Approach Considerations
Laboratory findings in infantile osteopetrosis include the following:
- Serum calcium - Generally reflects oral intake; hypocalcemia can occur and cause rickets if it is severe enough
- Parathyroid hormone (PTH) - Often is elevated (secondary hyperparathyroidism)
- Acid phosphatase - Increased due to increased release from defective osteoclasts
- Creatinine kinase isoform BB (CK-BB) - levels are increased due to increased release from defective osteoclasts
Laboratory findings in adult osteopetrosis include the following:
- Acid phosphatase and CK-BB - Concentrations are often increased in type II disease
- Serum bone-specific alkaline phosphatase - Values may also be increased in various types of the disease
Genetic screening
In addition to the routine laboratory investigations listed above, mutation screening of appropriate candidate genes should be undertaken in patients whose presentation corresponds to any of the known genetic lesions. Knowledge of the molecular basis of the osteopetrosis allows clinicians to provide informed genetic counseling and, in some cases, to choose appropriate therapy.
Procedures
Bone biopsy is not essential for diagnosis, because radiographs usually are diagnostic. Histomorphometric studies of bone may be useful to predict the likelihood that BMT will succeed. Patients with crowded bone marrow are less likely than others to respond to a transplant.
Histologic findings
Failure of osteoclasts to resorb skeletal tissue is the pathognomonic feature of true osteopetrosis. Remnants of mineralized primary spongiosa are seen as islands of calcified cartilage within mature bone. Woven bone is commonly seen. Osteoclasts can be increased, normal, or decreased in number.
Histologic analysis has revealed that type I adult-onset osteopetrosis is not a genuine form of osteopetrosis, because it lacks the characteristic findings.
Radiography
Radiologic features of osteopetrosis are usually diagnostic. Because osteopetrosis encompasses a heterogeneous group of disorders, findings differ according on the variant.[14]
Patients usually have generalized osteosclerosis. Bones may be uniformly sclerotic, but alternating sclerotic and lucent bands may be noted in iliac wings and near the ends of long bones. The bones may be clublike or may have the appearance of a bone within bone (endobone). Radiographs may also show evidence of fractures or osteomyelitis.
The entire skull is thickened and dense, especially at the base. Sinuses are small and underpneumatized. Vertebrae are extremely radiodense. They may show alternating bands, known as the rugger-jersey sign (see Table 3).
Differentiating type 1 from type 2 adult osteopetrosis
Two types of adult osteopetrosis are identified on the basis of radiographs. Typing the patient's disease may be important in predicting a fracture pattern, because type II disease appears to increase the risk of fracture (see Table 3). Radiographic characteristics of type I and type II disease are as follows:
- Type I disease - Sclerosis of the skull mainly affects the vault with marked thickening; the spine does not show much sclerosis.
- Type II disease - Sclerosis is found mainly in the base of the skull; the spine always has the rugger-jersey appearance, and the pelvis always shows subcristal sclerosis; transverse banding of metaphysis is common in patients with type II disease but not in patients with type I disease (this finding confirms type II disease, but its absence does not necessarily indicate type I disease)
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| Characteristic | Adult onset | Infantile | Intermediate |
| Inheritance | Autosomal dominant | Autosomal recessive | Autosomal recessive |
| Bone marrow failure | None | Severe | None |
| Prognosis | Good | Poor | Poor |
| Diagnosis | Often diagnosed incidentally | Usually diagnosed before age 1y | Not applicable |
| Gene | Protein | Lesion | Phenotype | Human Equivalent | Key References |
| Csf1 | M-CSF | Naturally occurring op allele (frame shift) | Reduced size, short limbs, domed skull, absence of teeth, poor hearing, poor fertility, extramedullary hematopoiesis, rescued by administration of M-CSF | None known | Yoshida et al, 1990 |
| Csf1r | M-CSF receptor | Targeted disruption in exon 3 | Reduced size, short limbs, domed skull, absence of teeth, poor fertility, extramedullary hematopoiesis, slightly more severe than Csf1opphenotype | None known | Dai et al, 2002 |
| Tnfsf11 | RANKL | Targeted disruptions | Osteopetrosis, failure of lymph nodes to develop | None known | Kong et al, 1999; Kim et al, 2000 |
| Tnfrsf11a | RANK | Targeted disruptions | Osteopetrosis, failure of lymph nodes to develop | Duplications in exon 1 found in Paget disease and in familial expansile osteolysis | Li et al, 2000 |
| Ostm1 | Osteopetrosis-associated transmembrane protein 1 | Naturally occurring deletion | Abnormal coat color, short lifespan, chondrodysplasia, failure of tooth eruption, osteopetrosis | Infantile malignant osteopetrosis | Chalhoub et al, 2003 |
| Acp5 | Tartrate resistant acid phosphatase (acid phosphatase 5) | Targeted disruption | Chondrodysplasia, osteopetrosis | None known | Hayman et al, 1996 |
| Car2 | Carbonic anhydrase II | N -ethyl-N -nitrosourea (ENU) mutagenesis | No skeletal phenotype in mouse, renal tubular acidosis, growth retardation | Osteopetrosis with renal tubular acidosis | Lewis et al, 1988 |
| Clcn7 | Chloride channel 7 | Targeted disruptions | Chondrodysplasia, osteopetrosis, failure of tooth eruption, optic atrophy, retinal degeneration, premature death | Autosomal dominant type 2 osteopetrosis, autosomal recessive osteopetrosis | Kornak et al, 2001; Cleiren et al, 2001 |
| Ctsk | Cathepsin K | Targeted disruption | Osteopetrosis with increased osteoclast surface | Pycnodysostosis | Saftig et al, 1998; Kiviranta et al, 2005 |
| Gab2 | Grb2 -associated binder 2 | Targeted disruption | Osteopetrosis, defective osteoclast maturation | None known | Wada et al, 2005 |
| Mitf | Micro-ophthalmia–associated transcription factor | Spontaneous mutations, ENU mutagenesis, radiation mutagenesis, targeted disruption, untargeted insertional mutagenesis | Pigmentation failure, failure of tooth eruption, osteopetrosis, microphthalmia, infertility in both sexes | Waardenburg syndrome, type 2a; Tietz syndrome, ocular albinism with sensorineural deafness | Hodgkinson et al, 1993; Steingrimsson et al, 1994 |
| Src | c-SRC | Targeted disruption | Osteopetrosis, failure of tooth eruption, premature death, reduced body size, female infertility, poor nursing | None known | Soriano et al, 1991 |
| Tcirg1 | 116-kD subunit of vacuolar proton pump | Spontaneous deletion, targeted disruption | Osteopetrosis, failure of tooth eruption, chondrodysplasia, small size, premature death | Autosomal recessive osteopetrosis | Li et al, 1999; Scimeca et al, 2000; Frattini et al, 2000 |
| Traf6 | Tumor necrosis factor (TNF)-receptor–associated factor 6 | Targeted disruptions | Osteopetrosis, failure of tooth eruption, decreased body size, premature death, impaired maturation of dendritic cells | None known | Naito et al, 1999; Lomaga et al, 1999; Kobayashi et al, 2003 |
| Characteristic | Type I | Type II |
| Skull sclerosis | Marked sclerosis mainly of the vault | Sclerosis mainly of the base |
| Spine | Does not show much sclerosis | Shows the rugger-jersey appearance |
| Pelvis | No endobones | Shows endobones in the pelvis |
| Transverse banding of metaphysis | Absent | May or may not be present |
| Risk of fracture | Low | High |
| Serum acid phosphatase | Normal | Very high |
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