Osteopetrosis

Vignette says a 7 year old male child presents to the pediatric clinic with complaints of frequent bone fractures, recurrent infections and visual impairment; His mother reports that he has had multiple fractures, even with minimal trauma over the past few years; His mother also reports that he has had several episodes of pneumonia and ear infections requiring hospitalizations in the past; Examination shows pale conjunctiva, macrocephaly with frontal bossing and hepatosplenomegaly; Neurological examination shows decreased visual acuity in both eyes and decreased hearing in both ears; Complete blood count (CBC) shows pancytopenia; X-ray shows diffuse osteosclerosis; Bone marrow biopsy shows dense, sclerotic bone with little marrow space; Diagnosis?

Diagnosis is Osteopetrosis. 

Osteopetrosis (also known as "marble bone disease"), is a genetic disorder characterized by defective osteoclast function leading to impaired bone resorption and the accumulation of abnormally dense bones.

Pathophysiology:- Deficiency of carbonic anhydrase → failure to resorb bone by osteoclasts (i.e. poor osteoclast function due to type II carbonic anhydrase deficiency). 

Clinical features:- 

1. Thick bones which fracture easily (i.e. pathologic fractures).

2. Vision and hearing impairment.

3. CN deficits and hydrocephalus (due to narrowing of foramen in the brain).

4. Type II RTA (i.e. proximal RTA).

5. Pancytopenia and hepatosplenomegaly (due to bone expansion leading to bone marrow narrowing and extramedullary hematopoiesis).

Diagnosis:- 

1. CBC shows pancytopenia.

2. X-ray shows diffuse osteosclerosis (aka “marble bone disease”). 

3. Elevated tartrate-resistant acid phosphatase (TRAP). 

4. Genetic testing shows mutation in the CLCN7 or TCIRG1 gene.

5. Bone marrow biopsy shows dense, sclerotic bone with little marrow space.

Management:- 

1. Supportive measures include pain management, physical therapy, and management of recurrent infections.

2. Calcium and vitamin D supplementation.

3. Erythropoietin or blood transfusions for anemia.

4. IFN-gamma (as it activates osteoclasts).

5. Bone marrow transplantation is the only curative treatment.