773 Osteopetrosis is a heterogeneous group of sclerosing bone diseases due to impaired bone and cartilage resorption, result- ing from absence or defective function of osteoclasts.
GENETICS/BASIC DEFECTS
1. Inheritance of recognized subtypes of human osteopetrosis a. Malignant infantile osteopetrosis: autosomal reces-
sive inheritance
b. More benign osteopetrosis primarily affecting adults:
two subtypes based on radiographic features
i. Autosomal dominant osteopetrosis type I (locus 11q12-13)
ii. Autosomal dominant osteopetrosis type II (Albers-Schönberg disease) (dominant negative CLCN7 mutations) (locus chromosome 16p13.3) c. Intermediate forms
i. An autosomal recessive disease with milder mutations
ii. Early diagnoses of the more severe end of the autosomal dominant spectrum
d. Carbonic anhydrase isoenzyme type II deficiency (CAII): autosomal recessive
e. Vacuolar proton pump deficiency (ATP6i/TCIRG1) (locus 11q13.3-q13.5): autosomal recessive
f. CLC-7 chloride pump deficiency (loss of function CLCN7 mutations) (locus 16p13.3): autosomal recessive g. Neuronopathic osteopetrosis (osteopetrosis and infan-
tile neuroaxonal dystrophy): autosomal recessive h. Osteopetrosis with agenesis of corpus callosum: auto-
somal recessive i. Dysosteosclerosis
i. Autosomal recessive ii. X-linked also reported
2. Basic defects: absence or defective function of osteoclasts results in defective remodeling of bone with partial or complete obliteration of marrow cavities, producing bone which is dense but has an increased tendency to fracture
CLINICAL FEATURES
1. Malignant infantile osteopetrosis
a. Usually diagnosed during the first year of life b. Signs and symptoms
i. Presenting signs a) Blindness b) Failure to thrive
c) Seizures due to hypocalcemia d) Infections
e) Pathologic fractures
ii. Neurovascular involvement: the most serious con- sequences of the osteopetrosis are cranial nerves, blood vessels and the spinal cord compression by
either gradual occlusion or lack of growth of skull foramina
iii. Visual impairment
a) Optic atrophy: some degree of optic atrophy are present in most patients. Blindness is observed in many children with severe forms of autosomal recessive osteopetrosis b) Nystagmus
c) Strabismus d) Proptosis
e) Limited extraocular movement
iv. Compression of facial and trigeminal nerves a) Produce paralysis, spasm or neuralgia b) Involvement of the trigeminal nerve tend
to occur in type I autosomal dominant osteopetrosis
c) Involvement of the facial nerve predominant in type II disease
v. Hearing loss
a) Poor drainage of the middle ear
b) Narrowing of the internal acoustic meatus c) Osteosclerosis
vi. Blood vessel compression
a) Stenosis of arterial supply (internal carotid artery, vertebral artery)
b) Stenosis of venous supply vii. Craniofacial features
a) Macrocephaly b) Frontal bossing c) Hypertelorism d) Exophthalmos e) Flat nasal bridge
f) Chronic rhinitis
g) Jaw: a frequent site of osteomyelitis h) Obligate mouth breathing in most children
secondary to obstruction of the upper airway viii. Compromised nutritional state due to difficulty in eating and breathing resulting from limited posterior nasophrynx from bony overgrowth ix. Psychomotor retardation
a) Secondary to hydrocephalus
b) Secondary to apnea due to upper airway obstruction
c) Common in carbonic anhydrase isoenzyme type II deficiency
x. Bone marrow failure
a) Results from bone marrow encroachment b) Leads to extramedullary hematopoiesis
and hepatosplenomegaly (abdominal pro- tuberance)
c) Frequently progresses to hypersplenism and pancytopenia
d) Signs secondary to thrombocytopenia (petechi- ae, ecchymoses, epistaxis, melena, gingival bleeding, intracerebral hemorrhages) e) Carries a high mortality
2. Autosomal dominant osteopetrosis type I a. Chronic bone pain
b. Cranial nerve palsies c. Hearing loss
d. Not associated with increased fracture rate
3. Autosomal dominant osteopetrosis type II (Albers- Scho˝nberg disease)
a. Originally described by Albers-Scho˝nberg in 1904 b. The most common form of osteopetrosis
c. The prevalence: 5.5 in 100,000
d. The term “benign osteopetrosis”: a misnomer for autosomal dominant osteopetrosis type II because of the possibility of severe clinical complications e. Most prominent symptoms
