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Osteopetrosis (OP) is a heterogeneous group of rare, heredity bone disorders with variable clinical features involving the bones of the body. OP is characterized by increased bone density, which is caused by aberrant osteoclast-mediated bone resorption. This syndromic disorder comes with a series of problems and, unless recognized and treated early, can lead to a multitude of further grave complications. We report a rare case of a female patient who reported chronic unhealed extraoral draining sinus present over the left submandibular region with pathologic fracture of the left mandibular angle, which, if, was diagnosed early with the identification of the osteopetrosis syndrome, could have been managed more conservatively., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Osteopetrosis encompasses rare inherited metabolic bone disorders with defect in the osteoclast activity. Severe forms of presentation such as malignant infantile osteopetrosis are seen in infants and milder forms in older children. The clinical presentation includes failure to thrive, severe pallor, optic atrophy and hepatosplenomegaly. The disorder is characterised by dense bone on radiography, hence the name marble bone disease. A 10-month-old boy who presented with developmental delay, failure to thrive, nystagmus (which the mother described as wandering eye movements), splenomegaly of 16 cm and hepatomegaly of 8 cm. Investigations demonstrated severe anaemia (5.7 g/dL) and thrombocytopenia (34 x 109/L). Radiological signs which help in the diagnosis include diffuse sclerosis, bone within bone appearance, sandwich vertebrae and Erlenmeyer flask deformity. Plain radiography is an easily available and cost effective tool which can aid in the diagnosis of osteopetrosis.

Background: Osteopetrosis is a rare inherited disease caused by a lack of osteoclastic bone resorption, resulting in increased bone mass with insufficient mechanical strength. Patients usually present with complications such as pathologic fractures, cranial neuropathies, and bone marrow failure. Diagnosis is based on suggestive clinical and imaging findings, with genetic testing to confirm diagnosis and identify the subtype., Case Presentation: The patient is an eight-year-old girl who came to our hospital with complaints of bilateral arm swelling and visual disturbances for four years and a history of fracture of the left lower extremity two years before presentation. Physical examination revealed nontender bilateral arm swelling and a shorter left leg. The laboratory tests were within normal limits. A skeletal radiograph showed typical radiographic features of osteopetrosis., Conclusion: It is important to consider osteopetrosis in patients presenting with pathologic fractures and cranial neuropathies. Typical imaging findings can provide rapid diagnosis in severe cases., (© 2024 Bethlehem Tesfasilassie Kibrom, et al.)

Objective: To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. Methods: This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Results: Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) vs. 0.4 (0.2, 0.6) years, Z =-2.60, P =0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) vs. 1.1 (0.8, 1.6) mmol/L, Z =-2.59, P =0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) vs. 56 (37, 82) U/L, Z =-3.38, P =0.001) and the level of neutrophils (14.0 (9.9, 18.1) vs. 9.2 (6.7, 11.1) ×10 9 /L, Z =-2.07, P =0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) vs. 6.3 (2.5, 9.7) μg/L, Z =2.83, P =0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% vs. 83.3%±7.6%, χ ²=0.56, P =0.456). Conclusions: TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.

Background: Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III., Aim: To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III., Methods: This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients., Results: The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/μL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS)., Conclusion: In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Osteopetrorickets is a rare complication of autosomal recessive ("malignant") osteopetrosis. Its prompt diagnosis is essential, because early suspicion of infantile osteopetrosis enables treatment with human stem cell transplantation, depending on the gene involved. It is important to identify not only the characteristic radiological changes of rickets, but also the coexistence of increased bone density, so as not to miss this very rare entity. Herein, a brief case report is presented., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Mutation in OSTM1 give rise to the rarest and most lethal subtype of malignant infantile osteopetrosis (MIOP), and an improved understanding of OSTM1-associated MIOP would help with informed decision-making regarding symptom management and early palliative care referral. This retrospective study describes the clinical and laboratory features of patients with a genetic diagnosis of OSTM1 MIOP made between January 2011 and December 2021 in the Department of Pediatrics, Al-Adan Hospital, Kuwait. Twenty-two children had confirmed homozygous deletion in OSTM1 (13 females, nine males). Consanguinity was reported in almost all parents. 72.7% were diagnosed before the age of two months, most commonly incidentally with a high clinical suspicion. All 22 patients developed upper respiratory symptoms, hepatosplenomegaly, poor feeding, and had severe developmental delay. 80% of patients developed pain and/or irritability, and 40.9% were diagnosed with primary seizures. Bone fractures developed in 27% of patients, most likely iatrogenic, and some patients had hernia and gum abnormalities. The mean survival was 10.9 months. The clinical presentation, symptomatology, and mortality of our cohort were compared with other cases of OSTM1 MIOP identified through a comperhensive search of the PubMed database. The findings conclude that OSTM1 MIOP is a multi-systemic disease with distinct clinical features, of which neurological complications are the most severe and include nociplastic pain and irritability. Although orthopedic complications influence the trajectory of most patients with other forms of osteopetrosis, OSTM1 MIOP is driven by its neurological complications. Hence, OSTM1 should be regarded as a neurodegenerative disease with osteopetrosis as a comorbidity that warrants early palliative care referral., (© 2022 Wiley Periodicals LLC.)

