A 28-year-old woman presents with a 2-year history of progressive joint pain, skin hyperextensibility, and easy bruising. Physical examination reveals hypermobile joints and velvety skin texture. She reports a family history of similar symptoms in her mother. Which investigation is most appropriate to confirm the suspected diagnosis of Ehlers-Danlos syndrome (EDS) Type III (vascular EDS)?

Explanation

## Investigation of Choice for Vascular EDS **Key Point:** Genetic sequencing for COL3A1 gene mutations is the gold standard confirmatory test for vascular EDS (Type III), which accounts for ~90% of vascular complications in EDS. ### Why COL3A1 Sequencing? Vascular EDS is caused by mutations in the COL3A1 gene, which encodes type III collagen — the predominant collagen in blood vessels, GI tract, and uterus. Identifying the specific mutation: - Confirms the diagnosis definitively - Enables genetic counselling for family members - Allows risk stratification for vascular rupture, GI perforation, and uterine rupture - Guides management (e.g., β-blockers, losartan, activity restriction) ### Diagnostic Approach for EDS Subtypes | Investigation | Best For | Rationale | |---|---|---| | **Genetic sequencing (COL3A1)** | Vascular EDS (Type III) | Definitive; identifies mutation; guides management | | **Skin biopsy + EM** | Classical EDS (Type I/II) | Shows abnormal collagen fibril diameter & morphology | | **Procollagen III peptide** | Screening only | Non-specific; elevated in many collagen disorders | | **Hydroxyproline/lysine** | Metabolic disorders | Not diagnostic for EDS | **High-Yield:** Vascular EDS is the most life-threatening subtype; spontaneous arterial rupture, bowel perforation, and uterine rupture can occur without warning. Early genetic diagnosis is critical. **Clinical Pearl:** Patients with vascular EDS often have a characteristic facial appearance (thin lips, small chin, prominent eyes) and acrogeria (premature skin aging of hands and feet), which should raise suspicion for COL3A1 mutations. **Warning:** Skin biopsy alone cannot distinguish between EDS subtypes — electron microscopy findings may be subtle or normal in vascular EDS. Genetic testing is required for definitive subtype classification.