Overview
Definition:
Osteopetrosis, also known as Albers-Schönberg disease or marble bone disease, is a rare inherited disorder characterized by defective osteoclast function, leading to impaired bone resorption and an accumulation of dense, brittle bone
This leads to bone marrow failure and increased susceptibility to fractures.
Epidemiology:
The incidence varies by subtype, with the severe autosomal recessive form (ARO) occurring in approximately 1 in 100,000 to 1 in 250,000 live births
The autosomal dominant form (ADO) is more common, occurring in 1 in 20,000 to 1 in 250,000 individuals
ARO typically presents in infancy, while ADO may present later in childhood or adulthood.
Clinical Significance:
Osteopetrosis poses significant challenges due to its impact on bone marrow function leading to cytopenias, increased risk of fractures, and cranial nerve compression
Understanding its pathophysiology, genetic basis, and management is crucial for pediatricians and residents preparing for DNB and NEET SS exams.
Clinical Presentation
Symptoms:
Infantile osteopetrosis (ARO) often presents within the first few days or weeks of life
Symptoms include failure to thrive
Poor feeding
Recurrent infections due to neutropenia
Anemia causing pallor and lethargy
Easy bruising or bleeding due to thrombocytopenia
Visual impairment due to optic nerve compression
Hearing loss due to auditory nerve compression
Cranial nerve palsies
Seizures
Hydrocephalus
Osteomyelitis
In milder ADO, symptoms may be subtle and include pathological fractures, bone pain, or incidental findings on imaging.
Signs:
Macrocephaly
Hydrocephalus
Optic atrophy
Papilledema
Proptosis
Strabismus
Deafness
Facial nerve palsy
Cranial nerve palsies
Short stature
Deformities like bowed long bones
Osteomyelitis
Bone deformities visible on examination, particularly of the skull and long bones.
Diagnostic Criteria:
Diagnosis is typically made based on characteristic radiographic findings, biochemical abnormalities, and confirmation of genetic mutations
There are no universally accepted specific diagnostic criteria beyond the constellation of clinical and radiological findings, but the demonstration of defective osteoclast activity is central.
Diagnostic Approach
History Taking:
Detailed family history for consanguinity or similar conditions in relatives
History of recurrent infections
Developmental milestones
Nutritional status
History of fractures, particularly after minor trauma
Ocular and auditory symptoms
Neurological symptoms.
Physical Examination:
Complete physical examination focusing on growth parameters, head circumference, fundoscopy for optic disc abnormalities, cranial nerve assessment, assessment for skeletal deformities, neurological examination for signs of increased intracranial pressure or nerve compression, and examination for signs of infection.
Investigations:
Skeletal survey: Generalized increased bone density ("marble bone" appearance), thickened cortical bone, absent medullary cavity, characteristic "bone-in-bone" appearance on long bones and vertebrae, obliteration of paranasal sinuses and mastoid air cells
Basal ganglia calcifications may be seen
Hematological tests: Complete blood count (CBC) to assess for anemia, neutropenia, and thrombocytopenia
Serum chemistry: Normal or slightly elevated serum calcium and phosphate
Elevated alkaline phosphatase
Vitamin D levels
Parathyroid hormone levels
Genetic testing: Identification of mutations in genes such as TCIRG1 (for ARO), CLCN7 (for ADO), PLEKHM1, and others is diagnostic
Bone marrow biopsy: May show normal or hypercellular marrow with impaired or absent osteoclasts
Rarely performed in the diagnostic workup of typical cases.
Differential Diagnosis:
Other causes of generalized skeletal hyperostosis including: Melorheostosis
Pyknodysostosis
Diaphyseal dysplasia (Camurati-Engelmann disease)
Osteopoikilosis
Fluorosis
Metastatic calcification
Lead poisoning
Myelofibrosis
Thickened bone on plain radiographs can also be seen in conditions like thalassemia major or sickle cell disease due to increased erythropoiesis, though the pattern is different.
Management
Initial Management:
Immediate management focuses on supportive care and addressing acute complications
This includes prompt treatment of infections, management of anemia and bleeding disorders, and evaluation of visual and auditory deficits.
