Caffey Disease

Prostaglandin-Mediated Pathogenesis

Mechanism: Elevated prostaglandin E2 (PGE2) levels have been found in affected infants and may explain the bone changes.

Evidence Supporting Theory:

• Elevated serum PGE2 levels in affected infants
• NSAIDs (indomethacin) are effective in symptom control
• PGE2 is known to stimulate osteoclast activity and periosteal bone formation
• Resolution of symptoms correlates with normalization of PGE2 levels

Process: Elevated PGE2 leads to periosteal inflammation, which causes subperiosteal new bone formation, creating cortical thickening, and the clinical presentation of swelling and irritability follows.

This theory remains the most widely accepted explanation for sporadic Caffey disease.

COL1A1 Gene Mutation

Familial Form: Autosomal dominant inheritance with variable penetrance.

Gene Mutation: R836C missense mutation in the COL1A1 gene on chromosome 17q21.

Protein Effect: This mutation affects the alpha-1 chain of type I collagen, leading to abnormal collagen structure and bone fragility.

Clinical Implications:

• Earlier onset (may present prenatally)
• More severe clinical course
• Higher recurrence rate
• Genetic counseling recommended for affected families

The COL1A1 mutation links Caffey disease to the broader spectrum of type I collagen disorders, though the clinical presentation differs from osteogenesis imperfecta.

Microscopic Findings

Periosteum: Marked thickening with hypervascular granulation tissue.

Cortex: Subperiosteal new bone formation with woven bone deposited on lamellar cortex.

Soft Tissue: Edema and inflammatory infiltrate in overlying soft tissues.

Bone Marrow: Generally normal, no evidence of infection or malignancy.

Resolution Phase: Woven bone gradually remodels to lamellar bone, cortex returns to normal thickness.

These findings help differentiate from osteomyelitis (which shows necrosis and sequestrum) and malignancy (which shows abnormal cells).

Plain Radiograph Findings

Early Changes (Week 1-2):

• Soft tissue swelling overlying bone
• Periosteal elevation may be subtle

Classic Changes (Week 2-6):

• Laminated or solid periosteal reaction along diaphysis
• Cortical thickening (hyperostosis)
• New bone formation is smooth and uniform
• May see "double cortex" appearance

Late Changes (Month 3-12):

• Gradual remodeling of thickened cortex
• Return to normal bone contour

Key Differentiating Features:

• DIAPHYSEAL involvement (not metaphyseal)
• No fractures visible
• Smooth periosteal reaction (not aggressive)
• Mandible involvement nearly pathognomonic

Always obtain X-rays of clinically affected areas plus skeletal survey if NAI is in the differential.

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Blood Tests

Inflammatory Markers:

• ESR: Mildly to moderately elevated (20-60 mm/hr)
• CRP: Mildly elevated
• WCC: Normal or mildly elevated

Other Tests:

• Alkaline phosphatase: May be elevated (reflects bone turnover)
• Vitamin C levels: Normal (excludes scurvy)
• Blood cultures: Negative (excludes osteomyelitis)

Genetic Testing:

• Consider COL1A1 mutation testing if familial form suspected
• Useful for genetic counseling in affected families

Laboratory findings are non-specific and primarily help exclude other diagnoses rather than confirm Caffey disease.

When to Use Additional Imaging

Bone Scan (Technetium-99m):

• Shows increased uptake in affected bones
• Can identify subclinical involvement
• Not required for diagnosis but may show extent

MRI:

• Rarely needed for Caffey disease
• Shows periosteal edema and new bone formation
• Useful to exclude osteomyelitis if diagnostic uncertainty
• No abscess or sequestrum in Caffey disease

Ultrasound:

• May show soft tissue swelling and periosteal thickening
• Limited role in diagnosis

In most cases, clinical presentation and plain radiographs are sufficient for diagnosis. Advanced imaging is reserved for atypical presentations or when excluding other pathology.

Non-Accidental Injury

This is the CRITICAL differential - missing NAI is a patient safety failure.

Red Flags for NAI:

• Delay in seeking care
• History inconsistent with injury pattern
• Multiple injuries at different stages
• Retinal hemorrhages
• Subdural hematoma

When in doubt, involve child protection services and perform a full skeletal survey.

