Osteopetroses, emphasizing potential approaches to treatment.

Osteopetroses are a heterogeneous group of rare genetic bone diseases sharing the common hallmarks of reduced osteoclast activity, increased bone mass and high bone fragility. Osteoclasts are bone resorbing cells that contribute to bone growth and renewal through the erosion of the mineralized matrix. Alongside the bone forming activity by osteoblasts, osteoclasts allow the skeleton to grow harmonically and maintain a healthy balance between bone resorption and formation. Osteoclast impairment in osteopetroses prevents bone renewal and deteriorates bone quality, causing atraumatic fractures. Osteopetroses vary in severity and are caused by mutations in a variety of genes involved in bone resorption or in osteoclastogenesis. Frequent signs and symptoms include osteosclerosis, deformity, dwarfism and narrowing of the bony canals, including the nerve foramina, leading to hematological and neural failures. The disease is autosomal, with only one extremely rare form associated so far to the X-chromosome, and can have either recessive or dominant inheritance. Recessive ostepetroses are generally lethal in infancy or childhood, with a few milder forms clinically denominated intermediate osteopetroses. Dominant osteopetrosis is so far associated only with mutations in the CLCN7 gene and, although described as a benign form, it can be severely debilitating, although not at the same level as recessive forms, and can rarely result in reduced life expectancy. Severe osteopetroses due to osteoclast autonomous defects can be treated by Hematopoietic Stem Cell Transplant (HSCT), but those due to deficiency of the pro-osteoclastogenic cytokine, RANKL, are not suitable for this procedure. Likewise, it is unclear as to whether HSCT, which has high intrinsic risks, results in clinical improvement in autosomal dominant osteopetrosis. Therefore, there is an unmet medical need to identify new therapies and studies are currently in progress to test gene and cell therapies, small interfering RNA approach and novel pharmacologic treatments.

[Genetic basis for skeletal disease. Molecular advances in sclerosing bone disorders].

Sclerosing bone disorders are caused by impaired osteoclastic bone resorption or increased bone formation. Osteopetrosis, a representative disease caused by impaired bone resorption, is a heterogeneous disease, and various molecules have been recently identified to be responsible. In infantile malignant osteopetrosis, there are osteoclast-rich and osteoclast-poor forms, which are caused by dysfunction of osteoclasts and impaired osteoclastogenesis, respectively. As to the sclerosing bone diseases related to the increased bone formation, molecular analyses of these disorders uncovered the involvement of TGF-beta and Wnt signaling in the regulation of bone mass.

Marathon of Eponyms: 1 Albers-Schönberg disease (osteopetrosis).

The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009 in press). The use of eponyms in diseases of the head and neck is mainly in specialities dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This paper summarises data about Albers-Schönberg disease.

Genetics, pathogenesis and complications of osteopetrosis.

Human osteopetrosis is a rare genetic disorder caused by osteoclast failure, which ranges widely in severity. In the most severe forms, deficient bone resorption prevents enlargement of bone cavities, impairing development of bone marrow, leading to hematological failure. Closure of bone foramina causes cranial nerve compression with visual and hearing deterioration. Patients also present with osteosclerosis, short stature, malformations and brittle bones. This form is fatal in infancy, has an autosomal recessive inheritance and is cured with hematopoietic stem cell transplantation, with a rate of success <50% and unsatisfactory rescue of growth and visual deterioration. It relies on loss-of-function mutations of various genes, including the TCIRG1 gene, encoding for the a3 subunit of the H+ATPase and accounting for >50% of cases, the ClCN7 and the OSTM1 genes, which have closely related function and account for approximately 10% of cases, also presenting with neurodegeneration. Further genes are implicated in rare forms with various severities and association with other syndromes and, recently, the RANKL gene has been found to be mutated in a subset of patients lacking osteoclasts. Autosomal recessive osteopetrosis may also have intermediate severity, with a small number of cases due to loss-of-function mutations of the CAII or the PLEKHM1 genes. Dominant negative mutations of the ClCN7 gene cause the so-called Albers-Schönberg disease, which represents the most frequent and heterogeneous form of osteopetrosis, ranging from asymptomatic to intermediate/severe, thus suggesting additional genetic/environmental determinants affecting penetrance. Importantly, recent work has demonstrated that osteoblasts may also contribute to the pathogenesis of the disease, either because they are affected by intrinsic defects, or because their activity may be enhanced by deregulated osteoclasts abundantly present in most forms. Therapy is presently unsatisfactory and effort is necessary to unravel the gene defects yet unrecognized and identify new treatments to improve symptoms and save life.

