A Three-Generation Pedigree of Multifocal Heterotopic Ossification With Bilateral Involvement

Area of Science:

• Genetics
• Orthopedics
• Rare Diseases

Background:

• Heterotopic ossification (HO) is categorized into nonhereditary (NHHO) and hereditary (HHO) forms.
• Hereditary HO includes fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH), each linked to distinct gene mutations.
• ACVR1 gene sequencing is crucial for FOP diagnosis, with few autosomal dominant inheritance cases reported.

Purpose of the Study:

• To investigate the clinical, genetic, and pedigree characteristics of a 3-generation Chinese family with multifocal and bilateral HO.
• To identify the underlying genetic mutations in ACVR1 associated with the observed HO phenotype.
• To determine if the family's condition represents a known FOP variant or a novel HHO form.

Main Methods:

• Clinical assessment and pedigree analysis of affected family members.
• Exon sequencing of the ACVR1 gene for all family members and sporadic NHHO patients.
• Comparative analysis of identified mutations with known FOP and HHO genetic variations.

Main Results:

• The study identified a 3-generation Chinese family with 4 affected individuals presenting multifocal and bilateral HO.
• All affected family members and sporadic NHHO patients shared two novel, homozygous silent mutations in the ACVR1 gene: c.270C>T and c.690G>A.
• The clinical presentation in this family did not align with classic or atypical FOP, suggesting a distinct syndrome.

Conclusions:

• The identified novel ACVR1 mutations in this Chinese family may indicate a new FOP-variant syndrome or a previously undocumented form of HHO.
• This is the first documented case of a 3-generation Chinese family with multifocal and bilateral HO linked to these specific ACVR1 mutations.
• Further research is warranted to elucidate the pathogenicity and clinical implications of these unique genetic findings in heterotopic ossification.