75 Osteopetrosis, Infantile Type
Albers-Schönberg disease, marble bone disease, malignant and lethal forms of osteopetrosis included
Large square head, ptosis, deterioration in vision, pro- gressive deafness, chronic nasal congestion, anemia, hepatosplenomegaly, brittle bones, early death
Frequency: Rather rare; estimated incidence 1 in 200,000 (more than 500 published cases); higher fre- quency in Costa Rica and Saudi Arabia.
Genetics
Autosomal recessive (OMIM 259700, 259720); caused either by mutation in the TCIRG1 subnunit of the vacuolar proton pump at 11q13.4-q13.5, or by muta- tion in the chloride channel (CLCN7) gene at 16p13;
mutation detected also in the human homolog of the mouse ‘grey-lethal’ gene (GL) at 6q21.
Clinical Features
• Enlarged, square head, prominent forehead
• Hypertelorism, ptosis, strabismus, nystagmus, blindness due to optic nerve compression
• Delayed dentition, dental caries
• Chronic rhinitis
• Recurrent infections, osteomyelitis of mandible
• Hearing loss
• Hydrocephalus (from narrowing of foramina at skull base)
• Leukoerythroblastic anemia (extramedullary hematopoiesis)
• Hepatosplenomegaly
• Severe anemia, pancytopenia (obliteration of marrow cavity)
• Hypocalcemia, tetany
• Failure to thrive
• Multiple fractures (of prenatal onset in the lethal form)
• Early death (perinatal in the lethal form, in 1
stde- cade in less severely affected patients if untreated)
Differential Diagnosis
• Osteopetrosis, benign (adult type, AD)
• Osteopetrosis, intermediate (AR)
• Osteopetrosis with paraplegia
• Osteopetrosis with renal tubular acidosis
• Osteomesopyknosis
• Pyknodysostosis
Radiographic Features Generalized Bone Defects
• Uniformly dense skeleton (by 3 months of age), with lack of differentiation between cortex and medullary cavity
• Undermodeled, clubbed metaphyses
• In longer survivors,evidence of intermittent activ- ity of sclerosing process: alternating radiolucent and sclerotic transverse bands in metaphyses of long bones; arcuate bands paralleling the iliac crests; bone-within-bone appearance (central portions homogeneously dense, peripheral por- tions less dense, irregularly structured); ‘sand- wich’ appearance of vertebral bodies (dense end- plates, normal density centrally)
• Multiple fractures Skull
• Thick, dense skull, most pronounced at the base
• Sclerosis of orbital margins and sphenoid bones
• Narrowing of foramina of skull
• Poorly aerated sinuses and mastoids
• Malformed teeth Chest
• Homogeneously dense ribs and clavicles
• Enlargement of liver shadow
Bibliography
Armstrong DG, Newfield JT, Gillespie R. Orthopedic manage- ment of osteopetrosis: results of a survey and review of the literature. J Pediatr Orthop 1999; 19: 122–32
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Clin Genet 1987; 31: 86–90
Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, Villa A, Vacher J. Grey-lethal mutation in- duces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 2003; 9: 399–406
Dudin AA, Rambaud-Cousson A. Syndrome of infantile osteo- petrosis and Hirschsprung disease in seven children born to four consanguineous unions in two families. Am J Med Genet 1993; 47: 1083–5
Elster AD, Theros EG, Key LL, Stanton C. Autosomal recessive osteopetrosis: bone marrow imaging. Radiology 1992; 182:
507–14
Elster AD, Theros EG, Key LL, Chen MY. Cranial imaging in autosomal recessive osteopetrosis. Part II. Skull base and brain. Radiology 1992; 183: 137–44
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Gorlin RJ. Craniotubular bone disorders. Pediatr Radiol 1994;
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Loria-Cortes R, Quesada-Calvo E, Cordero-Chaverri E. Osteo- petrosis in children: a report of 26 cases. J Pediatr 1977; 91:
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Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savarirayan R, Villa A, Orchard P, Vezzoni P, Albertini A, Frattini A, Pagani F. TCIRG1-dependent recessive osteopet- rosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA. Hum Mutat 2004; 24: 225–35
Osteopetrosis, Infantile Type 805
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Fig. 75.1 a, b. Patient 1, age 3 months. Calvarium, skull base, and facial bones are thickened and sclerotic. Striking sclerosis of the orbital margins. Mandibular angle is markedly increased
a b
Fig. 75.2. a, b Patient 2, newborn. Diffuse increase in density of the vertebrae, thoracic cage, and acetabula. Note vertebral notches due to vascular channels. c Patient 3, age 2 years and 6 months. Vertebrae, ribs, and clavicles are homogeneously dense
a b c
Osteopetrosis, Infantile Type 806
Fig. 75.3. a Patient 1, age 3 months. Note diffuse sclerosis of the central por- tions of pelvic bones and proximal femurs, surrounded by a thin contour of reduced density (bone-within-bone appearance). b Patient 1, age 3 months.
Long bones are uniformly sclerotic, with lack of cortical and cancellous bone demarcation. Metaphyses are undermodeled and are crossed by transverse bands of decreased density, testifying to periods of rest and renewed growth
a
b
Fig. 75.4. a Patient 1, age 3 months.
Note diffuse sclerosis involving tubular bones in arm and hand, with absent differentiation be- tween cortex and medullary cavi- ty. Note also metaphyseal flaring, and subtle metaphyseal transverse lines of decreased density at wrist. b Patient 3, age 2 years and 6 months. Uniform sclerosis is seen at ends of tubular bones of hand, while shafts are essentially unaffected
a b
