What causes blue sclera?

Causes of Blue Sclera

Blue sclera is primarily caused by osteogenesis imperfecta (OI), but can also be associated with other genetic syndromes, metabolic disorders, and certain systemic diseases. 1

Osteogenesis Imperfecta (OI)

• Blue sclera is a characteristic clinical feature of OI, particularly in types I, III, IV, and VII 1
• The blue coloration occurs due to increased scleral translucence from abnormal collagen structure 2
• In OI, the collagen fibers of the sclera are approximately 50% narrower than normal and more uniform in size, allowing the underlying uveal pigment to show through 2
• Recent research using the 'BLUES' procedure has demonstrated that blue sclera can be objectively quantified with 89% sensitivity and 87% specificity for diagnosing OI 3

Pathophysiological Mechanisms

• In OI, mutations in COL1A1 and COL1A2 genes affect the production of type I collagen, a major structural protein in the eyes 4
• Decreased thickness of the cornea and sclera is an important factor causing blue sclera 4
• In severe OI, polymeric collagen is less resistant to depolymerization, suggesting defective cross-linking 5
• In milder forms of OI with blue sclera, the polymeric collagen may have normal stability but reduced total amount 5

Other Causes of Blue Sclera

Genetic Syndromes

• Ehlers-Danlos syndrome (vascular form/type IV) - characterized by thin skin, easy bruising, and blue sclera 1
• Loeys-Dietz syndrome - features include blue sclera, arterial tortuosity, and hypertelorism 1

Metabolic Disorders

• Hypophosphatasia - characterized by defective bone mineralization and blue sclera 1
• Hypophosphatemic osteomalacia ("rickets") - can present with blue sclera, osteomalacia, and poor growth 1

Normal Physiological Variant

• Blue sclerae can occur in normal infants before 12 months of age 1
• This normal finding should be differentiated from pathological causes 1

Other Considerations

• Preterm birth - associated with decreased bone mineralization that may contribute to blue sclera 1
• Certain medications can induce scleral pigmentation changes 6

Clinical Significance

• Recognition of blue sclera should prompt evaluation for associated conditions, particularly OI 6
• In infants with unexplained fractures, the presence of blue sclera may suggest OI rather than non-accidental injury 1
• However, blue sclera alone is not diagnostic, as it can be a normal finding in infants under 12 months 1
• When evaluating a child with fractures and blue sclera, additional features such as family history of fractures, hearing loss, abnormal dentition, and short stature should be assessed 1

Diagnostic Approach

• Complete physical examination to identify other features of OI or related syndromes 7
• Genetic testing for COL1A1/COL1A2 mutations when OI is suspected 1
• Biochemical testing including serum calcium, phosphorus, alkaline phosphatase, and vitamin D levels to rule out metabolic bone disorders 1
• Consider ophthalmologic evaluation to assess for other ocular abnormalities that may be present in OI 4

Blue sclera represents an important clinical sign that may indicate underlying systemic disease, particularly connective tissue disorders like OI, and warrants appropriate evaluation to determine its cause and clinical significance.