Osteopetrosis is a heterogeneous group of rare hereditary diseases characterized by increased bone mass of poor quality. Autosomal-dominant osteopetrosis type II (ADOII) is most often caused by mutation of the CLCN7 gene leading to impaired bone resorption. Autosomal recessive osteopetrosis (ARO) is a more severe form and is frequently accompanied by additional morbidities. We report an adult male presenting with classical clinical and radiological features of ADOII. Genetic analyses showed no amino-acid-converting mutation in CLCN7 but an apparent haploinsufficiency and suppression of CLCN7 mRNA levels in peripheral blood mononuclear cells. Next generation sequencing revealed low-frequency intronic homozygous variations in CLCN7, suggesting recessive inheritance. In silico analysis of an intronic duplication c.595-120_595-86dup revealed additional binding sites for Serine- and Arginine-rich Splicing Factors (SRSF), which is predicted to impair CLCN7 expression. Quantitative backscattered electron imaging and histomorphometric analyses revealed bone tissue and material abnormalities. Giant osteoclasts were present and additionally to lamellar bone, and abundant woven bone and mineralized cartilage were observed, together with increased frequency and thickness of cement lines. Bone mineralization density distribution (BMDD) analysis revealed markedly increased average mineral content of the dense bone (CaMean T-score + 10.1) and frequency of bone with highest mineral content (CaHigh T-score + 19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except for an unusually circular shape. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture. While the skeletal phenotype and medical history were suggestive of ADOII, genetic analysis revealed that this is a possible mild case of ARO due to deep intronic mutation., (© 2022. The Author(s).)

Autosomal recessive osteopetrosis (ARO) is a group of disease characterized by osteoclast dysfunction inhibiting bone resorption and bone turnover, with TCIRG1-associated ARO being more common leading to autosomal recessive infantile malignant osteopetrosis (OPTB1, MIM entry number # 259700). While most patients with TCIRG1-associated osteopetrosis present a malignant clinical course and shortened lifespan, a few cases of non-malignant TCIRG1-associated osteopetrosis have been reported. 24-year-old female patient came to us with limp gait, hip pain in both sides, and severe stiffness. She had suffered many fractures, bilateral hip osteoarthritis, right leg was 2 cm shorter compared with left leg. Whole Exome Sequencing was conducted, the result and subsequent Sanger's sequencing shown the patient had a compound heterozygous genotype at TCIRG1 (c.1194dup, p.Gly399ArgTer and c.334G>A, p.Gly112Arg), these two variants found were not previously reported. Sanger's sequencing revealed two other siblings whom suffer the same disorder had similar genotype to the proband; the parents were found to be heterozygous. This is the first case of TCIRG1-associated osteopetrosis reported in Vietnam and one of the few cases of nonmalignant TCIRG1-associated osteopetrosis, in which detailed clinical and genetic work-up were performed., (© 2022 Wiley Periodicals LLC.)

Infantile malignant osteopetrosis (IMOP) is a rare bone resorptive disorder with an autosomal recessive inheritance pattern. It is characterized by increased bone density due to osteoclastic failure in differentiation or function. The clinical manifestations of IMOP start at birth or infancy with varied rings according to the type and degree of osteopetrosis. We presented a 3-year-old female patient referred to us due to chronic anaemia six months ago. The physical examination revealed hepatosplenomegaly, axial hypotonia, and visual impairment. Blood investigation revealed pancytopenia and hypocalcemia. Radiologic studies revealed a generalized increase in bone density, abnormal metaphyseal remodelling, and rain atrophy. The bone marrow aspiration (BMA) shows dry tap and hypocellularity of all cell lines. IMOP was diagnosed depending on clinical, radiologic, and BMA results. In conclusion, IMOP is relatively uncommon. Accurate diagnosis should be made through clinical, BMA, and radiologic investigations, especially in a resource-limited setting, as performed in our case., Competing Interests: The authors declare no competing interests., (Copyright: Saeed Thabet et al.)

