Alternative titles; symbols
SNOMEDCT: 725050005; ORPHA: 53; DO: 0110938;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Osteopetrosis, autosomal dominant 2 | 166600 | Autosomal dominant | 3 | CLCN7 | 602727 |
A number sign (#) is used with this entry because of evidence that autosomal dominant osteopetrosis-2 (OPTA2) is caused by heterozygous mutation in the CLCN7 gene (602727) on chromosome 16p13.
An autosomal recessive form of osteopetrosis (OPTA4; 611490) is also caused by mutation in the CLCN7 gene.
Autosomal dominant osteopetrosis-2 (OPTA2) is characterized by segmentary osteosclerosis, predominantly at the vertebral endplates ('rugger-jersey spine'), iliac wings ('bone within bone' sign), and skull base. Clinical manifestations include cranial nerve palsies, mandibular osteomyelitis, osteoarthritis of the hip, and nontraumatic fractures, particularly of the long bones (Cleiren et al., 2001). OPTA2 accounts for 70% of cases of autosomal dominant osteopetrosis (Del Fattore et al., 2008).
For a discussion of genetic heterogeneity of autosomal dominant osteopetrosis, see OPTA1 (607634).
Salzano (1961) reviewed dominant cases of osteopetrosis and found that fragility of bones and dental abscess are leading complications. A more malignant form, inherited as a recessive (see OPTB1, 259700), causes anemia and early death from interference with the bone marrow. Welford (1959) described 14 affected male members of 5 generations of a family. All affected persons had facial paralysis beginning usually at about the age of 12 years. Main clinical features are fractures and osteomyelitis, especially of the mandible. By x-ray the vertebral bodies have a characteristic 'sandwich' appearance resulting from sclerosis of the upper and lower plates with intervening less dense area. Long bones of the extremities may show a 'bone-within-bone' appearance. Osteosclerosis, sometimes termed osteopetrosis, is a feature of pycnodysostosis (265800). Follow-up on the family reported by Ghormley (1922) was provided by McKusick (1961). Johnston et al. (1968) studied 2 families. In one pedigree, the disorder was twice nonpenetrant. Elevated acid phosphatase was a feature in all but one of the affected persons.
Andersen and Bollerslev (1987) suggested that autosomal dominant osteopetrosis has 2 distinct radiologic types. Both have universal osteosclerosis, but in type I, the most striking finding is pronounced sclerosis of the cranial vault while the spine is almost unaffected; in type II, the sclerosis of the skull is most pronounced at the base, the vertebrae always have endplate thickening, and in the pelvis, the iliac wings contain convex arcs of sclerotic bone. Age and sex distribution did not differ between the types and each 'bred true' within given families.
By review of radiographs of 34 patients with autosomal dominant osteopetrosis, Bollerslev and Andersen (1988) defined 2 distinct types. Type I showed pronounced sclerosis of the skull with an enlarged thickness of the cranial wall. Sclerosis of the skull in type II was most striking at the base. In type II, there was a typical 'rugger-jersey spine,' and endobones (bones within a bone) were seen in the pelvis. Radiographic studies of the long bones did not show any difference between the 2 types. Compared to normal controls, there was a normal total subperiosteal width, but a significantly increased cortical thickness, and thus a reduced medullary cavity, suggesting normal bone formation and disturbed bone resorption. Bollerslev and Andersen (1988) found that serum phosphate was lower in type I compared to type II (P less than 0.01), and serum acid phosphatase was markedly increased in type II (P less than 0.01), suggesting differences between the 2 types in bone mineral metabolism and structural function of the osteoclasts.
Walpole et al. (1990) described a large Australian family known to have 13 cases of osteopetrosis in 4 generations. The phenotypic spectrum varied from an asymptomatic condition in adults to a severely affected infant in the most recent generation who presented with anemia, hepatosplenomegaly, hydrocephalus, and blindness. Although the wide spectrum of severity in osteopetrosis is well known, they found only 1 report of the severe infantile form occurring in a dominant pedigree with mainly mild adult cases (Thomson, 1949). It is possible that the mother of the severely affected proband had osteopetrosis or that the father was heterozygous for the infantile form, making the proband a compound heterozygote. The possibility of an extramarital mating with another osteopetrotic individual was considered unlikely, but paternity was not checked with markers.