Marble bone disease: a review of osteopetrosis and its oral health implications for dentists.

Osteopetrosis is one cause of osteosclerosis and may result in such serious oral complications as osteomyelitis and exposed necrotic bone. Dentists should be aware of patients with the disease because of its effect on osteoclast function, which results in impaired wound healing. The purpose of this paper is to review the causes, pathogenesis and differential diagnosis of osteopetrosis and to provide guidance to dentists on the management of patients with osteopetrosis.

Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II.

CONTEXT: Genetic factors are important determinants of bone mineral density (BMD). The fact that mutations in the ClC-7 chloride channel cause autosomal dominant osteopetrosis (ADOII) make the CLCN7 gene an attractive candidate for the regulation of bone density. OBJECTIVE: The objective of the study was to investigate the association between polymorphisms in the CLCN7 gene and BMD in postmenopausal women and with clinical variability in ADOII. DESIGN: This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene. PARTICIPANTS: A total of 425 postmenopausal women aged 64 +/- 7 yr participated in the study. We also investigated an ADOII family with low penetrance comprising 18 mutation carriers. MAIN OUTCOME MEASURE(S): In our postmenopausal cohort, individual single-nucleotide polymorphism genotypes and haplotypes were analyzed for association with BMD at the lumbar spine and the femoral neck and with the bone resorption marker deoxypyridinoline (D-Pyr/Crea). The same polymorphisms on the nonmutated CLCN7 allele were investigated for association with the variability of the ADOII phenotype. RESULTS: Analysis by multiple linear regression revealed a significant association between the ss genotype of the VNTR and higher Z-score values (P = 0.029). The haplotype 4, which comprises the long allele of the VNTR, was found to be significantly associated with lower femoral neck Z-score values (P = 0.011). Furthermore, we found an association of the ss genotype of the VNTR with lower levels of the bone resorption marker D-Pyr/Crea (P = 0.015), whereas haplotype 4 was associated with higher D-Pyr/Crea levels (P = 0.039). In the ADOII family, we could demonstrate that haplotype 3, which contains the s-allele of the VNTR, is associated with a slightly higher probability that mutation carriers develop osteopetrosis (P = 0.029). In both cases the association seems largely to be driven by the VNTR genotype but is further strengthened if surrounding polymorphisms are added to the analysis. CONCLUSION: We observed a significant association of CLCN7 polymorphisms with the variance of BMD and bone resorption marker levels in postmenopausal women and with the variability of the ADOII phenotype.

Osteopetrosis--a review and report of two cases.

We present a brief review of the rare condition of osteopetrosis together with two case reports of this disease in the same family affecting the jaws. The first in a 41-year-old woman, and the second in her 39-year-old brother. Plain films and computed tomography showed marked sclerosis of the affected bones with obliteration of the medullary cavities and thickening of the cortices as well as multiple absent and unerupted teeth. In addition radiographs showed discrete mixed radiopaque/radiolucent areas consistent with the appearance of fibro-cemento-osseous dysplasia, but which may also represent part of the overall spectrum of bone changes in osteopetrosis.

Measurement of tartrate-resistant acid phosphatase and the brain isoenzyme of creatine kinase accurately diagnoses type II autosomal dominant osteopetrosis but does not identify gene carriers.

Autosomal dominant osteopetrosis type II (ADO2) is typically diagnosed from radiographs, which demonstrate the pathognomonic findings of osteosclerosis and endobone formation. Individuals with ADO2 also have elevated serum levels of tartrate-resistant acid phosphatase (TRAP) and the BB isoenzyme of creatine kinase (CK-BB). In the current study, we tested the utility of these enzymes in making or refuting a diagnosis of ADO2. Furthermore, because ADO2 has incomplete penetrance, we examined whether TRAP and CK-BB were helpful in identifying gene carriers. We studied eight families, measured serum levels of TRAP and CK-BB in 52 affected individuals and 12 obligate gene carriers, and compared their values with age-matched controls. Our results demonstrate that affected patients have significantly elevated levels of both TRAP and CK-BB. In contrast, gene carriers have values that are not different from controls. Furthermore, in our study population, TRAP and CK-BB have a high diagnostic sensitivity and specificity, particularly in children. From this large study of ADO2 patients and carriers, we conclude that: 1) TRAP and CK-BB are significantly elevated in patients with ADO2, 2) obligate carriers cannot be adequately identified by measurement of these analytes, and 3) TRAP and CK-BB are highly sensitive and specific diagnostic tests that can efficiently and effectively screen high-risk individuals who have not had previous radiographic assessment.

