What are the possible causes of a child with blue-gray sclera (blue-gray discoloration of the white part of the eye) since infancy?

Blue-Gray Sclera in a Four-Year-Old: Differential Diagnosis

The most likely cause of persistent blue-gray sclera since infancy in a four-year-old is osteogenesis imperfecta (OI) type I, though normal physiologic blue sclera (which should have resolved by 12 months), other OI subtypes, and several rare genetic conditions must be considered. 1

Primary Diagnostic Consideration: Osteogenesis Imperfecta

OI type I is the leading diagnosis when blue sclera persist beyond infancy and remain intensely blue throughout childhood. 2 This autosomal dominant collagen disorder presents with:

• Distinctly blue sclerae that remain intensely blue throughout life (pathognomonic for OI type I) 2
• History of fractures from minimal trauma, though bone fragility may be mild 1
• Possible dentinogenesis imperfecta (abnormal tooth development) 1, 3
• Family history of fractures, early hearing loss, or blue sclera 1
• Normal or near-normal stature (approximately two-thirds maintain normal height) 4

Other OI Subtypes to Consider

• OI type III and IV may present with blue sclera in infancy, but the intensity typically fades by age four, resulting in normal scleral hue by adolescence 2. Since your patient still has blue-gray sclera at age four, these types are less likely but possible.
• OI type VII characteristically presents with blue sclera 1
• OI type VI typically has white or only faintly blue sclera and would be unlikely 5

Other Genetic Causes

Connective Tissue Disorders

• Ehlers-Danlos syndrome (vascular type/type IV): presents with thin skin, easy bruising, and blue sclera, though blue sclera are rare in EDS 1
• Loeys-Dietz syndrome: features blue sclera, arterial tortuosity, and hypertelorism (widely spaced eyes) 1

Metabolic Bone Disorders

• Hypophosphatasia: defective bone mineralization with blue sclera, elevated urinary phosphoethanolamine, and low serum alkaline phosphatase 4, 1
• Hypophosphatemic osteomalacia ("rickets"): presents with blue sclera, poor growth, low serum phosphorus, and elevated alkaline phosphatase 4, 1

Critical Clinical Evaluation

Perform a targeted physical examination looking for:

• Growth parameters: measure height and weight percentiles 1
• Skeletal examination: palpate for old fracture sites, assess for limb deformities or bowing 1
• Dental assessment: look for gray or brown discolored teeth with translucent appearance (dentinogenesis imperfecta) 1, 3
• Skin examination: check for bruising patterns, skin hyperextensibility, or abnormal scarring 1
• Complete ophthalmologic examination: evaluate for other ocular abnormalities beyond scleral color 1

Obtain detailed history including:

• Family history: multiple fractures across generations, early-onset hearing loss, blue sclera in relatives 1
• Fracture history: number, location, and mechanism of any fractures 1
• Birth history: prematurity (preterm infants may have physiologic blue sclera from decreased bone mineralization) 1
• Medication exposure: corticosteroids, diuretics, total parenteral nutrition 1

Diagnostic Testing Algorithm

Initial laboratory evaluation should include: 1

• Serum calcium, phosphorus, and alkaline phosphatase
• Urinary calcium excretion
• 25-hydroxyvitamin D level

If OI is suspected based on clinical features, proceed with: 1, 6

• Genetic testing for COL1A1/COL1A2 mutations (confirms diagnosis in most OI cases)
• Radiographic skeletal survey to evaluate for fractures, bone mineralization, and characteristic deformities 1

Biochemical collagen testing from cultured skin fibroblasts may be considered if genetic testing is inconclusive and clinical suspicion remains high 4

Important Clinical Pitfalls

Blue sclera are normal in infants before 12 months of age 4, 1. However, at four years old with persistent blue-gray sclera since infancy, this is pathologic and requires investigation.

If fractures are present, carefully distinguish OI from non-accidental injury. 4, 1 Key differentiating features favoring OI include: family history of fractures, blue sclera persisting beyond infancy, dentinogenesis imperfecta, and characteristic radiographic findings. 1, 6 However, infants with OI types IV, V, and VI may have normal sclera and present only with fractures, making diagnosis challenging. 4, 1

The absence of fractures does not exclude OI type I, as some individuals have mild bone fragility. 7 Additionally, cardiac valvular abnormalities can occur in OI type I due to collagen defects affecting cardiac tissue. 7