Bollerslev and Mosekilde (1993) found that bone resorption appears to be defective and bone formation normal in both types of patients. The frequency of fractures is increased in type II patients and normal in type I patients, in whom biomechanical investigations have shown normal or even increased trabecular bone strength.
Benichou et al. (2000) reported the clinical and radiologic manifestations in 42 patients with autosomal dominant osteopetrosis, purportedly the largest series reported to that time. The inclusion criterion was presence on radiographs of the spine of vertebral endplate thickening, producing the classic sandwich vertebra appearance. They found various patterns of sandwich vertebra. The classic bone-within-bone appearance was present in most but not all skeletal sites. The radiologic penetrance of the disease was high (90%) and increased after 20 years of age. As many as 81% of their patients experienced clinical manifestations. Fractures were common (78% of patients) and healed slowly. Hip osteoarthritis developed in 27% of patients and required arthroplasty in 9 of the 16 affected hips. Nonmandibular osteomyelitis occurred in 4 cases (11%); 24% of patients had thoracic or lumbar scoliosis. Orthopedic surgery was performed in 52.8% of patients, of whom half had at least 3 surgical procedures for internal fracture fixation, arthroplasty, limb deformity correction, or treatment of surgical complications. There was a high rate of surgical complications, including nonunion, infection, prosthesis loosening, and intraoperative fractures. Nearly two-thirds of patients (64%) had stomatologic manifestations, including mandibular osteomyelitis in 4 patients (11%). Cranial nerve involvement responsible for hearing loss, bilateral optic atrophy, and/or facial palsy was present in 14 patients but was clearly attributable to the osteopetrosis in only 6 cases (16%). Benichou et al. (2000) suggested that the name 'benign osteopetrosis' is a misnomer.
Waguespack et al. (2007) studied 311 subjects from 11 families segregating autosomal dominant osteopetrosis caused by mutation in the CLCN7 gene: 62 individuals with OPTA2, 32 unaffected mutation carriers, and 217 controls. Ninety-two percent of OPTA2 patients had at least one sequela of the disease. Gene carriers did not have an increased risk of disease manifestations, but were found to have significant increases in bone mineral density (p less than 0.05). Compared with controls, patients had a significantly increased prevalence of fracture (84 vs 36%; p less than 0.0001) and osteomyelitis (16 vs 0.9%; p less than 0.0001). Severe fractures (defined as greater than 10 fractures of any type and/or greater than 1 hip/femur fracture) were identified only in patients, and osteomyelitis typically occurred in the maxilla or mandible in older adults. Severe vision loss occurred in 12 (19%) of 62 patients, and in 11 of the 12 cases, the onset was clearly in childhood. Two patients (3%) had significant bone marrow failure, requiring hematologic supportive care. Waguespack et al. (2007) concluded that OPTA2 is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, as well as occasional bone marrow failure. Sequelae of OPTA2, which can be identified as early as infancy, appear to worsen over time. Fracture is the most prevalent consequence of OPTA2, although other more severe manifestations of disease can occur and should not be confused with recessive forms of osteopetrosis, particularly when identified in early childhood.
The transmission pattern of OPTA2 in the families reported by Cleiren et al. (2001) was consistent with autosomal dominant inheritance.
Yoneyama et al. (1989) found elevated creatine kinase of the so-called BB type (CKB; 123280) in 3 adults with osteopetrosis. Yoneyama et al. (1992) demonstrated marked elevation of BB isozyme fraction of serum creatine kinase for male sibs with this disorder. Patients with other sclerosing bone diseases showed no such elevation. Hiroyama et al. (1987) found the brain isozyme to be elevated in infantile osteopetrosis (see OPTB1, 259700).
