Autosomal Dominant Osteopetrosis Research Articles

Osteopetrosis

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy.

Maxillomandibular osteomyelitis in osteopetrosis. Report of a case and review of the literature

Osteopetrosis is a rare hereditary group of bony displasias. They range from a devastating metabolic disease (including severe malignant infantile osteopetrosis) to other conditions with a more benign phenotype (autosomal dominant osteopetrosis I and II). Several case reports have been published of infectious complications affecting the mandible but maxillary affectation is quite rare. We present the case of a 23-year-old woman with a malignant recessive form of osteopetrosis complicated by repeated episodes of osteomyelitis (caused by actinomyces) of the mandible and maxilla.

CLCN7 polymorphisms and bone mineral density in healthy premenopausal white women and in white men

Introduction Mutations in the chloride channel 7 gene ( CLCN7) cause osteopetrosis, and polymorphisms of CLCN7 in the non-disease allele are associated with penetrance of the autosomal dominant osteopetrosis (ADO) phenotype. Studies have also shown an association between CLCN7 polymorphisms and bone mineral density (BMD) in women. However, there is no study to date that has examined whether CLCN7 polymorphisms underlie normal variation of peak BMD in healthy premenopausal white women and in white men. Methods Six single nucleotide polymorphisms (SNPs) and one variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene were genotyped. Association was tested between CLCN7 gene polymorphisms and both lumbar spine and femoral neck BMD. Healthy premenopausal white sisters (age 33.1 ± 7.2, n = 1692) and healthy white brothers (age 33.6 ± 10.9, n = 715) were studied. Results No significant association between CLCN7 gene polymorphisms and BMD at the lumbar spine or femoral neck was found in white women or white men. Conclusions Genetic variation in the CLCN7 gene is not a major contributor to the variability in peak BMD at the femoral neck and lumber spine in healthy premenopausal white women and in white men.

Case Reports: Treatment of Subtrochanteric and Ipsilateral Femoral Neck Fractures in an Adult with Osteopetrosis

We describe a patient with autosomal-dominant osteopetrosis, a subtrochanteric fracture, and an ipsilateral femoral neck fracture treated with a hip spica cast Although the fracture united with coxa vara and external rotation deformities, the patient successfully returned to his normal activities of daily living. Operative fracture treatment in patients with osteopetrosis is difficult, and our patient provides evidence that with nonoperative treatment these patients can return to a functional level when operative treatment is not an option.

Sclerosing bone disorders

Sclerosing bone disorders are a diagnostic challenge. However, hereditary sclerosing disorders often have characteristic radiological features that allow their diagnosis. Osteocondensation can result from decreased bone resorption; malignant recessive osteopetroses have been related to mutations in several genes necessary for osteoclast function and also, more recently, to osteoclast differentiation (RANK-L). Albers-Schonberg disease or autosomal-dominant osteopetrosis type II has the characteristic 'sandwich vertebrae' and 'bone within bone' radiological features. It has been related to mutation in chloride channel 7, which is necessary for osteoclast acidification. Osteocondensation can also be related to increased bone formation. Camurati-Engelman dysplasia is a disabilitating disorder with leg pain and weakness, and thickening of the diaphysis of long bones on x ray. It is due to activating mutations in the gene encoding TGF-beta, a growth factor that increases bone formation. Other less common recessive or dominant sclerosing disorders, such as endosteal hyperostosis, sclerostosis, van Buchen disease and high bone mass syndrome, are due to mutations in two genes (LRP5 and SOST) of the Wnt pathway that induce increased osteoblast activity. Recent elucidation of the molecular mechanism responsible for several hereditary diseases with osteocondensation has improved our comprehension of bone remodelling. It has allowed the discovery of new targets for the treatment of postmenopausal osteoporosis, some of which are already being investigated in clinical trials. Molecular mechanism for some hereditary osteocondensation remains to be discovered.

