What is the management approach for osteopetrosis, especially in severe infantile forms, according to Nelson textbook of paediatrics?

Management of Osteopetrosis in Severe Infantile Forms

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for malignant infantile osteopetrosis (MIOP) and should be performed as early as possible to prevent irreversible cranial nerve damage and death. 1, 2

Immediate Recognition and Referral

Severe infantile osteopetrosis (MIOP) presents within the first year of life with:

• Poor feeding and failure to thrive 3
• Progressive bone marrow failure requiring transfusions 4
• Hepatosplenomegaly from extramedullary hematopoiesis 1
• Cranial nerve compression causing blindness and deafness 5
• Pathological fractures despite increased bone density 5
• Seizures from electrolyte disturbances in advanced disease 3

Early diagnosis and immediate referral to specialized pediatric transplant centers is critical, as 70% of untreated patients die within 6 years of life. 6

Definitive Treatment: HSCT

Timing and Urgency

HSCT must be performed urgently once MIOP is diagnosed, ideally before irreversible neurological complications develop. 1, 2 The rapidly progressive nature of MIOP necessitates prompt treatment—neurosensory manifestations (blindness, deafness) are generally not reversible once established. 2

Donor Selection

Acceptable donor options in order of preference: 4, 6, 2

• HLA-matched sibling or family donors (preferred, with survival rates up to 100% in recent series) 4
• Matched unrelated donors (acceptable alternative) 4, 2
• Haploidentical family donors (viable option with modern conditioning, showing good outcomes) 4, 6
• Unrelated cord blood (used successfully in some cases) 6

Conditioning Regimen

Fludarabine-based conditioning with busulfan and cyclophosphamide is the standard approach. 6 For haploidentical or unrelated donors, add ATG/ALG, mycophenolate mofetil, and methotrexate for GVHD prophylaxis. 6 All patients receive cyclosporine for GVHD prevention. 6

Expected Outcomes

• Neutrophil engraftment occurs at approximately 15-16 days post-transplant 6
• Platelet engraftment occurs at approximately 43 days 6
• Survival rates of 70-80% are achievable with modern protocols 4, 6
• Even partial or transient donor chimerism can correct hematological manifestations 2

Supportive Management Pre-Transplant

While awaiting HSCT, provide: 3, 1

• Intensive dialysis if stage 5 CKD develops (common in infantile oxalosis-related cases, though this is distinct from typical MIOP) 3
• Transfusion support for cytopenias 4
• Nutritional support including tube feeding to meet growth requirements 3
• Fracture management with careful orthopedic consultation 3
• Monitoring for electrolyte disturbances 3

Post-Transplant Monitoring

Acute Complications

• Acute GVHD occurs in most patients (grade I-II in 75%, grade III-IV in 25%) but is generally controllable with anti-GVHD therapy 6
• Graft failure (primary or secondary) occurs in approximately 20% of cases 2
• Monitor for infection, given immunosuppression 1

Long-Term Follow-Up

Patients require lifelong monitoring for: 5, 1

• Skeletal complications including atypical fractures with delayed healing
• Dental abscesses (often underestimated complication)
• Progressive deafness and visual loss (may not be reversible even post-HSCT)
• Bone marrow function
• Growth and development

Special Considerations for Indian Context

Haploidentical transplantation is particularly relevant in the Indian context where matched unrelated donors may be less readily available, and this approach has shown good outcomes in Chinese cohorts with similar genetic backgrounds. 6 The survival rate of 87.5% with haploidentical donors makes this a viable option when matched donors are unavailable. 6

Critical Pitfalls to Avoid

• Do not delay transplant waiting for "optimal" timing—earlier is always better before neurological damage occurs 1, 2
• Do not assume bone density equals bone strength—these patients have high fracture risk despite radiographic density 5
• Do not discharge patients from follow-up post-transplant—lifelong monitoring is essential 5
• Do not overlook dental complications—regular dental surveillance prevents serious infections 5

Intermediate Forms (Age >5 Years)

For patients diagnosed after age 5 with intermediate osteopetrosis (less severe mutations in TCIRG1, CLCN7, RANK, SNX10, or CA2), HSCT remains the only curative option and should be considered when debilitating skeletal complications accumulate. 4 These patients show significant improvement in symptoms and quality of life post-transplant with median follow-up of 4 years. 4