Background: The osteosclerotic skeletal dysplasias (OSSDs) are a heterogeneous group of disorders characterized by systemic bone sclerosis. Little is known about OSSDs because of their rarity. We conducted a cross-sectional nationwide survey of OSSDs and examined the incidence, epidemiology, and therapeutic interventions on these disorders., Methods: This study consisted of a two-step survey. The number of patients with OSSDs who had visited medical institutions between April 2017 and March 2018 was reported from a total of 341 facilities (1364 departments from pediatrics, orthopaedic surgery, neurosurgery, and otolaryngology in each facility) by the first questionnaire. In the secondary survey, their clinical features were assessed by collecting demographic data, diagnostic details, current status, family histories, therapeutic interventions, histories of bone fracture and osteomyelitis, severity assessed by the modified Rankin Scale (mRS) and recent lifestyle conditions of the patient by the EQ-5D., Results: In the first survey, 51 facilities (56 departments) reported one or more OSSDs patients, including 50 patients with osteopetrosis and 57 patients of other OSSDs. Among 87 patients eligible for inclusion in the analysis in the secondary survey, we investigated detailed information on the 42 patients with osteopetrosis. The number of initial visits of osteopetrosis patients during the surveillance period was five per year, indicating that the estimated incidence of osteopetrosis seemed to be 0.6 per 100,000 live births. Eighty-six bone fractures were reported in 22 patients (52%), and interventions of pseudarthrosis were conducted in five patients. Nine patients (23%) showed significant disabilities with the mRS of grade 3 or higher. Neurological complications and severe anemia were the factors that deteriorate patients' quality of life., Conclusions: This is the first study to examine the detailed epidemiology of OSSDs in Japan. We demonstrated that the incidence of OSSDs is extremely rare. Bone fragility and delayed fracture healing seem to be important orthopaedic problems for patients with osteopetrosis., Competing Interests: Declaration of competing interest The authors declare that we have no conflicts of interest., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Malignant infantile osteopetrosis is a rare inherited disorder with neurological complications and a shortened life expectancy. Vision loss is typically attributed to osseous compression of the optic nerves at the level of the optic canal. Fundus imaging is reported, as well as the first optical coherence tomography and optical coherence tomography angiography in this rare condition. Imaging revealed optic nerve pallor, subfoveal ellipsoid zone disruption, and an enlarged foveal avascular zone. These results provide insight regarding other potential mechanisms of vision loss in these patients. [ Ophthalmic Surg Lasers Imaging Retina 2022; 53:398-402.] .

Osteopetrosis (Marble bone disease) is a very rare congenital genetic disease of skeleton, resulting from defective bone resorption, due to functionally defective osteoclast, leading to accumulation of excessive bone mass. Malignant infantile osteopetrosis (MIO) is one of the varieties of osteopetrosis, which is fatal and is diagnosed in early infancy. Malignant infantile osteopetrosis is present with abnormal bone remodeling, hematological abnormities, features of extramedullary hematopoiesis. Radiology is the key of diagnosis. In this case, we present a 5-monthold male infant diagnosed as malignant infantile osteopetrosis, who presented with bronchopneumonia, anemia, thrombocytopenia, hepatosplenomegaly, failure to thrive (FTT).

Brain abscess formation is extremely rare in patients with osteopetrosis. Herein, we report a case of viridans streptococci brain abscess in an immunocompromised child diagnosed with osteopetrosis. The patient presented with a sudden change in mental status and convulsions. Radiological evaluation revealed a temporal lobe brain abscess, and intravenous antibiotherapy was started immediately. The patient underwent abscess drainage, and laboratory investigation of pus material revealed viridans streptococci.