Conservative management of bilateral femoral neck fractures in a child with autosomal dominant osteopetrosis

Management of minimally displaced femoral neck fractures in paediatric patients with autosomal dominant osteopetrosis (ADO) remains unclear as only small numbers have been reported. There are no detailed reports on successful conservative treatment. Common causes of failure in this particular area include non-union and development of coxa vara. Although there are no quantitative studies, case reports have influenced most authors to recommend operative treatment. It is well recognised that operative treatment of osteopetrotic bone is challenging. Problems arise intraoperatively due to the bone hardness, and postoperatively due to altered biomechanics and defective remodelling. This case of a child with ADO who suffered two asynchronous compression-side stress fractures in the femoral neck demonstrates that non-operative management can be satisfactory. After 8 weeks with partial weight-bearing the fractures were stable. At the latest follow-up 2.5 and 4 years after the fractures the patient presented with an excellent clinical and radiological outcome. There was no development of coxa vara.

Acquired encephaloceles and epilepsy in osteopetrosis

Osteopetrosis is a condition in which there is a defect in bone resorption by osteoclasts. With thickening of the skull and skull base, the cranial capacity becomes compromised and skull foramina gradually occlude, resulting in a wide range of neurological symptoms and signs. We present a case of autosomal dominant osteopetrosis with temporal lobe epilepsy and nasal obstruction due to acquired bifrontal encephaloceles associated with a decreased intracranial capacity. Neurosurgical reconstruction of the frontal skull base alleviated the symptoms of epilepsy and nasal obstruction.

Osteomyelitis of the Maxilla Secondary to Osteopetrosis: A Report of 2 Cases in Sisters

The incidence of osteomyelitis has dramatically reduced since the introduction of antibiotics. When it now occurs in Western society, the possibility of predisposing immunosuppressive conditions or underlying bony pathology should be considered. Osteomyelitis is a complication in 10% of cases of osteopetrosis. Osteopetrosis (marble bone disease, Albers-Schonberg disease, osteosclerosis fragilis generalisata) is a congenital sclerosing disease of bone caused by aberrant osteoclast mediated bone resorption. There is normal production of bone with lack of physiological resorption. The disease represents a spectrum of clinical variants because of the heterogeneity of genetic defects resulting in osteoclast dysfunction. Three clinically distinct forms are recognized: an infantile malignant autosomal recessive form, an intermediate autosomal recessive form, and an adult benign autosomal dominant form. Infantile malignant autosomal recessive osteopetrosis is diagnosed within the first year of life. Patients typically present with pathologic fracture or failure to thrive with frequent respiratory, head and neck, or bony infections. Physical examination shows lethargy, small stature, marked hepatosplenomegaly, and dysmorphic features including macrocephaly, frontal bossing, and hypertelorism. Neural palsies may occur, particularly affecting the optic, oculomotor, and facial nerves because of progressive thickening of bone at the expense of the neural canals. Intermediate autosomal recessive osteopetrosis is usually diagnosed toward the end of the first decade of life. Patients often present with pathological fracture. Clinical characteristics include delayed motor and cognitive development, mild disproportionate short stature, mild hepatosplenomegaly, and dysmorphic features such as macrocephaly and frontal bossing. Cranial nerve compression and mandibular osteomyelitis are common features. This form of osteopetrosis is rare. Most patients survive into adulthood but with significant disability. Autosomal dominant osteopetrosis (adult benign osteopetrosis) is a much milder condition. Patients have a normal life expectancy and many are asymptomatic. Patients may present in adulthood with recurrent fractures, back pain, bone pain, or osteomyelitis, particularly of the mandible. Cranial nerve palsies and osteoarthritis of the hips and knees are other potential features. Autosomal dominant osteopetrosis is divided into 2 radiological subtypes. In type I, cranial sclerosis and thickening affects mainly the calvarium. The calvarium is almost normal in type II, but the cranial base is sclerotic. Although both types involve generalized skeletal sclerosis, patients with the type II subtype have a higher risk for fractures.