Autosomal dominant osteopetrosis: report of a Norwegian family with radiographic or anamnestic findings differing from the generally accepted classification.

OBJECTIVE: Autosomal dominant osteopetrosis is currently divided into two, possibly three subgroups. The present study of a Norwegian family, however, suggests that such a grouping is not generally valid. PATIENTS AND METHODS: A Norwegian family has been studied over four generations. Information about the two older generations was obtained mainly from hospital files and by interviewing members of the family. Radiographs were obtained from the two younger generations. RESULTS AND CONCLUSION: Of a total 14 family members, nine patients consisting of six women and three men were studied. Within the same family, patients could be classified as belonging to different subgroups of osteopetrosis defined elsewhere, and at least three of them could be classified as belonging to more than one group. The present study suggests that the generally accepted classification of autosomal dominant osteopetrosis should be questioned.

Creatine kinase brain isoenzyme (BB-CK) presence in serum distinguishes osteopetroses among the sclerosing bone disorders.

Creatine kinase (CK) isoenzyme BB-CK is predominantly found in brain and is not normally detected in the blood. A few recent reports, however, have described BB-CK in serum from several patients with osteopetrosis (OP). To evaluate the presence and specificity of BB-CK in serum in the osteopetroses among disorders that increase skeletal mass, we quantitated total CK activity and CK isoenzymes in 15 patients representing the five major clinical forms of OP (2 infantile, 3 intermediate, 7 adult [2 type I, 5 type II], and 3 carbonic anhydrase II [CA II] deficiency cases) and in 22 patients representing 14 other types of sclerosing bone disease. All OP patients (except the two adult type I subjects) had BB-CK readily detected in their serum. Conversely, only 1 of the 22 patients with other sclerosing bone disorders had detectable BB-CK in serum (1 of 3 patients with fibrodysplasia [myositis] ossificans progressiva who had barely measurable activity). In three OP patients (one of two with the infantile form and two of five with adult, type II disease), BB-CK values were sufficiently high that serum total CK activity was elevated. In a newborn with malignant OP, both cord blood plasma and peripheral blood serum had substantial amounts of BB-CK. In three subjects (with adult type II OP), who were restudied 2-6 years later, BB-CK was still elevated in their blood. BB-CK in serum appears to distinguish the osteopetroses among the sclerosing bone disorders. Absence of serum BB-CK in adult type I disease suggests that this condition may not be a genuine form of OP. Assay of BB-CK in fetal blood could be studied as a means for prenatal diagnosis of malignant OP. Why the osteoclast failure that characterizes all true forms of OP is associated with BB-CK in the circulation is a new question for skeletal biologists.

Autosomal dominant osteopetrosis: bone mineral measurements of the entire skeleton of adults in two different subtypes.

Bone mineral content (BMC) and density (BMD) were measured by dual-energy X-ray absorptiometry in two subtypes of autosomal dominant osteopetrosis (ADO). Both types have been radiologically characterized by diffuse symmetrical osteosclerosis, but with characteristic differences. Increased thickness of the cranial vault is a typical finding in type I ADO, whereas endobones in the pelvis and end-plate thickening in the spine are obligate findings in type II. Eleven patients with type I from three kindreds, and seven patients with type II, one family participated in the study, and were compared with 18 age- and sex-matched normal controls. Whole-body BMC and BMD were measured, and regions of special interest were selected: head, axial, and appendicular skeleton. Moreover, lumbar spine and femoral neck scans were performed. Whole-body BMC and BMD, mostly reflecting cortical bone, were markedly increased in both types compared with normals. A pronounced osteosclerosis was present in the axial as well as the appendicular skeleton. Median BMD was markedly increased in the axial skeleton by 51% (44-56) and 42% (33-56), (median differences with 95% CI), respectively, for types I and II compared to normal controls, and in the appendicular skeleton by 48% (37-59) and 38% (16-45). No overlap between observed ranges of patients and controls was observed. A positive correlation between age and whole-body BMD was demonstrated in ADO, but not in the control group, indicating progressive osteosclerosis with age. Median BMD of the lumbar spine, which mostly reflects trabecular bone, showed increased densities in both types, 71% (51-84) and 59% (37-93), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Benign osteopetrosis: a review of 42 cases showing two different patterns.