Wiskott-Aldrich syndrome (WAS) and osteopetrosis are 2 different, rare hereditary diseases. Here we report clinical and molecular genetics investigations on an infant patient with persistent thrombocytopenia and prolonged fever. He was clinical diagnosed as osteopetrosis according to clinical presentation, radiologic skeletal features, and bone biopsy results. Gene sequencing demonstrated a de novo homozygous mutation in 5'-untranslated region of TNFRSF11A, c.-45A>G, which is relating to osteopetrosis. Meanwhile, a hemizygous transition mutation in WAS gene, c.400G>A diagnosed the infant with WAS. This is the first clinical report for the diagnosis of osteopetrosis coinheritance with WAS in a single patient., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Over half of children with rare genetic diseases remain undiagnosed despite maximal clinical evaluation and DNA-based genetic testing. As part of an Undiagnosed Diseases Program applying transcriptome (RNA) sequencing to identify the causes of these unsolved cases, we studied a child with severe infantile osteopetrosis leading to cranial nerve palsies, bone deformities, and bone marrow failure, for whom whole-genome sequencing was nondiagnostic., Methods: We performed transcriptome (RNA) sequencing of whole blood followed by analysis of aberrant transcript isoforms and osteoclast functional studies., Results: We identified a pathogenic deep intronic variant in CLCN7 creating an unexpected, frameshifting pseudoexon causing complete loss of function. Functional studies, including osteoclastogenesis and bone resorption assays, confirmed normal osteoclast differentiation but loss of osteoclast function., Conclusion: This is the first report of a pathogenic deep intronic variant in CLCN7, and our approach provides a model for systematic identification of noncoding variants causing osteopetrosis-a disease for which molecular-genetic diagnosis can be pivotal for potentially curative hematopoietic stem cell transplantation. Our work illustrates that cryptic splice variants may elude DNA-only sequencing and supports broad first-line use of transcriptome sequencing for children with undiagnosed diseases., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Osteopetrosis comprises a rare, heterogeneous group of heritable conditions that are characterized by a defect in bone resorption by osteoclasts. We report the case of a 53-year-old woman with previously undiagnosed osteopetrosis who presented with a pathologic proximal humeral fracture secondary to pleomorphic sarcoma, which is previously undescribed in the English literature. Management of the primary lesion necessitated ablative surgery, but the malignancy nonetheless was associated with rapidly progressive metastatic disease., (Copyright Journal of Radiology Case Reports.)

Osteopetrosis (OP), also known as marble bone disease is an extremely rare inherited skeletal disorder, characterised by abnormal functioning of the osteoclasts that results in incremental bone deposition with lack of normal bone remodelling. This leads to the formation of hard and brittle bone can readily fracture. The compromised quality of marrow tissue with poor vascularity reduces bone healing and increases the risk of infections. The risk of jawbone osteomyelitis in patients with OP is high and invariably involves mandible. Involvement of maxilla is rare and has been sparingly reported in the literature. This paper highlights a case of extensive necrosis of maxilla and mid-face skeleton following tooth extraction in a patient with OP. Review of the English literature identifying 23 previously published reports of maxillary osteomyelitis in patients with OP is also presented. Demographic details, history of tooth extraction, extent of involvement, clinical presentation, imaging finding, treatment provided and the outcome have been discussed., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Malignant Infantile Osteopetrosis (MIOP) is a rare and severe genetic disorder due to abnormal osteoclast activity., Objective: To report an infant who presented Malignant Infantile Osteopetrosis, reviewing the most relevant diagnostic and therapeutic aspects., Clinical Case: A ten- month-old male infant with diagnosis of MIOP confirmed after presenting thrombocytopenia and visceromegaly. He was the first child of non-consanguineous parents, and among the findings, he presented severe hepatosplenomegaly, thrombocytopenia, and anemia; visual and hearing impair ment, and repeated infections. The diagnosis was confirmed by genetic study, which identified two heterozygous mutations in the TCIRG1 gene. Hematopoietic stem cells were transplanted without hematological recovery. The patient died due to occlusive venous disease., Discussion: MIOP is a rare, severe, and early-onset disease, with a high rate of suspicion necessary in the presence of hepa- tosplenomegaly and bone marrow failure. Early diagnosis and hematopoietic stem cells transplanta tion are the only potentially therapeutic interventions of this lethal entity.

Purpose: To investigate the difference in the optic canal diameter between children with autosomal recessive malignant infantile osteopetrosis and normal children, and to assess the influence of hematopoietic stem cell transplantation on the optic canal diameter., Methods: Twenty pediatric patients with malignant infantile osteopetrosis and 22 normal control children were included in this study. Eleven patients with malignant infantile osteopetrosis underwent hematopoietic stem cell transplantation. The measurements included optical canal diameter and flash visual evoked potential. Comparisons of these measurements between patients with malignant infantile osteopetrosis and normal controls as well as before and after hematopoietic stem cell transplantation were performed. The correlation between age and optic canal diameter was analyzed using Pearson correlation analysis., Results: The mean optic canal diameter before hematopoietic stem cell transplantation was 1.65 ± 0.54 mm in patients with malignant infantile osteopetrosis and 3.38 ± 0.60 mm in the control group (P < .001). The mean optic canal diameter after hematopoietic stem cell transplantation was 2.72 ± 0.66 mm, which was significantly different from the pre-transplantation measurement (P < .001). The P2 latency for the flash visual evoked potential after hematopoietic stem cell transplantation (152.3 ± 36.4 ms) was significantly less than that before transplantation (165.5 ± 27.7 ms; P = .051). Pearson correlation analysis revealed a significant correlation between age and optic canal diameter (r = 0.722, P < .001)., Conclusions: The optic canal was narrower in pediatric patients with malignant infantile osteopetrosis than in age-matched normal controls. This condition can be relieved through hematopoietic stem cell transplantation and the impaired conductibility of the optic nerve can be improved in some cases. [J Pediatr Ophthalmol Strabismus. 2019;56(1):35-42.]., (Copyright 2018, SLACK Incorporated.)