Autosomal Dominant Osteopetrosis: Clinical Severity and Natural History of 94 Subjects with a Chloride Channel 7 Gene Mutation

Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO. The primary objectives were to improve our understanding of ADO clinical characteristics and to study the natural history of the disease in the largest series of patients reported to date. This study was primarily a retrospective cross-sectional analysis of individuals with a ClCN7 mutation that was conducted over a 4-yr period at a tertiary referral center and through family reunions. Longitudinal data on a subset of subjects were also studied. We studied 311 subjects from 11 ADO families, including 62 individuals with ADO (patients with the classic clinical phenotype based on radiographs and/or biochemistry), 32 unaffected gene carriers (subjects with the gene mutation but no radiographic and/or biochemical phenotype), and 217 controls who did not harbor a ClCN7 gene mutation. Clinical data were collected through patient interviews and examinations, medical records, and/or self-reported responses on a questionnaire that was completed by all subjects. The prevalence of fracture, osteomyelitis, visual loss, and bone marrow failure was determined. Differences in clinical manifestations were analyzed according to affected vs. carrier status, age, and underlying genotype. Ninety-two percent of ADO subjects had at least one sequela of the disease. Gene carriers did not have an increased risk of disease manifestations, although they were found to have significant increases in bone mineral density (P < 0.05). Compared with controls, subjects with ADO had a significantly increased prevalence of fracture (84 vs. 36%; P < 0.0001) and osteomyelitis (16 vs. 0.9%; P < 0.0001). Severe fractures (defined as > or =10 fractures of any type and/or greater than one hip/femur fracture) were identified only in ADO subjects, and osteomyelitis typically occurred in the maxilla or mandible in older adults. Visual loss, which typically had its onset in childhood, and bone marrow failure occurred in 19 and 3% of ADO subjects, respectively. Adults were more likely to manifest an ADO clinical characteristic, but no definitive genotype-phenotype relationship could be concluded. Longitudinal data suggest that the ADO clinical phenotype worsens over time. ADO caused by mutations in the CLCN7 gene is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, and occasional bone marrow failure. The sequelae of ADO, which can be identified as early as infancy, appear to worsen over time. Fracture is the most prevalent consequence of ADO, 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.

Disease Status in Autosomal Dominant Osteopetrosis Type 2 Is Determined by Osteoclastic Properties

Asymptomatic gene carriers and clinically affected ADO2 subjects have the same ClCN7 mutation. We examined osteoclastic bone resorption in vitro as well as osteoclast formation, several markers, acid secretion, and cytoskeletal structure. We found that ADO2 expression results from osteoclast specific properties. Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. However, of those individuals with a ClCN7 mutation, one third are asymptomatic gene carriers who have no clinical, biochemical, or radiological manifestations. Disease severity in the remaining two thirds is highly variable. Human peripheral blood mononuclear cells were isolated and differentiated into osteoclasts by stimulation with hRANKL and human macrophage-colony stimulating factor (hM-CSF). Study subjects were clinically affected subjects, unaffected gene carriers, and normal controls (n = 6 in each group). Pit formation, TRACP staining, RANKL dose response, osteoclast markers, acid secretion, F-actin ring, and integrin alpha(v)beta3 expression and co-localization were studied. Osteoclasts from clinically affected subjects had severely attenuated bone resorption compared with those from normal controls. However, osteoclasts from unaffected gene carriers displayed similar bone resorption to those from normal controls. In addition, the resorption lacunae from both unaffected gene carriers and normal controls appeared much earlier and spread much more rapidly than those from clinically affected subjects. As time progressed, the distinction between clinically affected subjects and the other two groups increased. No significant difference was found in acidic secretion or osteoclast formation between the three groups. Osteoclast cytoskeletal organization showed no difference between the three groups but there was low cellular motility in clinically affected subjects. Osteoclasts from the unaffected gene carriers, in contrast to those from the clinically affected subjects, functioned normally in cell culture. This finding supports the hypothesis that intrinsic osteoclast factors determine disease expression in ADO2. Further understanding of this mechanism is likely to lead to the development of new approaches to the treatment of clinically affected patients.