i. Bone pain
ii. Multiple fractures: frequent (78%), perhaps due to the reduced elasticity of the brittle bone iii. Mandibular osteomyelitis
f. Other signs
i. Hip osteoarthritis
ii. Thoracic or lumbar scoliosis iii. Hearing loss
iv. Visual loss v. Optic atrophy vi. Facial palsy
vii. Multiple dental abscesses 4. “Intermediate” form of osteopetrosis
a. Usually diagnosed during the first decade and survive into adulthood
b. Short stature c. Frontal bossing
d. Mild hepatosplenomegaly
5. Carbonic anhydrase isoenzyme type II deficiency a. Most cases have been reported from Middle East or
the Mediterranean region
b. Osteopetrosis with renal tubular acidosis (usually dis- tal type)
c. Short stature d. Fractures
e. Psychomotor retardation
f. Cranial nerve compression (>50%) g. Optic atrophy and visual loss h. Cerebral calcifications
i. Minor hematological impairment j. Craniofacial features
i. Micrognathia
ii. Narrow prominent nose iii. Poorly developed philtrum k. Abnormal dentition
i. Peg-shaped carious teeth with malocclusion ii. Delayed eruption of the teeth
iii. Retained primary dentition l. Visual failure
m. Episodic hypokalemic paralysis in some patients 6. Vacuolar proton pump deficiency
a. Visual failure
b. Symptomatic hypocalcemia in the first month (50%) i. Early or late neonatal convulsions
ii. Irritability iii. Jittering episodes c. Fractures
d. Mild to severe hematological impairment e. Hepatosplenomegaly
f. Failure to thrive g. Poor growth h. Reduced life span
7. ClC-7 chloride pump deficiency: severe osteopetrosis 8. Neuronopathic osteopetrosis
a. Causing rapid neurodegeneration and death within the first year
b. Widespread axonal spheroids and accumulation of ceroid lipofuscin
c. Often accompanied by severe hematological impairment d. Gross hepatosplenomegaly
e. Severe anemia/thrombocytopenia f. High arched palate
g. Gum hypertrophy h. Hyperreflexia
i. Clonus j. Opisthotonos k. Fisting
l. Poor head control m. Irritability
n. Early death
9. Osteopetrosis with agenesis of corpus callosum: possible variant to neuronopathic osteopetrosis
10. Dysosteosclerosis a. Bone fractures
b. Developmental delay with occasional mental retar- dation
c. Cranial nerve impingement i. Visual loss (optic atrophy) ii. Hearing loss
iii. Facial nerve paralysis d. Osteomyelitis of the mandible e. Macular atrophy of the skin
f. Flattened fingernails 11. Differential diagnosis
a. Hyperostosis corticalis generalisata (van Buchem syndrome)
i. Diffuse/widespread sclerosis of the cortex, usu- ally sparing spine
ii. Hyperphosphatasemia b. Oculo-dento-osseous dysplasia
i. An autosomal dominant disorder ii. Enlarged mandible
iii. Focal osteosclerosis in the pelvis iv. Other findings
a) Microphthalmia b) Large jaw
c) Hypoplasia of tooth enamel c. Osteitis deformans (Paget disease)
i. Localized osteosclerosis in one or a few regions of the skeleton
ii. Local pain
iii. Bone marrow biopsy finding
d. Progressive diaphyseal dysplasia (Camurati-Engelmann disease)
i. An autosomal dominant disorder with variable expression
ii. Caused by domain-specific mutations of the TGFB gene located on chromosome 19q13 encod- ing transforming growth factor β-1
iii. Major clinical features a) Leg pain
b) Muscular weakness c) Waddling gait d) Failure to thrive iv. Major radiographic features
a) Fusiform sclerosis of cortical surfaces and subendosteum
b) Sclerosis of the skull base e. Pyknodysostosis
i. An autosomal recessive disorder ii. Generalized osteosclerosis iii. Open fontanel
iv. Associated with mental retardation and dwar- fism
f. Heavy metals (lead, bismuth)
i. Presence of radiodense lines (Harris lines) ii. Elevated levels of heavy metals
g. Mastocytosis
i. Poorly demarcated sclerosis in the pelvis, ribs, vertebrae, skull, and proximal long bones ii. Not uniformly symmetric
iii. Elevated histamine level h. Renal osteodystrophy
i. Widespread sclerosis of the skeleton ii. Increased density less clear
iii. Elevated serum parathyroid hormone iv. Elevated renal function test
i. Metastatic carcinomas (breast, prostate, lung, kidney, and thyroid)
i. Dispersed in random fashion
ii. Bone marrow biopsy often diagnostic j. Osteosclerosis or myelofibrosis
i. Diffuse increased bone density with a smooth and even density