A finding of high bone mineral density (BMD) from routine dual-energy X-ray absorptiometry (DXA) screening is not uncommon. No consensus exists about the definition of high BMD, and T-score and/or Z-score cutoffs of ≥+2.5 or ≥+4 have been suggested. The many disorders that can result in high BMD are usually classified based on whether the BMD changes are focal vs. generalized or acquired vs. constitutional. In over half the cases, careful interpretation of the DXA report and images identifies the cause as an artefact (e.g., degenerative spinal disease, vascular calcifications, or syndesmophytes) or focal lesion (e.g., sclerotic bone metastasis or Paget's disease). Generalized acquired high BMD may be secondary to a diverse range of disorders such as fluorosis, diffuse bone sclerosis related to renal osteodystrophy, hematological diseases, and hepatitis C. Identification of the cause may require additional investigations such as imaging studies, serum tryptase assay, or serological tests for the hepatitis C virus. Finally, high BMD is a feature of many genetic diseases, most notably osteopetrosis and the disorders caused by mutations in the sclerostin gene SOST (sclerosing bone dysplasia and van Buchem disease) or in the LRP5 gene encoding the low-density lipoprotein receptor-related protein 5 (which is the Wnt co-receptor)., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Autosomal malignant osteopetrosis is a rare condition arising from dysfunction of bone-resorbing osteoclasts, in which diagnosis requires a high suspicion index. Treatment of choice is allogeneic stem cell transplantation. Best outcomes occur if the procedure is carried out before damage to cranial nerves ensues; nonetheless, patients improve their clinical condition., Case Report: An 8-month-old infant was referred for hematology consultation for cytopenias, hepatomegaly, and growth failure. Autosomal malignant osteopetrosis was diagnosed on the basis of physical findings, alteration in calcium and phosphorus metabolism, and hyperdensity of bone. DNA was obtained from the patient and parents; compound heterozygosity of the TCIRG1 gene with a previously non-described deletion (c.1809&#95;1818del) was identified., Conclusions: A new pathogenic mutation of TCIRG1 was identified in a Mexican osteopetrotic patient. Hematopoietic stem cell transplantation was offered as the best available treatment but declined by the parents. An early recognition and wider access to this procedure should be implemented., (Copyright: © 2018 SecretarÍa de Salud.)

Background: High bone mass (HBM) disorders are a group of clinically and genetically heterogeneous bone diseases characterized by increased bone density on radiographs, due to progressive bone overgrowth or impaired bone resorption, or both. Some HBM cases are secondary to other diseases, such as chronic hepatitis C virus infection. Despite the great advance in gene diagnostic technology, the majority of HBM individuals remain undiagnosed., Objective: In this review, we will summarize the clinical, radiological and biochemical characteristics of HBM cases due to varying etiologies, since these features are helpful in the differential diagnosis of HBM., Results: Each subgroup of HBM cases shows distinctive clinical, radiological and biochemical characteristics. HBM, due to bone overgrowth, was designated as sclerosteosis, as a result of mutations located in genes critically involved in the Wnt/beta-catenin signal pathway. Mutations in genes encoding factors relevant to the differentiation and maturation of osteoclasts, or critical for the acidification and resorption of osteoclasts may lead to osteopetrosis. Hepatitis C associated osteosclerosis is characterized by a generalized increase in bone mass and markedly elevated serum levels of bone specific alkaline phosphatase., Conclusion: The clarification of the etiologies of HBM may have a breakthrough role in understanding the molecular mechanisms involved in bone metabolism and may provide new pathways for the intervention of osteoporosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Two main forms of osteopetrosis are recognized, a severe autosomal recessive form (MIM 259700) with an incidence of approximately 1 in 250,000 births and a mild autosomal dominant form (MIM166600) with an incidence of 1 in 20,000 births. Intrinsic disturbances of osteoclastic function due to mutations in genes encoding osteoclast-specific subunits of the vacuolar proton pump (TCIRG1, CLCN7) are found in most patients with recessive form. Mutations of CLCN7 are observed in dominant form of osteopetrosis .The recessive form of ostreopetrosis, i.e., malignant infantile osteopetrosis (MIOP) presents early in life with extreme sclerosis of the skeleton and reduction of marrow space. Signs/symptoms of MIOP appear as early as neonatal age. As there is defect in bone marrow children present with deficiency of red blood cells, white blood cells and platelets. There is extramedullary haemopoiesis, cranial nerve compressions and severe growth failure. The condition also presents with early and late onset neonatal sepsis and is often lethal in the first decade of life due to secondary infections. Treatment is mainly supportive. The only curative treatment is stem cell transplantation. This is a case report of a new-born who was admitted in nursery of Ayub Teaching Hospital initially with complains of neonatal jaundice and sepsis , and a second time with lower respiratory tract infection. Death was eventually due to sepsis. Workup led to diagnosis of Malignant infantile osteopetrosis.

