A 28-year-old woman presents to the rheumatology clinic with a 2-year history of progressive joint pain, skin fragility, and easy bruising. On examination, she has hyperextensible skin, joint hypermobility, and recurrent subluxations. Biochemical analysis shows abnormal procollagen processing with defective lysyl hydroxylase activity. What is the most appropriate next step in management?

Explanation

## Clinical Diagnosis: Ehlers–Danlos Syndrome Type VI (Kyphoscoliotic EDS) ### Pathophysiology **Key Point:** Lysyl hydroxylase deficiency impairs hydroxylation of lysine residues in collagen, preventing normal cross-linking and resulting in structurally weak connective tissue. The enzyme lysyl hydroxylase (LOX) catalyzes hydroxylation of lysine to hydroxylysine, which is essential for aldol cross-linking between collagen molecules. Without adequate cross-links, collagen fibrils are mechanically weak despite normal amino acid composition. ### Why Vitamin C is the Correct Next Step **High-Yield:** Lysyl hydroxylase is a vitamin C–dependent enzyme. Vitamin C (ascorbic acid) is a cofactor for prolyl hydroxylase and lysyl hydroxylase, both of which require it for hydroxylation of proline and lysine residues. **Clinical Pearl:** In EDS Type VI (and scurvy), high-dose vitamin C supplementation (1–4 g/day) can partially restore enzyme activity and improve collagen cross-linking, reducing skin fragility and stabilizing joint hypermobility over months. ### Management Algorithm ```mermaid flowchart TD A[Suspected EDS Type VI<br/>Lysyl hydroxylase deficiency]:::outcome --> B{Confirm diagnosis}:::decision B -->|Clinical + biochemical<br/>evidence present| C[High-dose Vitamin C<br/>1-4 g/day]:::action C --> D[Genetic counselling<br/>Autosomal recessive]:::action D --> E[Ophthalmology screening<br/>Retinal detachment risk]:::action E --> F[Physiotherapy &<br/>joint protection]:::action F --> G[Monitor for<br/>aortic involvement]:::outcome ``` ### Genetic Counselling Rationale **Key Point:** EDS Type VI is **autosomal recessive**, caused by mutations in PLOD1 gene (lysyl hydroxylase 1). Genetic counselling is essential for family screening and reproductive planning. ### Why Other Options Are Incorrect | Option | Why Wrong | |--------|----------| | Colchicine + echocardiography | Colchicine is used in familial Mediterranean fever and gout, not EDS. While echocardiography may be needed later to screen for aortic root dilatation (in Type IV EDS), it is not the immediate next step. | | Skin biopsy + HLA typing | Biopsy may show thin, fragmented collagen fibrils on EM, but it is diagnostic confirmation, not management. HLA typing is irrelevant to EDS Type VI. | | IVIG + aortic monitoring | IVIG is for autoimmune/immunodeficiency conditions. Aortic dissection is a risk in Type IV EDS (vascular), not Type VI. | **Clinical Pearl:** Patients with EDS Type VI require **ophthalmology screening** (retinal detachment risk) and **orthopedic follow-up** (progressive kyphoscoliosis, joint instability). Vitamin C supplementation is initiated immediately to slow progression. [cite:Robbins 10e Ch 7]