ii. Bone marrow biopsy finding
DIAGNOSTIC INVESTIGATIONS
1. Blood work-up for infantile malignant osteopetrosis a. Anemia
b. Leukopenia c. Thrombocytopenia d. Reticulocytosis e. Pancytopenia
f. Hypocalcemia
g. Inconsistent hypophosphatemia
h. Defective superoxide generation in peripheral leukocytes 2. Radiographic features
a. Malignant infantile osteopetrosis
i. Increased density of the entire skeleton
ii. Complete absence of the medullary canal in severe cases
iii. Lack of remodeling gives rise to metaphyseal widening or a “club-shaped” appearance of the long bones
iv. “Bone within a bone” phenomena or “endobones”
seen especially in the pelvis, vertebrae, hands, and feet v. Transverse radiolucent bands within the meta- physeal regions of the long bones: attributed to periodic variations in the ability to resorb bone vi. Longitudinal striations in the long bones: attrib-
uted to periosteal elevation by trauma or microfractures
vii. Increasingly thickened skull with a “hair-on- end” appearance
viii. Common occurrence of fractures
a) Especially epiphyseal separations and femur fractures
b) Diaphyseal and metaphyseal fractures: usu- ally transverse or short oblique pattern b. Various subtypes of osteopetrosis
i. Vacuolar proton pump deficiency a) Generalized increased bone density
b) Bone-within-bone appearance due to perio- steal new bone formation
c) Modeling deformities
d) Pseudorickets (widened and irregular meta- physes)
e) Metaphyseal lucencies in some children f) Fractures: common particularly affecting
acromial processes, long bones, posterior ribs, and pubic bones
ii. Carbonic anhydrase isoenzyme type II deficiency a) Thick sclerotic skull base
b) Generalized osteopetrosis c) Faulty modeling of metaphyses d) Transverse striations in metaphyses e) Arcuate striations in iliac bones
f) Bone-within-bone appearance g) Sandwich vertebrae
h) Intracranial calcifications iii. Neuronopathic osteopetrosis
a) Typical findings of severe malignant infan- tile osteopetrosis
b) Mild to severe cerebral atrophy
iv. Osteopetrosis with agenesis of the corpus callosum a) As with neuronopathic osteopetrosis b) Absence of the corpus callosum v. Dysosteosclerosis
a) Thickening and sclerosis of cranial vault, base of skull, ribs, and clavicle
b) Sclerotic long bones with splayed submeta- physeal clear zones
c) Platyspondyly
d) Retarded white matter myelination e) Intracerebral calcifications c. Autosomal dominant osteopetrosis type I
i. Generalized/diffuse osteosclerosis affects espe- cially the cranial vault
ii. Sclerotic skull base
iii. Vertebral bodies comparatively normal but the vertebral arches appearing dense
d. Autosomal dominant osteopetrosis type II (Albers- Scho˝nberg disease)
i. A spectacular radiological appearance with the segmental distribution of dense bone
ii. Characterized by diffuse osteosclerosis, predom- inantly involving spine, pelvis, and skull base a) Thickened vertebral end-plates (“sandwich
vertebrae”, Rugger-Jersey spine)
b) Classic “bone-within-bone” appearance/
endobone structures (especially in pelvis) c) Thickened (dense) skull base
iii. Common sclerotic bands in the metaphyses iv. Fractures
a) Common (78%) b) Heal slowly
v. Mandibular osteomyelitis vi. Hip osteoarthritis (27%)
vii. Thoracic or lumbar scoliosis (24%)
viii. Cranial nerve encroachment leading to hearing loss, bilateral optic atrophy, and/or facial palsy (16%)
3. Major pathologic features
a. General features for malignant infantile osteopetrosis i. Obliteration of the marrow spaces by unre- sorbed primary trabecular bone and calcified cartilage
ii. The cartilage cores not remodeled despite an increased number of osteoclasts
iii. Absent or diminished ruffled border of the osteo- clast by electron microscopy
b. Vacuolar proton pump deficiency: increased osteo- clasts
c. ClC-7 chloride pump deficiency: normal numbers of osteoclasts (in mice)
d. Neuronopathic osteopetrosis
i. Autofluorescent neuronal ceroid lipofuscin ii. Widespread eosinophilic neuroaxonal spheroids e. Autosomal dominant osteopetrosis type I: normal
appearance of trabecular bone remodeling
f. Autosomal dominant osteopetrosis type II (Albers- Scho˝nberg disease)
i. Defective trabecular bone remodeling ii. Increased number of osteoclasts iii. Frequent delayed healing of fractures