Radiographs of 42 patients with benign osteopetrosis were reviewed. Clinical notes were available for approximately half of these. According to the classification of Bollerslev and Andersen in 1987, 29 patients had type II disease of whom 18 sustained fractures. Thirteen patients had type I disease; only one of these patients sustained fractures. Transverse banding of the metaphyses was a common feature in type II disease; it was not seen in any of the type I cases. This review confirms that type II patients are at high risk of fracture, while type I patients are not. The presence of sclerotic metaphyseal bands distinguishes between the two types, its presence being enough to confirm type II. However, its absence is not an indication of type I disease, since it is not seen in all cases of type II. Banding does not correlate with liability to fracture. Typing patients with the benign form of osteopetrosis is important in order to anticipate the fracture pattern.

[Osteopetrosis: report of 2 cases and review of the literature]. / Osteopetrose: relato de dois casos e revisão da literatura.

Osteopetrosis is a rare inherited disease with incidence of 1:500.000 in north american population and characterized by increased skeletal density and fractures. Clinically three types can be distinguished: infantile malignant form, benign form of adult and intermediate type. We report two cases of intermediate form describing and commenting the clinical and radiological features.

[Recessive osteopetrosis. Identification of a form of medium severity]. / La forme récessive de l'ostéopétrose. Individualisation d'une forme de gravité intermédiaire.

BACKGROUND: Several distinct forms of osteopetrosis have been identified. Some of the autosomally recessive inherited forms are benign, much like the autosomal dominant form. Others are more malignant. PATIENTS: The clinical data, skeletal radiographs, histological features and histories of 32 children with osteopetrosis were analyzed retrospectively. RESULTS: The 32 patients, belonging to 20 sibships were divided into two groups. The first group included 24 patients, aged 1 day-11 months (mean 4.5 months), suffering from hepatosplenomegaly, anemia, thrombocytopenia and optic atrophy in early infancy. They also had a generalized increase in bone density, abnormal bone remodeling, rachitic lesions and a "bone-within-bone" appearance. Biopsies showed severe bone resorption and myelofibrosis. 19 of the 20 patients whose outcomes were known died during the first year of life. The second group included 8 patients, aged 40 days-3 years (mean: 11 months). Hepatosplenomegaly appeared later, anemia was less severe and thrombocytopenia occurred in only 1 patient. However, all 8 patients suffered from optic atrophy and 3 were deaf. Radiographs showed bone growth without rachitic lesions. Biopsies from 2 patients showed bone resorption, but no myelofibrosis. The outcome was less severe: 6 patients, now aged 8 months to 8 years, have survived, 3 of them for over 5 years. Genetic investigation showed patterns compatible with autosomal recessive inheritance in both groups, with similar sets of features within each sibship. CONCLUSION: This study reveals a new type of recessively inherited osteopetrosis. It can be classified as an intermediate form, distinct from both the malignant and the benign forms, and also distinct from osteopetrosis with carbonic anhydrase II deficiency.

Bone surface structure in osteopetrotic grey lethal (gl/gl) and microphthalmic (mi/mi) mutant mice as revealed by scanning electron microscopy.

The surface structure of bone from two genetically distinct osteopetrotic strains of mice, grey lethal (gl) and microphthalmic (mi) has been examined by scanning electron microscopy. Although both conditions produce a classical osteopetrotic phenotype the means by which this is achieved is quite different. gl mice appear to retain woven bone and show no evidence of resorption: mi mice show evidence of imperfect remodelling. These results are in accordance with what is already known of osteoclast structure and function in these mutations.

Radiological, biochemical and hereditary evidence of two types of autosomal dominant osteopetrosis.

Review of the radiographs of 34 patients with autosomal dominant osteopetrosis revealed two distinct phenotypical types. Both were strictly family-related and exhibited progressive sclerosis with aging. Descriptive, radiogrammetric and biochemical analyses were performed. Type I showed a pronounced sclerosis of the skull with an enlarged thickness of the cranial wall. The 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 ("bone within a bone") were seen in the pelvis. The radiogrammetric investigations of the long bones did not show any difference between the two types. Compared to normal controls, there was a normal total subperiosteal width (W), but a significant enlarged cortical thickness (C) (P less than 0.01), and thus a reduced medullary cavity (M), suggesting normal bone formation and disturbed bone resorption. 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 two types in bone mineral metabolism and structural functions of the osteoclasts. The two types may represent two different entities with the same mode of inheritance, and in both cases with affected bone resorption.