Intermediate Autosomal Recessive Osteopetrosis Research Articles

Further understanding on osteopetrotic femoral fractures: a case report and literature review

BackgroundOsteopetrosis is a genetic disease characterized by defects in osteoclast formation and function. There were a few cases of subtrochanteric femur fractures treated with dynamic hip screw (DHS) in patients with osteopetrosis, but unfortunately the healing outcome was rather poor.Case presentationWe present our experience for treating a patient with intermediate autosomal recessive osteopetrosis (IRO) suffering from subtrochanteric femur fracture. In this case, we successfully used dynamic hip screw (DHS) internal fixation through meticulous preoperative planning and postoperative care, as well as application of surgical techniques. The patient displayed stable internal fixation with no limitation of activities during follow-up for 15 months. In addition to this case, a review of previous case reports showed an increasing number of case reports demonstrating that surgical treatment-related complications could be avoided preoperatively, intraoperatively, and postoperatively.ConclusionDHS for this patient, who suffered from subtrochanteric fractures with osteopetrosis, was successfully implemented. In the light of a comprehensive literature review, preoperative planning, surgical techniques, and postoperative rehabilitation care can significantly reduce the complications.

Novel CLCN7 mutations cause autosomal dominant osteopetrosis typeII and intermediate autosomal recessive osteopetrosis.

Osteopetrosis refers to a group of rare genetic bone diseases that are clinically characterized by increased bone mass and fragility. The principal pathogenic defect in patients with chloride channel7 (CLCN7) gene‑dependent osteopetrosis is reduced osteoclast activity, which leads to decreased bone resorption. Mutations in the CLCN7 gene result in autosomal dominant osteopetrosis typeII (ADO‑II), autosomal recessive osteopetrosis (ARO) and intermediate ARO (IARO). In the present study, eight mutations in the CLCN7 gene were identified in six patients with familial osteopetrosis and one patient with sporadic osteopetrosis. Heterozygous mutations c.856C>T (R286W), c.2236T>G (Y746D), c.296A>G (Y99C) and c.937G>A (E313K), and a splice mutation (c.2232‑2A>G) in the CLCN7 gene were detected in patients with ADO‑II. A homozygous mutation c.2377G>C (G793R), and a compound heterozygous mutation c.1409C>T (P470L) and c.647_648dupTG (K217X) were detected in two Chinese families with IARO. Among these mutations, two heterozygous mutations (c.2236T>G and c.2232‑2A>G), one homozygous mutation (c.2377G>C) and the compound heterozygous mutation (c.1409C>T and c.647_648dupTG) are novel, to the best of our knowledge. The present findings not only broaden the allelic spectrum of CLCN7 mutations, but also provide increased knowledge of the clinical phenotypes observed in Chinese patients with osteopetrosis.

Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1.

The osteopetroses and related sclerosing bone dysplasias can have a broad range of manifestations. Especially in the milder forms, sandwich vertebrae are an easily recognizable and reliable radiological hallmark. We report on four patients from three families presenting with sandwich vertebrae and platyspondyly. The long bone phenotypes were discordant with one patient showing modeling defects and patchy osteosclerosis, while the second displayed only metaphyseal sclerotic bands, and the third and fourth had extreme metaphyseal flaring with uniform osteosclerosis. Two of the four patients had experienced pathological fractures, two had developmental delay, but none showed cranial nerve damage, hepatosplenomegaly, or bone marrow failure. According to these clinical features the diagnoses ranged between intermediate autosomal recessive osteopetrosis and dysosteosclerosis. After exclusion of mutations in CLCN7 we performed gene panel and exome sequencing. Two novel mutations in SLC29A3 were found in the first two patients. In the third family a TCIRG1 C-terminal frameshift mutation in combination with a mutation at position +4 in intron 2 were detected. Our study adds two cases to the small group of individuals with SLC29A3 mutations diagnosed with dysosteosclerosis, and expands the phenotypic variability. The finding that intermediate autosomal recessive osteopetrosis due to TCIRG1 splice site mutations can also present with platyspondyly further increases the molecular heterogeneity of dysosteosclerosis-like sclerosing bone dysplasias.

Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADOII) and intermediate autosomal recessive osteopetrosis (ARO) in seven Chinese families

ABSTRACTObjectives: Defects in the chloride channel 7 (CLCN7) gene lead to autosomal dominant osteopetrosis type II (ADOII, OPTA2 MIM 166600) and autosomal recessive osteopetrosis, autosomal recessive 4 (ARO, OPTB4 MIM 611490). The objective of the present study was to expand the mutational spectrum and analyze the correlation between mutational sites and clinical phenotypes.Methods: Seven affected individuals from unrelated Chinese families were clinically examined. X-ray examination and biochemical markers were evaluated. The 25 exons of CLCN7 and exon-intron boundaries were amplified and analyzed; we also used μ-CT to distinguish the features of sclerotic bone from the great trochanter of Pt 6 using the bones of unaffected subject in vitro.Results: We identified six cases of OPTA2 and one case of OPTB4. One OPTA2 patient displaying life-threatening symptoms died, and the OPTB4 patient presenting a relatively mild clinical course survived. We identified eight different CLCN7 mutations, including three novel mutations (p.G240E, p.F318S, and p.S753W), and μ-CT analysis showed that the volumetric bone mineral density, total porosity and open porosity of sclerotic bone were higher than the control.Conclusions: The present study revealed three novel mutations, showed the dense but brittle sclerotic bones of an OPTA2 patient, characterized OPTA2 symptoms from benign to fatal and reported a rare intermediate case of ARO in a Chinese population.

Novel CLCN7 compound heterozygous mutations in intermediate autosomal recessive osteopetrosis

Osteopetrosis is a heritable disorder of the skeleton that is characterized by increased bone density on radiographs caused by defects in osteoclast formation and function. Mutations in >10 genes are identified as causative for this clinically and genetically heterogeneous disease in humans. We report two novel missense variations in a compound heterozygous state in the CLCN7 gene, detected through targeted exome sequencing, in a 15-year-old Japanese female with intermediate autosomal recessive osteopetrosis.

Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADO-II) and intermediate autosomal recessive osteopetrosis (IARO) in Chinese patients.

Osteopetrosis is a group of genetic bone disorders. Mutations in the chloride channel 7 gene (CLCN7) lead to chloride channel defect, which results in autosomal dominant osteopetrosis type II (ADO-II), autosomal recessive osteopetrosis (ARO), and intermediate autosomal recessive osteopetrosis (IARO). In the present study, we identified seven novel mutations of the CLCN7 gene and reported the first case of IARO with compound heterozygous mutation in Chinese population. Osteopetrosis is a heritable bone disorder due to the deficiency of or function defect in osteoclasts. Mutations in the CLCN7 lead to chloride channel defects, which result in osteopetrosis with diverse severity ranging from asymptomatic or relatively mild symptoms in ADO-II to the very severe phenotype in ARO. Heterozygous mutations in CLCN7 are associated to ADO-II, while homozygous and compound heterozygous mutations in CLCN7 may result in ARO and IARO. To date, a total of 24 mutations in CLCN7 were identified in ADO-II, and only 3 mutations were identified in IARO. In the present study, we reported seven unrelated ADO-II patients and one IARO patient from Chinese population and elucidated the characteristics of CLCN7 gene mutations in these patients. All 25 CLCN7 exons and exon-intron boundaries from genomic DNA were amplified and sequenced in eight affected individuals suffering from ADO-II/IARO. The clinical, biochemical, and radiographic analysis were evaluated to compare the differences between ADO-II and IARO both in genotype and phenotype. The results showed that there were seven novel CLCN7 mutations identified in these ADO-II/IARO patients, including six heterozygous missense mutations (p.L224R, p.S290Y, p.R326G, p.G347R, p.S473N, and p.L564P) and a novel splice mutation (p.K691FS). The compound heterozygous mutations (p.L224R and p.K691FS) were firstly observed in one IARO patient. The present study would enrich the database of CLCN7 mutations and improve our understanding of this heritable bone disorder.

Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia

Osteopetrosis is a group of genetic bone disorders. There are three types of osteopetrosis: autosomal recessive osteopetrosis (ARO), autosomal dominant osteopetrosis type II (ADO II), and intermediate autosomal recessive osteopetrosis (IARO). The prevalence of ADO II is about 1:100,000, while no more than 20 cases of IARO have been reported worldwide. We present the first Chinese IARO patient with a novel homozygous variant in CLCN7 gene (p. Pro470Leu) and an ADO II patient with a heterozygous variant in CLCN7 gene (p. Arg286Trp). In addition to general osteosclerosis, the striking features of these two patients are unerupted teeth with root dysplasia. We speculate that ClC-7 in different tooth cells may contribute directly to the root development, the defect of ClC-7 may have a dose dependent effect on the phenotype of root dysplasia, and the tooth position may also affect the root phenotype with dysfunctional ClC-7.

A New Heterozygous Mutation (R714C) of the Osteopetrosis Gene, Pleckstrin Homolog Domain Containing Family M (With Run Domain) Member 1 (PLEKHM1), Impairs Vesicular Acidification and Increases TRACP Secretion in Osteoclasts

We studied phenotypic and cellular aspects in a patient with a heterozygous mutation of the PLEKHM1 gene and obtained some indications regarding the role of the protein in bone cell function. Plekhm1 is involved in osteoclast endosomal vesicle acidification and TRACP exocytosis, contributing to events involved in osteoclast-osteoblast cross-talk. The gene PLEKHM1 encodes a nonsecretory adaptor protein that localizes to endosomal vesicles. A highly truncated Plekhm1 protein was previously found in a patient with intermediate autosomal recessive osteopetrosis. We describe a new heterozygous mutation in the PLEKHM1 gene in a patient presenting with low vertebral and femoral T-scores and areas of focal sclerosis. Clinical evaluation, mutational analysis, assessment of in vitro osteoclast morphology and activity, transfection studies, and evaluation of osteoclast-osteoblast cross-talk were carried out. Direct DNA sequencing showed a heterozygous C to T substitution on cDNA position 2140 of the PLEKHM1 gene, predicted to lead to an R714C mutant protein. The mutation was not found in 104 control chromosomes. In vitro, patient's osteoclasts showed normal formation rate, morphology, number of nuclei, and actin rings but lower TRACP activity and higher endosomal pH than control osteoclasts. The patient had high serum PTH and TRACP, despite low TRACP activity in osteoclasts in vitro. HEK293 cells overexpressing either wildtype or Plekhm1-R714C showed no difference in localization of the variants, and co-transfection with a TRACP vector confirmed low TRACP activity in cells carrying the R714C mutation. RAW 264.7 osteoclast-like cells expressing the Plekhm1-R714C variant also showed low TRACP activity and reduced ability to acidify endosomal compartments compared with cells expressing the wildtype protein. Reduced intracellular TRACP was caused by increased protein secretion rather than reduced expression. TRACP-containing conditioned medium was able to increase osteoblast alkaline phosphatase, suggesting the focal osteosclerosis is a result of increased osteoclast-osteoblast coupling. We provide further evidence for a role of Plekhm-1 in osteoclasts by showing that a novel mutation in PLEKHM1 is associated with a complex bone phenotype of generalized osteopenia combined with "focal osteosclerosis." Our data suggest that the mutation affects endosomal acidification/maturation and TRACP exocytosis, with implications for osteoclast-osteoblast cross-talk.

Fracture Treatment in Intermediate Autosomal Recessive Osteopetrosis

Fracture Treatment in Intermediate Autosomal Recessive Osteopetrosis

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.

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)....

Malignant Infantile Osteopetrosis - A Case Report

DOI: 10.3329/bjch.v30i1.6183Bangladesh J Child Health 2006; VOL 30 (1/2/3): 36-39