Introduction: Osteopetrosis is a connective tissue disorder resulting from abnormally dense bone predisposing patients to fracture. The clinical pattern of fractures across time and space as well as suggestive radiographic findings usually raises diagnostic suspicion. Multiple genetic mutations resulting in dysfunctional osteoclasts have been implicated in the pathogenesis of osteopetrosis with variable inheritance patterns. In severe cases, usually inherited in an autosomal recessive pattern, the medullary cavity important in the production of normal blood cell progenitors is replaced by defective endochondral bone, leading to pancytopenia and consequential extramedullary hematopoiesis., Materials and Methods: This is a case report from a patient presenting to Naval Medical Center San Diego, a large Military Treatment Facility constituting a regional referral center for Navy Medicine West and serving approximately 250,000 eligible patients with more than 6,200 military and civilian staff. The genetic analysis was performed by Connective Tissue Gene Tests (CTGT) using the CTGT Osteopetrosis NextGen sequencing panel, consisting of 13 genes associated with osteopetrosis. A literature review was performed using PUBMED and Google Scholar to identify information on osteopetrosis and mutation implications., Results: We present a 19-year-old male with clinical osteopetrosis resulting from compound heterozygosity of several mutated alleles within the PLEKHM1 gene, which is important to endosomal and lysosomal vesicular function. To date, most mutations discovered involve genes coding for intracellular enzymes, like carbonic anhydrase, or cell surface transporters, such as the osteoclast H + -ATPase proton pump and the chloride channel, engaged in the acidification of bone at the interface of the osteoclastic ruffled border and the bone matrix. This case represents one of the few reports of inherited defects within the PLEKHM1 gene, resulting in defective osteoclastic ruffled border formation and consequential inadequate bone resorption., Conclusions: This patient's lack of hematologic deficiencies and survival into adulthood portend an improved long-term prognosis and may infer prognostic insight in future cases with similar genetic abnormalities. In patients presenting with skeletal abnormalities and pathologic fractures in early adulthood, the clinician should consider osteopetrosis as a potential explanatory mechanism. Genetic characterization can elucidate cellular pathophysiology and potentially guide treatment modalities. Patients are typically managed with lifestyle adjustments limiting traumatic fracture and antiresorptive medications, typified by the bisphosphonate class. Since osteoclasts derive from a hematopoietic precursor, the only definitive curative therapy present is hematopoietic stem cell transplant. In the future, novel genomic level modulation may confer the ability to correct underlying point mutations and spare individuals from the morbidity associated with bone marrow transplant., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

Autosomal recessive osteopetroses (AROs) are rare, genetically heterogeneous skeletal diseases with increased bone density that are often lethal if left untreated. A precise molecular classification is relevant for the patient's management, because in some subgroups hematopoietic stem cell transplantation (HSCT), which is the only curative therapy, is contraindicated. In two unrelated ARO patients, the molecular analysis revealed the presence of a synonymous variant in known ARO genes, namely in the TCIRG1 gene in one patient and in the CLCN7 in the other patient, predicted to impact on the splicing process. In the latter case, sequencing of the transcript confirmed the splicing defect, whereas in the former, for whom an RNA sample was not available, the defect was reconstructed in vitro by the minigene technology. These results strongly suggest that these synonymous changes were responsible for the disease in our patients. Our findings are novel with respect to ARO and add to the few reports in literature dealing with different diseases, underlining the importance of cDNA analysis for the correct assessment of exonic changes, even when exome sequencing is performed. In particular, we highlight the possibility that at least in some cases ARO is due to synonymous changes, erroneously considered clinically silent, in the genes already described in literature, and suggest carefully reevaluating the sequencing results of these genes when mutations are not found at a first analysis. In addition, with respect to the CLCN7 gene, we suggest that synonymous variants might also contribute to the large spectrum of severity typical of CLCN7-dependent osteopetrosis through more subtle, but not negligible, effects on protein availability and functionality. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Osteopetrosis represents a heterogeneous group of rare, hereditary bone disorders with variable clinical features, and an increase in bone density. Osteomyelitis of the jaws is a significant complication of osteopetrosis. In this article, a reported patient with osteopetrosis complicated by osteomyelitis of the mandible was examined. The patient was treated with intravenous antibiotic therapy, debridement of necrotic bone and hyperbaric oxygen therapy; in addition, the authors attempted to implant the calcium sulfate and vancomycin to reconstruct the bone defect. The patient demonstrated satisfactory healing, and no recurrence of osteomyelitis was observed during the 6-month follow-up period. The treatment of osteopetrosis complicated by osteomyelitis of the mandible is difficult. The treatment of osteopetrosis complicated by osteomyelitis is controversial. The authors recommend the following sequential treatment of osteopetrosis complicated by osteomyelitis of the mandible: systemic antibiotic therapy and hyperbaric oxygen therapy before and after surgery; debridement of the necrotic bone; sufficient periosteal coverage and adequate soft tissue to cover the wound; implantation with calcium sulfate and vancomycin to reconstruct the bone defect as much as possible, which may be helpful in treating the disease.

