalities: Depressed nasal bridge, variable ear malformations (large, simple, or low-set ears), and a slightly coarse facial appearance.
• Oral manifestations: Gingival thickening and masses that can interfere with feeding and airway function. Dental abnormalities, such as mispositioned teeth and curved dental roots, are common.
• Hematologic and immunologic findings: Hypoalbuminemia, mild anemia, thrombocytosis, and variable immunodeficiency, with approximately one-third of individuals showing impaired immune responses.
• Other features: Hepatomegaly, susceptibility to fractures, and recurrent infections. Rare cases of squamous cell carcinoma and colon cancer have been reported. Cardiovascular involvement is largely unknown, though an instance of atrial thrombus has been documented.
Clinical Grading System:
A clinical grading system for HFS has been proposed (Denadai et al., 2012), categorizing the disease from mild to severe/lethal:
• Mild forms: Predominantly skin and/or gingival involvement.
• Moderate forms: Progressive joint contractures, bone abnormalities, and possible internal organ involvement.
• Severe/lethal forms: Multisystem involvement, including severe protein-losing enteropathy, sepsis, or organ failure, leading to a high risk of early mortality.
Individuals with severe disease often succumb to infections or complications of protein-losing enteropathy. In contrast, those with milder phenotypes may have a later onset, allowing survival into adulthood, though with varying degrees of disability and disease burden.
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