iv. Increased total acid phosphatases probably reflects the increased number of osteoclast that are unable to resorb bone
v. Observation of large multinucleated osteoclasts suggests a defect in osteoclast function rather than differentiation, as in infantile osteopetrosis g. Intermediate form
i. Mild to marked increased bone density of the axial skeleton and long bones
ii. Defects of modeling seen especially at the distal femurs which may have “Erlenmeyer flask”
deformity
iii. Frequent coxa vara and pathologic long bone fractures
iv. Problematic dental malocclusion and caries
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal recessive disorder: 25%
ii. Autosomal dominant disorder: low unless one of the parent is affected
b. Patient’s offspring
i. Autosomal recessive disorder: low unless the spouse is a carrier
ii. Autosomal dominant disorder: 50%
2. Prenatal diagnosis a. Prenatal radiography
i. Made at the 25th week of pregnancy at risk for autosomal recessive osteopetrosis
ii. Fetal radiographic findings
a) Marked sclerosis of osteopetrotic bone b) Metaphyseal splaying and clubbing of both
femurs
b. Prenatal diagnosis available for pregnancies with a 25%
risk for fetuses affected with malignant osteopetrosis i. By amniocentesis or CVS
ii. Using linked micro-satellite markers in the region of chromosome 11q12-13
c. DNA mutation analysis of fetal DNA for the pregnancy at risk for malignant autosomal recessive osteopetrosis by amniocentesis or CVS when the mutation is previ- ously characterized in the family
3. Management a. Supportive care
b. Blood transfusion for anemia secondary to a failure of bone marrow development
c. Risk of recurrent infections viewed as an indication for bone marrow transplantation
d. Optical nerve decompression in mildly affected older children
e. Early insertion of ventilatory “grommet” tube for hearing impairment secondary to a combination of bony compression of the nerve, sclerosis of the mid- dle ear ossicles, and/or chronic middle ear effusion f. Nasal gastric feeding for children with chronic anemia
and feeding problems caused by bulbar nerve involve- ment, nasal congestion, and recurrent infections g. A high risk of anesthetic morbidity and mortality in
patients with malignant osteopetrosis primarily related to airway and respiratory factors
h. Manage osteomyelitis i. Pus drainage
ii. Appropriate antibiotic therapy iii. Surgical debridement
iv. Reconstruction if indicated i. Orthopedic cares for fractures
j. Corticosteroids and calcitriol with some short term initial benefit but with debatable long-term benefit k. Recombinant human gamma interferon
i. Enhances bone resorption and leukocyte function ii. Effects on morbidity and survival remain unclear l. Bone marrow or peripheral blood stem cell transplan-
tation
i. Rational: Osteoclasts are derived from hematopoietic stem cells
ii. Long-term disease-free survival has been achieved in approximately 70% of infants receiving trans- plants from matched sibling donors
a) Repopulating the bones with functioning osteoclasts by successful infusion of donor marrow
b) Beginning the process of remodeling and restoration of normal calcium homeostasis c) Radiographic changes of osteopetrosis
expected to gradually returning to normal four months to two years following bone marrow transfusion
d) Improvement and resolution of the rachitic changes: the first observation after bone marrow transplantation
e) Immune recovery f) Improved growth
m. Improving results with the use of high-dose peripher- al blood stem cell grafts for infantile osteopetrosis from alternative donors, including those from parents mismatched for up to one-half of their HLA-type (haploidentical)
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Fig. 1. Radiographs of a girl with Albers-Scho˝ngberg syndrome at 3 years (arm, pelvis, and foot) and at 10 years (arm and chest) showing sclerotic bones with loss of corticomedullary differentiation, fracture at the left humerus, and endobone appearance of phalanges of the hands and feet.
Fig. 2. A 14-year-old boy with osteopetrosis showing sclerotic bones with loss of corticomedullary differentiation and multiple fractures, illustrated by a series of radiographs.