Individuals with autosomal dominant osteoporosis type II (OPTA2) have elevated serum levels of tartrate-resistant acid phosphatase (TRAP; 171640) and the BB isoenzyme of creatine kinase (CKBB). Waguespack et al. (2002) tested the utility of these enzymes in making or refuting a diagnosis of OPTA2. Furthermore, because OPTA2 has incomplete penetrance, they examined whether TRAP and CKBB were helpful in identifying gene carriers. They studied 8 families, measured serum levels of TRAP and CKBB in 52 affected individuals and 12 obligate gene carriers, and compared their values with those of age-matched controls. Their results demonstrated that affected patients have significantly elevated levels of both TRAP and CKBB. In contrast, gene carriers have values that are not different from those of controls. Furthermore, in their study population, TRAP and CKBB had a high diagnostic sensitivity and specificity, particularly in children. Waguespack et al. (2002) concluded that (1) TRAP and CKBB are significantly elevated in patients with OPTA2; (2) obligate carriers cannot be adequately identified by measurement of these analyses; and (3) measurements of TRAP and CKBB are highly sensitive and specific diagnostic tests that can efficiently and effectively screen high-risk individuals who have not had previous radiographic assessment.
Key et al. (1984) demonstrated benefit from the potent bone-resorbing agent calcitriol, which is a metabolite of vitamin D.
Salzano (1961) estimated the frequency of the dominant form of osteopetrosis in Brazil to be about 1 in 100,000.
Cleiren et al. (2001) stated that the OPTA2 is the most common form of osteopetrosis, with a prevalence of up to 5.5 cases per 100,000 individuals.
In an extended Danish family with the type II disorder, Van Hul et al. (1997) found presumed linkage to microsatellite markers in the 1p21 region. The chromosomal region was analyzed for possible linkage between Albers-Schonberg disease and the gene for macrophage colony-stimulating factor (CSF1; 120420), a hematopoietic growth factor that plays an important role in the proliferation of macrophages and osteoclasts from hematopoietic stem cells. Refined mapping appeared to exclude CSF1 as the site of the mutation in their family.
White et al. (1999) studied 2 families from Indiana with osteopetrosis type II to determine if the disease locus in these families was also linked to chromosome 1p21. They used 6 microsatellite repeat markers which demonstrated linkage to the CSF1 region in the Danish study to perform linkage analysis in the new kindreds. Multipoint analysis excluded linkage of the disease to chromosome 1p21 in both families. In addition, no haplotype segregated with the disorder in either family. The authors concluded that there is locus heterogeneity for osteopetrosis type II.
Benichou et al. (2001) performed a genomewide linkage scan of an extended French family with autosomal dominant osteopetrosis type II, which allowed them to localize the disease locus to chromosome 16p13.3. Analysis of microsatellite markers in 5 further families could not exclude this chromosome region. A summed maximum lod score of 12.70 was generated with marker D16S3027, at a recombination fraction of 0.0. On the basis of the key recombinants in the families, a candidate region of 8.4 cM was delineated, flanked by marker D16S521 distally and D16S423 proximally. Surprisingly, one of the families analyzed by Benichou et al. (2001) was the Danish family in which van Hul et al. (1997) found presumed linkage to 1p21. In that family, linkage to 16p13.3 could not be excluded, since a maximum lod score of 4.21 at theta = 0.0 was generated with marker D16S3027. Because no other family with type II osteopetrosis had been proved to have linkage to 1p21, Benichou et al. (2001) considered it most likely that the disease-causing gene was located in this family at 16p13.3. The possibility that type II is genetically homogeneous with a single gene on 16p13.3 was raised.
In affected individuals from 12 unrelated families with autosomal dominant osteopetrosis, including the Danish family initially linked to chromosome 1p21 by Van Hul et al. (1997) and 8 families previously studied by Van Gaal et al. (1978), Manzke et al. (1982), and Benichou et al. (2001), Cleiren et al. (2001) identified heterozygosity for 7 different mutations in the CLCN7 gene (see, e.g., 602727.0004 and 602727.0005). Analysis of microsatellite markers indicated that the mutations arose independently in each family. Additionally, Cleiren et al. (2001) identified 1 patient with the severe autosomal recessive infantile form of osteopetrosis (OPTB4) who was homozygous for a CLCN7 missense mutation (L766P; 602727.0003), for which her asymptomatic parents were heterozygous. The authors concluded that type II autosomal dominant osteopetrosis is allelic to a subset of autosomal recessive osteopetrosis cases.
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