The angel in the marble

Case of the monthThe angel in the marbleD J A Butteriss, M Clarke and D BirchallD J A Butteriss1Department of Neuroradiology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, 2Ophthalmology Department, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this author, M Clarke1Department of Neuroradiology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, 2Ophthalmology Department, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this author and D Birchall1Department of Neuroradiology, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, 2Ophthalmology Department, Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this authorPublished Online:13 Feb 2014https://doi.org/10.1259/bjr/33391462SectionsPDF/EPUBFull Text ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail About References 1 Hall CM. International Nosology and Classification of Constitutional Disorders of Bone (2001). Am J Med Genet 2002;113:65–77. Crossref Medline ISI, Google Scholar2 Anderson PE, Bollerslev J. Heterogeneity of autosomal dominant osteopetrosis. Radiology 1987;164:233–5. Google Scholar3 Cure JK, Key LL, Goltra DD, VanTassel P. Cranial MR imaging of osteopetrosis. AJNR Am J Neuroradiol 2000;21:1110–5. Medline ISI, Google Scholar4 Stewart CG. Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol 2003;29:87–97. Crossref Medline ISI, Google Scholar5 Vanier V, Miller NR, Carson BS. Bilateral visual improvement after unilateral optic canal decompression and cranial vault expansion in a patient with osteopetrosis, narrowed optic canals, and increased intracranial pressure. J Neurol Neurosurg Psychiatry 2000;69:405–6. Crossref Medline ISI, Google Scholar Previous article FiguresReferencesRelatedDetailsCited byOrthopaedic Management of the Patient With OsteopetrosisJournal of the American Academy of Orthopaedic Surgeons, Vol. 15, No. 11 Volume 79, Issue 940April 2006Pages: 275-361 © The British Institute of Radiology History ReceivedMay 16,2005AcceptedJune 27,2005Published onlineFebruary 13,2014 Metrics Michelangelo, “I saw the angel in the marble and carved until I set it free.”Download PDF

Osteomyelitis of the mandible associated with autosomal dominant osteopetrosis: A case report

Osteopetrosis is a rare hereditary bone disorder presenting with variable clinical features and is characterized by an increase in bone density. The main clinical findings of the benign-type of osteopetrosis (autosomal dominant) are fractures and osteomyelitis of the mandible, leading to the detection of the disease. We report a case of autosomal dominant osteopetrosis with secondary mandibular osteomyelitis. Clinical and radiological patterns and treatment evaluation were assessed. The patient was referred for evaluation and treatment of an acute abscess in the left side of the face and osteomyelitis of the mandible. Several imaging studies were performed to assess the lesion and the adjacent bone and soft tissue structures. Treatment consisted of intravenous antibiotic therapy, debridement of the necrotic bone and sequestrum, and extra-oral drainage of the abscess, with submandibular access. Healing was uneventful.

Degradation of the Organic Phase of Bone by Osteoclasts: A Secondary Role for Lysosomal Acidification