The aim of this study was to identify the causative mutation in a family with an unusual presentation of autosomal dominant osteopetrosis (OPT), proximal renal tubular acidosis (RTA), renal stones, epilepsy, and blindness, a combination of features not previously reported. We undertook exome sequencing of one affected and one unaffected family member, followed by targeted analysis of known candidate genes to identify the causative mutation. This identified a missense mutation (c.643G>A; p.Gly215Arg) in the gene encoding the chloride/proton antiporter 7 (gene CLCN7, protein CLC-7), which was confirmed by amplification refractory mutation system (ARMS)-PCR, and to be present in the three available patients. CLC-7 mutations are known to cause autosomal dominant OPT type 2, also called Albers-Schonberg disease, which is characterized by osteosclerosis, predominantly of the spine, pelvis and skull base, resulting in bone fragility and fractures. Albers-Schonberg disease is not reported to be associated with RTA, but autosomal recessive OPT type 3 (OPTB3) with RTA is associated with carbonic anhydrase type 2 (CA2) mutations. No mutations were detected in CA2 or any other genes known to cause proximal RTA. Neither CLCN7 nor CA2 mutations have previously been reported to be associated with renal stones or epilepsy. Thus, we identified a CLCN7 mutation in a family with autosomal dominant osteopetrosis, RTA, renal stones, epilepsy, and blindness. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Malignant infantile osteopetrosis is a rare genetic disease characterized by increased bone density due to osteoclastic dysfunction. We report on the case of a 3-month-old girl who was referred to our hospital by the ENT department for severe anemia in the context of bilateral choanal atresia. Clinical examination showed failure to thrive, anemia, respiratory distress, bilateral choanal atresia, and chest deformation. The abdomen was soft with large hepatosplenomegaly. We noted a lack of eye tracking, no optical-visual reflexes, and left nerve facial paralysis. The blood count showed normocytic normochromic anemia with severe thrombocytopenia. The infectious work-up and blood smears were negative. The skeleton X-ray showed diffuse bone densification of the skull, long bones, pelvis, vertebrae, and ribs. The facial bone CT confirmed membranous choanal atresia. The molecular biology search for the TCIRG1 gene mutation was not available. The patient had supportive treatment (transfusion, oral steroid, vitamin D, oxygen, nutrition). Bone marrow transplantation was indicated but not available. She died at 6 months in a context of severe anemia and bleeding. Malignant infantile osteopetrosis is rare and symptoms are nonspecific. Diagnosis should be considered in young infants presenting refractory anemia, particularly in the context of choanal atresia. Bone marrow transplantation remains the only curative treatment., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Malignant infantile osteopetrosis is a rare congenital disease characterized by a dysfunction of osteoclasts followed by an abnormal bone densification. We report the case of a 5-month-old infant in whom this disease was suspected because of the clinical (hepatosplenomegaly, gingival hypertrophy), hematological (pancytopenia and hypocalcemia), and radiological criteria (abnormal bone density, periosteal reaction). The genetic investigation confirmed the diagnosis. Compound heterozygous mutations in the CLCN7 gene were identified, including an as yet undescribed mutation. The second mutation had already been described as being responsible for severe and irreversible neurological damage in patients with osteopetrosis. Since this patient presented severely delayed development, he was not eligible for bone marrow transplantation., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Osteopetrosis is a rare hereditary disorder of osteoclast dysfunction leading to abnormally dense and sclerotic bones that are fragile and break easily. It can be inherited in various patterns like autosomal-dominant, autosomal-recessive or as X-linked traits, but the most grievous forms of its inheritance are the autosomal-recessive ones, which show early onset and are associated with very poor prognosis. We report here the case of an asymptomatic young boy, who was diagnosed as the case of autosomal recessive osteopetrosis on the basis of his genetic studies. The reason for his unusual asymptomatic disease was the location of mutation in TCIRG1 gene that was revealed from his genetic studies. Another unusual point about him was his survival at this age, which is surprisingly rewarding as patients with autosomal recessive osteopetrosis usually die earlier by the age of 2-3 years.