Acute Haematogenous Osteomyelitis

Key Differentiating Features:

• Fever: High fever in osteomyelitis vs low-grade in Caffey
• Inflammatory markers: Markedly elevated CRP/ESR in osteomyelitis
• X-ray timing: Osteomyelitis X-ray changes take 10-14 days to appear
• X-ray pattern: Lytic lesion, periosteal reaction, sequestrum in osteomyelitis
• Location: Osteomyelitis favors metaphysis in children
• Blood culture: Positive in 50% of osteomyelitis
• Single bone: Osteomyelitis usually affects one bone; Caffey is often multifocal

Management if uncertain: Treat as osteomyelitis until proven otherwise - osteomyelitis requires urgent IV antibiotics.

Other Conditions to Consider

Scurvy (Vitamin C Deficiency):

• Age: 6-24 months (after weaning)
• History: Poor dietary intake of vitamin C
• X-ray: Subperiosteal hemorrhage, Wimberger ring, Frankel line
• Treatment: Vitamin C supplementation

Syphilitic Periostitis:

• Congenital syphilis can cause periosteal reaction
• Associated with other stigmata (saddle nose, Hutchinson teeth)
• Serological testing confirms diagnosis

Hypervitaminosis A:

• History of excessive vitamin A intake
• Diffuse cortical hyperostosis
• Resolves with cessation of vitamin A

Prostaglandin Therapy:

• Infants receiving PGE1 for ductus-dependent cardiac lesions
• Identical radiographic changes to Caffey disease
• Resolves when prostaglandin therapy stopped

Take a thorough history including dietary intake and medications to exclude these differentials.

Supportive Care

First-Line Treatment:

• NSAIDs: Indomethacin or ibuprofen for pain relief and anti-inflammatory effect
• Paracetamol: For additional analgesia and fever control
• Gentle handling: Minimize manipulation of affected limbs

Dosing (Indomethacin):

• 0.5-1 mg/kg/day divided into 2-3 doses
• Continue for 2-4 weeks then wean
• Monitor for GI side effects

Rationale for NSAIDs: The prostaglandin theory suggests elevated PGE2 drives the disease process. NSAIDs inhibit prostaglandin synthesis and provide both symptomatic relief and may shorten disease duration.

No role for antibiotics unless osteomyelitis cannot be excluded.

No role for corticosteroids - not proven beneficial and potential side effects.

Follow-Up Protocol

Clinical Review:

• Weekly during acute phase
• Monitor swelling, irritability, feeding
• Ensure symptoms are improving

Radiographic Follow-Up:

• Repeat X-ray at 4-6 weeks to confirm expected changes
• Further imaging only if clinical concern
• No need for serial X-rays if progressing well

Red Flags Requiring Re-evaluation:

• Worsening symptoms despite treatment
• New bone involvement after initial presentation
• High fever development
• Failure to improve by 3 months

Discharge from follow-up: When clinically resolved, usually by 6-12 months. No long-term orthopaedic follow-up required.

Counseling Points

Reassurance:

• Self-limiting condition with excellent prognosis
• No long-term bone problems expected
• Complete resolution by age 2 years

Expectations:

• Symptoms improve over weeks to months
• Bone thickening on X-ray may persist longer than symptoms
• Recurrence is rare but possible

Warning signs to return:

• High fever
• Worsening pain or swelling
• New areas of swelling
• Poor feeding or weight loss

Genetic counseling: Offer if familial form suspected, particularly if planning future pregnancies.

Complications of Caffey Disease

Caffey disease is remarkably benign with few true complications:

Acute Phase Complications:

• Feeding difficulties: If mandible severely affected
• Respiratory distress: Rare, if rib involvement is extensive
• Pseudoparalysis: Apparent limb weakness due to pain

Long-Term Complications:

• Bony asymmetry: Temporary cosmetic deformity during resolution phase
• Limb length discrepancy: Extremely rare, transient overgrowth reported

Prenatal Form (Severe):

• Polyhydramnios
• Hydrops fetalis
• Stillbirth or early neonatal death (rare)

The key message is that postnatal sporadic Caffey disease has no significant long-term orthopaedic complications and complete resolution is expected.

NSAID-Related Complications

Gastrointestinal:

• Gastritis, peptic ulceration
• GI bleeding (rare in infants)
• Mitigation: Use with feeds, monitor for blood in stool

Renal:

• Prostaglandin inhibition can affect renal blood flow
• Monitor in premature or unwell infants
• Ensure adequate hydration

Duration of Use:

• Short-term use (2-4 weeks) minimizes risks
• Wean as symptoms improve

Overall Risk: NSAIDs are safe for short-term use in otherwise healthy infants. The benefits of symptom control outweigh the small risks when used appropriately.

These landmark studies form the foundation of our understanding of Caffey disease.