Osteoclasts degrade bone matrix by secretion of hydrochloric acid and proteases. We studied the processes involved in the degradation of the organic matrix of bone in detail and found that lysosomal acidification is involved in this process and that MMPs are capable of degrading the organic matrix in the absence of cathepsin K. Osteoclasts resorb bone by secretion of acid by the vacuolar H+-adenosine triphosphatase (V-ATPase) and the chloride channel ClC-7, followed by degradation of the matrix, mainly collagen type I, by cathepsin K and possibly by matrix metalloproteinases (MMPs). However, the switch from acidification to proteolysis and the exact roles of both the ion transporters and the proteinases still remain to be studied. We isolated CD14+ monocytes from human peripheral blood from either controls or patients with autosomal dominant osteopetrosis type II (ADOII) caused by defective ClC-7 function and cultured them in the presence of RANKL and macrophage-colony stimulating factor (M-CSF) to generate osteoclasts. We decalcified cortical bovine bone slices and studied the osteoclasts with respect to morphology, markers, and degradation of the decalcified matrix in the presence of various inhibitors of osteoclast acidification and proteolysis, using normal calcified bone as a reference. We found that ADOII osteoclasts not only have reduced resorption of the calcified matrix, but also 40% reduced degradation of the organic phase of bone. We found that both acidification inhibitors and cathepsin K inhibitors reduced degradation of the organic matrix by 40% in normal osteoclasts, but had no effect in the ADOII osteoclasts. Furthermore, we showed that inhibition of MMPs leads to a 70% reduction in the degradation of the organic bone matrix and that MMPs and cathepsin K have additive effects. Finally, we show that osteoclastic MMPs mediate release of the carboxyterminal telopeptide of type I collagen (ICTP) fragment in the absence of cathepsin K activity, and therefore, to some extent, are able to compensate for the loss of cathepsin K activity. These data clearly show that osteoclastic acidification of the lysosomes plays a hitherto nonrecognized role in degradation of the organic matrix. Furthermore, these data shed light on the complicated interplay between acidification dependent and independent proteolytic processes, mediated by cathepsin K and the MMPs, respectively.

Polymorphisms in theCLCN7Gene Modulate Bone Density in Postmenopausal Women and in Patients with Autosomal Dominant Osteopetrosis Type II

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. 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. This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene. 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. 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. 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. 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.

Osteoclasts from Patients with Autosomal Dominant Osteopetrosis Type I Caused by a T253I Mutation in Low-Density Lipoprotein Receptor-Related Protein 5 Are Normal in Vitro, but Have Decreased Resorption Capacity in Vivo

Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts. To investigate the effect of the T253I mutation in LRP5 on osteoclasts, we isolated CD14+ monocytes from ADOI patients and assessed their ability to generate osteoclasts when treated with RANKL and M-CSF compared to that of age- and sex-matched control osteoclasts. We found normal osteoclastogenesis, expression of osteoclast markers, morphology, and localization of proteins involved in bone resorption, such as ClC-7 and cathepsin K. The ability to resorb bone was also normal. In vivo, we compared the bone resorption and bone formation response to T3 in ADOI patients and age- and sex-matched controls. We found attenuated resorptive response to T3 stimulation, despite a normal bone formation response, in alignment with the reduced number of osteoclasts in vivo. These data demonstrate that ADOI osteoclasts are normal with respect to all aspects investigated in vitro. We speculate that the mutations causing ADOI alter the osteoblastic phenotype toward a smaller potential for supporting osteoclastogenesis.

Analysis of variation in expression of autosomal dominant osteopetrosis type 2: Searching for modifier genes

Introduction: Autosomal Dominant Osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. Analysis of ADO2 in our pedigrees indicates that the penetrance is 66%, with a highly variable phenotype. Methods: To identify genes that modify disease status, we performed a 10 cM genome-wide scan using 400 microsatellite markers in 112 subjects from our 8 largest ADO2 families with mutations in the ClCN7 gene. Results were analyzed by parametric linkage analysis using autosomal dominant and recessive models for affects on disease status. Follow-up genotyping with additional microsatellite markers was performed for regions with LOD scores over 1.5. In addition, we compared the frequency of two nonsynonymous SNPs, rs12926089 (V418M) and rs11559208 (K691E), and one promoter SNP rs960467 in the normal ClCN7 allele between a sample of unaffected gene carriers and clinically affected subjects to test the hypothesis that genetic variation in the non-disease allele within the ClCN7 gene might influence disease expression. Results: We found potential evidence of linkage for a modifier gene(s) on 9q21–22 with a LOD score of 1.89, which is not statistically significant, but interesting. We also found that, for SNP V418M on the non-disease allele with the wild-type ClCN7 sequence, 94.92% (56/59) of clinically affected subjects and 78.13% (25/32) of unaffected gene carriers had a valine while 5.08% (3/59) of the affected subjects and 21.88% (7/32) of unaffected gene carriers had a methionine ( P < 0.03). Unfortunately, SNP K691E was not informative in our families. For SNP rs960467, on the non-disease allele with the wild-type ClCN7 gene, 87.93% (51/58) of clinically affected subjects and 62.50% (20/32) of unaffected gene carriers had a C allele while 12.07% (7/58) of the clinically affected subjects and 37.50% (12/32) of unaffected gene carriers had a T allele ( P < 0.007). As expected, the polymorphisms on the disease allele were not associated with disease status. Conclusions: Chromosome 9q21–22 may harbor a modifier gene(s) that affect(s) ADO2 disease status and severity. Additionally, we find the associations between the polymorphisms on the non-disease allele and unaffected gene carrier status.

Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment

Background: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO)....

Femoral Neck Fracture in a Child With Autosomal-Dominant Osteopetrosis: Failure of Spica Cast Treatment and Successful Outcome by Internal Fixation

A case report of a 6-year-old child with autosomal dominant osteopetrosis who sustained a closed femoral neck fracture initially treated with a spica cast with subsequent fracture displacement is presented. Further treatment included closed reduction and operative fixation, first, with a guide pin placement for a cannulated screw insertion that was abandoned because of the hardness of the bone. Three Kirschner wires were then inserted to maintain the closed reduction, followed by immobilization in a spica cast. At the 2-year follow-up, the child was completely free of any complications resulting from her injury and treatment. Radiographs showed no evidence of avascular necrosis in the affected femoral head. Review of the literature supports evidence for early operative fixation of such cases, whether or not the femoral neck fracture is nondisplaced or displaced.

Autosomal dominant osteopetrosis and maxillomandibular osteomyelitis

Osteopetroses represent a heterogeneous group of rare, hereditary bony dysplasias. They range from a devastating neurometabolic disease (including severe malignant infantile osteopetrosis) to 2 more benign conditions principally affecting adults: autosomal dominant osteopetrosis (ADO) type I and type II. The present study describes the maxillofacial manifestations associated with the 2 subgroups of ADO. In this paper, we present the oldest patient described in the literature with ADO type I (76 years old). We also document the first ADO type II patient described in the literature with synchronic osteomyelitis of the mandible and the maxilla.

Human osteopetroses and the osteoclast V-H+-ATPase acidification system

Osteopetroses are a heterogeneous group of human genetic diseases characterized by generalized increase in bone density due either to a decreased osteoclast population, defect in osteoclast function, or both. Current knowledge of the pathogenesis suggests defects that may be either intrinsic to osteoclast-monocyte lineage or extrinsic to the mesenchymal cells that support osteoblast ontogeny and activation. Four clinically distinct forms of human osteopetroses currently recognized are the infantile malignant autosomal recessive form, the intermediate autosomal recessive form, the adult benign autosomal dominant osteopetrosis type I, and the autosomal dominant osteopetrosis type II. Propensity to fracture is high in all types of osteopetrosis, and other characteristic clinical problems include hematologic and metabolic abnormalities, infections of affected bone, and neurologic sequela. Among the infantile malignant clinical forms 50-60% of patients present with defects in the OC116-KDa (also refers to ATP6i, TCIRGI, a3) subunit of the osteoclast vacuolar H+-ATPase (V-H+-ATPase) proton pump. Approaches that have been applied to the treatment of osteopetrosis include those aimed at stimulating host osteoclasts. These approaches however have met with little success, and it would appear that the future for the successful treatment of osteopetrosis lies with bone marrow transplantation. Various animal models mimicking some of the clinical subtypes of osteopetrosis have been generated in efforts to elicit further understanding of the pathogenesis. This review is an update on the various phenotypic presentations of human osteopetroses alongside their known animal models. Further studies on these animal models will not only expand our basic understanding of the molecular mechanisms of osteopetroses, but will also aid our ability to develop therapeutic means of intervention in diseases involving osteopetroses.