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.

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.

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.

[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.

A review of the osteopetroses.

The osteopetroses are a group of conditions which are characterized by varying combinations of bony sclerosis and modelling defects. Classical osteopetrosis may be inherited as an autosomal dominant or autosomal recessive: the former variety is benign, heterogeneous and comparatively common, while the latter is precocious, potentially lethal and rare. Many other craniotubular dysplasias and hyperostoses are loosely grouped with the osteopetroses. The commonest of these is the autosomal dominant form of craniometaphyseal dysplasia, while the others which are well known include Pyle disease, and van Buchem disease. Sclerosteosis is a progressive condition in which massive cranial thickening is associated with syndactyly and gigantism. Each of these disorders has specific clinical and radiographic features, which permit recognition. Diagnostic accuracy is crucial for treatment, prognostication and effective genetic management.

[Osteopetrosis (Albers-Schoenberg disease). III. Current nosographic aspects and relations to other condensing osteopathies]. / L'osteopetrosi (malattia di Albers-Schönberg) Nota III. - Aspetti nosografici attuali e rapporti con altre osteopatie condensanti

A malignant paediatric variety and an adult variety of Albers-Schönberg disease are normally distinguished. On the basis of recent findings and personal observation it would appear advisable to accept two different courses of Albers-Schönberg disease in adults: one resembling the malignant infant form and the other with slow, practically asymptomatic (apart, obviously, from the skeletal lesions) course allowing for prolonged survival. This classification is of considerable practical importance for prognosis and therapeutic purposes. Other hereditary-familial and constitutional condensing osteopathy pictures exist that present radiological stigmata similar to those seen in Albers-Schönberg disease. The interest of the relations between A-S disease and certain of these condensing osteopathic conditions is obvious.