Osteopetrosis is a hereditary disorder of bone characterized by sclerosis of bone and decreased marrow spaces. Due to depressed marrow function, this disorder can cause anemia, hepatosplenomegaly, recurrent infections and osteomyelitis of jaw. Excessive bone deposition in skull base leads to narrowing of foramina and cranial nerve compression. Bone marrow transplantation is the only curative treatment. Other treatments, like interferon gamma, corticosteroids, parathormone and erythropoietin are also used for management. Transfusion of blood, debridement of wound and antibiotics is used to manage complications. Due to its rarity, it is always difficult to diagnose osteopetrosis. Proper diagnosis and treatment decreases the long-term sequelae of the disease.

The initial clinical and hematologic presentation of infantile malignant osteopetrosis may be indistinguishable from that of juvenile myelomonocytic leukemia in infants. Timely radiographic imaging, however, allows straightforward delineation of these 2 severe diseases and facilitates immediate initiation of appropriate therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Osteopetrosis is a heterogeneous group of skeletal disorders. It is a rare genetic disease caused by osteoclast dysfunction, leading to invalid bone desorption and remodeling and an increase in skeletal mass and density. We present the case of a 52-year-old female with osteopetrosis of the temporal bone. She reported loss of hearing in her left ear 14 years ago because of a head trauma. Four months ago, she was conservatively treated because of sudden sensorineural hearing loss in her right ear with no improvement. Her pure tone average audiogram was bilaterally 90 dB with 10% speech recognition. The patient was implanted with a cochlear implant. Except for the extremely thick and dense cortical bone of the mastoid, surgery was uneventful. Speech recognition 6 months after the surgery showed 75%. The results were stable for 3 years follow-up. Patients with profound hearing loss caused by osteopetrosis may benefit from cochlear implantation.

The carbonic anhydrase II (CAII) deficiency syndrome is a rare autosomal recessive osteopetrosis with renal tubular acidosis (RTA) and cerebral calcifications (MIM259730). CAII deficiency syndrome is caused by mutations in the gene CAII, which encodes the enzyme carbonic anhydrase II. CAII mutations are rarely reported in the Asian population. Here, we described two unrelated CAII deficiency families of Chinese Han origin with clinical and genetic analysis. Altogether, 106 subjects, including 2 probands, 4 unaffected family members from two non-consanguineous Chinese families, and 100 healthy controls were recruited. All seven exons and the exon-intron boundaries of the CAII gene were amplified and directly sequenced. Reverse transcription PCR (RT-PCR) was used to study the effect of splice site mutation. All clinical and biochemical parameters of the probands were collected. Two novel mutations of CAII gene were identified by mutational analysis: A nonsense mutation in exon 4 (c.T381C p.Y127X) in both families; a splice mutation at the splice donor site of intron 3 (c.350+2T>C, IVS3+2T>C) in one family. The splice-site mutation causes exon 3 skipping in patient's mRNA resulting in an in-frame deletion and a novel premature stop codon. These mutations were predicted to result in a loss of function of CAII. This is the first report of CAII deficiency syndrome in Chinese population. Our findings extent the spectrum of CAII mutations observed in patients with CAII deficiency syndrome.

Objective: To explore the application of preimplantation genetic diagnosis (PGD) for infantile malignant osteopetrosis (IMO)., Methods: For a family affected with IMO, PGD was provided using combined parental mutation detection and haplotype constructions with microsatellite markers spanning the TCIRG1 gene. Prenatal diagnosis was performed on the chorionic villus and amniocentesis samples by direct sequencing., Results: Prenatal diagnosis showed that the fetus by the third pregnancy has carried the parental mutations [c.242delC (p.Pro81Argfs*85) and c.1114C>T (p.Gln372*)], and the pregnancy was terminated. PGD was subsequently performed through mutations detection and haplotype analyses following whole genome amplification (WGA) of each of 13 cells. The results showed that 6 of the 13 embryos were unaffected, 3 were carriers and 4 were affected. Well developed unaffected/carrier embryos were selected and transferred into the uterus. A single pregnancy was confirmed. Subsequently pre- and post-natal diagnoses have confirmed development of a healthy child., Conclusion: The study demonstrated the advantage of PGD over prenatal diagnosis when natural pregnancies have repeatedly produced IMO children/fetuses.