Background
Osteopetrosis is a clinical syndrome characterized by the failure of osteoclasts to resorb bone. As a consequence, bone modeling and remodeling are impaired. The defect in bone turnover characteristically results in skeletal fragility despite increased bone mass, and it may also cause hematopoietic insufficiency, disturbed tooth eruption, nerve entrapment syndromes, and growth impairment. (See Etiology and Presentation.)
Although human osteopetrosis is a heterogeneous disorder encompassing different molecular lesions and a range of clinical features, all forms share a single pathogenic nexus in the osteoclast. [1] Osteopetrosis was first described in 1904, by German radiologist Albers-Schönberg. (See Etiology.) [2]
Classification
In humans, three distinct clinical forms of the disease—infantile, intermediate, and adult onset—are identified based on age and clinical features. These variants, which are diagnosed in infancy, childhood, or adulthood, respectively, account for most cases. (See Table 1, below.)
Table 1. Clinical Classification of Human Osteopetrosis (Open Table in a new window)
Characteristic |
Adult onset |
Infantile |
Intermediate |
Inheritance |
Autosomal dominant [3] |
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 |
The classification of osteopetrosis shown above is purely clinical and must be supplemented by the molecular insights gained from animal models (see Table 2, in Etiology).
Tables
Characteristic |
Adult onset |
Infantile |
Intermediate |
Inheritance |
Autosomal dominant [3] |
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 |