Medical Management:
Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for severe ARO and should be considered in infancy
It aims to replace the defective hematopoietic stem cells with healthy ones, allowing for the development of functional osteoclasts
Allogeneic HSCT has shown significant improvement in survival and reversal of bone marrow failure
Calcitriol (active vitamin D analog) and calcium supplementation: May be beneficial in some cases, particularly for ADO, to enhance osteoclast activity
Dosage is individualized, typically starting with low doses like 0.1-0.25 mcg/kg/day, with careful monitoring of calcium and phosphate levels
Erythropoietin: For anemia
Granulocyte colony-stimulating factor (G-CSF): For neutropenia
Management of cytopenias may also involve packed red blood cell transfusions and platelet transfusions as needed.
Surgical Management:
Surgical intervention may be necessary for specific complications: Decompression of cranial nerves (optic, auditory, facial) for vision or hearing loss or palsies
Treatment of osteomyelitis with surgical debridement and antibiotics
Correction of severe skeletal deformities or pathological fractures, although surgical fixation can be challenging due to the brittle bone
Shunt placement for hydrocephalus.
Supportive Care:
Regular monitoring for hematological abnormalities, visual and auditory deficits, and neurological complications
Nutritional support and physical therapy to manage skeletal issues and maintain mobility
Genetic counseling for affected families
Prophylaxis against common infections
Careful management of pain associated with fractures or bone disease.
Complications
Early Complications:
Severe anemia, neutropenia leading to life-threatening infections, thrombocytopenia with bleeding diathesis, hydrocephalus, optic and auditory nerve compression leading to blindness and deafness
Cranial nerve palsies
Osteomyelitis
Pathological fractures.
Late Complications:
Chronic pain
Progressive visual and hearing loss
Recurrent infections
Persistent cytopenias
Skeletal deformities
Arthritis
Renal stones (rare)
Increased risk of malignant transformation (very rare, typically in ADO).
Prevention Strategies:
Early diagnosis and prompt initiation of HSCT for severe ARO can prevent or mitigate many early complications
Prophylactic antibiotics in individuals with recurrent infections
Careful bone handling to prevent fractures
Regular monitoring and management of cytopenias and nerve compression symptoms.
Prognosis
Factors Affecting Prognosis:
The severity of the disease and age of onset are the most critical prognostic factors
Severe ARO has a poor prognosis without HSCT, with significant morbidity and mortality in infancy and early childhood
ADO generally has a better prognosis, with many individuals living into adulthood, though with increased fracture risk and potential for progressive complications.
Outcomes:
With successful HSCT, patients with severe ARO can experience reversal of bone marrow failure, improved growth, and resolution of some bone abnormalities, leading to a significantly improved prognosis
For ADO, outcomes vary, with management focused on preventing fractures and treating complications
Lifespan is generally normal in milder forms.
Follow Up:
Lifelong follow-up is essential, particularly for patients with ADO, to monitor for fractures, bone pain, visual and auditory changes, cytopenias, and other potential complications
Regular skeletal surveys and hematological assessments are recommended
Patients who have undergone HSCT require long-term monitoring for graft function and potential transplant-related complications.
Key Points
Exam Focus:
Differentiate between autosomal recessive (ARO) and autosomal dominant (ADO) forms
Recognize characteristic radiographic findings like "bone-in-bone." Understand the central role of osteoclast dysfunction
Know that HSCT is curative for severe ARO
Identify common complications like marrow failure and nerve compression.
Clinical Pearls:
Always consider osteopetrosis in an infant with unexplained anemia, neutropenia, and fractures
Be vigilant for signs of cranial nerve compromise in affected children
Remember that fractures in osteopetrosis can occur with minimal trauma and can be difficult to manage surgically.
Common Mistakes:
Confusing osteopetrosis with other causes of bone density increase on imaging
Delaying HSCT referral for severe ARO
Underestimating the risk of infection in patients with neutropenia
Misinterpreting skeletal survey findings in mild ADO.