Osteopetrosis Clinical Presentation
- Author: Robert Blank, MD, PhD; Chief Editor: George T Griffing, MD more...
History and Physical Examination
Infantile osteopetrosis
Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. Failure to thrive and growth retardation are symptoms.
Bony defects and associated symptoms occur, including the following:
- Nasal stuffiness due to mastoid and paranasal sinus malformation is often the presenting feature of infantile osteopetrosis
- Neuropathies related to cranial nerve entrapment occur due to failure of the foramina in the skull to widen completely
- Manifestations include deafness, proptosis, and hydrocephalus.
- Dentition may be delayed
- Osteomyelitis of the mandible is common due to an abnormal blood supply
- Bones are fragile and can fracture easily
- Defective osseous tissue tends to replace bone marrow, which can cause bone marrow failure with resultant pancytopenia
- Patients suffer from anemia, easy bruising and bleeding (due to thrombocytopenia), and recurrent infections (due to inherent defects in the immune system)
- Extramedullary hematopoiesis may occur, with resultant hepatosplenomegaly, hypersplenism, and hemolysis
- Other manifestations include sleep apnea and blindness due to retinal degeneration
Adult osteopetrosis
Adult osteopetrosis (also called benign osteopetrosis) is diagnosed in late adolescence or adulthood. Two distinct types have been described, type I and type II, on the basis of radiographic, biochemical, and clinical features. (See Table 3, below.)[13]
Table 3. Types of Adult Osteopetrosis (Open Table in a new window)
| 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 |
Approximately one half of patients are asymptomatic, and the diagnosis is made incidentally; the diagnosis often made in late adolescence, because radiologic abnormalities start appearing only in childhood. In other patients, the diagnosis is based on family history. Still other patients might present with osteomyelitis or fractures.
Many patients have bone pains. Bony defects are common and include neuropathies due to cranial nerve entrapment (eg, with deafness, with facial palsy), carpal tunnel syndrome, and osteoarthritis. Bones are fragile and may fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in 10% of patients.
Other manifestations include visual impairment due to retinal degeneration and psychomotor retardation. Bone marrow function is not compromised.
Physical examination
Physical findings are related to bony defects and include short stature, frontal bossing, a large head, nystagmus, hepatosplenomegaly, and genu valgum in infantile osteopetrosis.
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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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