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Malignant infantile osteopetrosis is a rare inherited disease of bone metabolism, in which osteoclast dysfunction and diminished bone turnover lead to diffuse sclerosis with obliteration of the medullary cavities and narrowing of the skull base neural foramina. We report a case of malignant infantile osteopetrosis with bone marrow failure and optic atrophy that co-occurred with hypophosphatasia, another rare inherited bone disease, in a 6-year-old boy. Key imaging signs of these rare diseases are discussed.

Background: Osteopetrosis is a rare skeletal disease characterized by increased bone density caused by a malfunction of osteoclasts. Case presentation: An 8-year-4-month-old girl with multiple primary and permanent tooth impaction was diagnosed with osteopetrosis. In spite of typical manifestations of osteopetrosis in early childhood, including visual and hearing impairments, short stature, and dental abnormalities, diagnosis was severely delayed. Conclusion: Multiple impacted teeth may indicate a possible diagnosis of osteopetrosis. Dentists should perform an orthopantomography examination when eruption disturbances are encountered and systemic disease should also be suspected, with referral to a pediatrician when necessary.

Background: Osteopetrosis comprises a group of inherited disorders that are rare and result in abnormal bone structure. Bone remodeling is extremely inhibited because osteoclasts are nonfunctional or lacking. This condition causes overgrowth of bone with disappearance of the bone marrow, leading to aplastic anemia; obstruction of nerve passages in the skull leads to blindness and often hearing impairment. In most cases, osteopetrosis results in oral complications such as tooth deformation, hypomineralization, and delayed or absent tooth eruption. The only curative treatment is hematopoietic stem cell transplantation (HSCT). The main treatment of the oral complications during childhood and adolescence consists in protecting the erupted teeth against caries disease through prophylactic treatment aimed at optimal oral hygiene through frequent regular dental visits throughout life. Many patients with osteopetrosis require major oral rehabilitation to treat complications of the disease. Improved results of HSCT increase the likelihood that dental professionals will encounter patients with osteopetrosis. Case presentation: In this case report, we show that individuals with osteopetrosis who have severe oral complications can be treated successfully if they are treated for osteopetrosis at an early age. The boy had his dental care in pedodontics, and regular multidisciplinary meetings were held for future treatment planning. At the age of 15, he was then referred for rehabilitation. The initial evaluations revealed no further growth in the alveolar bone. The rehabilitation was done stepwise, with extraction of malformed and malpositioned teeth. Initially, the patient received a removable partial denture followed by reconstruction of the width of the alveolar process, titanium implants, temporary fixed bridges, and finally screw-retained titanium-ceramic bridges with titanium frames for the upper and lower jaws. Conclusions: The three-year follow-up after loading indicated

T Cell Immune Regulator 1, ATPase H + Transporting V0 Subunit A3 (TCIRG1 gene provides instructions for making one part, the a3 subunit, of a large protein complex known as a vacuolar H + -ATPase (V-ATPase). V-ATPases are a group of similar complexes that act as pumps to move positively charged hydrogen atoms (protons) across membranes. Single amino acid changes in highly conserved areas of the TCIRG1 protein have been linked to autosomal recessive osteopetrosis and severe congenital neutropenia. We used multiple computational approaches to classify disease-prone single nucleotide polymorphisms (SNPs) in TCIRG1. We used molecular dynamics analysis to identify the deleterious nsSNPs, build mutant protein structures, and assess the impact of mutation. Our results show that fifteen nsSNPs (rs199902030, rs200149541, rs372499913, rs267605221, rs374941368, rs375717418, rs80008675, rs149792489, rs116675104, rs121908250, rs121908251, rs121908251, rs149792489 and rs116675104) variants are likely to be highly deleterious mutations as by incorporating them into wild protein they destabilize the wild protein structure and function. They are also located in the V-ATPase I domain, which may destabilize the structure and impair TCIRG1 protein activation, as well as reduce its ATPase effectiveness. These mutants have not yet been identified in patients suffering from CN and osteopetrosis while (G405R, R444L, and D517N) reported in our study are already associated with osteopetrosis. Mutation V52L reported in our study was identified in a patient suspected for CN. Finally, these mutants can help to further understand the broad pool of illness susceptibilities associated with TCIRG1 catalytic kinase domain activation and aid in the development of an effective treatment for associated diseases. Copyright © 2022 Shinwari, Rehman, Liu, Bolkov, Tuzankina and Chereshnev.

Background: Osteopetrosis is a rare hereditary bone disease caused by mutated osteoclasts that are either in scarce abundance or have reduced efficiency. This condition leads to less bone resorption, and thus, denser, more fragile bones. Osteopetrosis leads to complications that can be severe and even fatal. Aim: To summarize the current knowledge of (a) how Osteopetrosis affects the oral health, dentition, and facial skeleton of patients with different disease subtypes, and (b) which treatmentoptions are used worldwide to treat the different orofacial complications and provide symptomrelief in the oral cavity. Methods: This review was based on published studies on oral health among patients witho steopetrosis that focused on diagnosis and treatment. Two searches were performed in PubMed, based on seven search terms: Osteopetrosis, oral, jaw, dental, craniofacial, mandible, and maxilla. After screening based on predefined inclusion and exclusion criteria; 30 articles were selected .Results: All 30 articles were case studies, which have a low grade of evidence. Thus, the data studied were at high risk of bias. The 30 articles included 40 patients. The most common observed complication was osteomyelitis. Conclusion: The data highlighted the importance of good oral hygiene and tissue-conservative treatment in preventing complications from infection. Osteomyelitis should be treated with acombination of surgery, antibiotics, and hyperbaric oxygen therapy. Follow up should continue throughout life to ensure successful treatment of this chronic disease.

Malignant infantile osteopetrosis also called Albers-Schönberg disease or Marble bones it includes a syndrome that causes hard and brittle bones, it also affects wide and short bones, prone to fractures that are difficult to treat. They are classified into two large groups: Autosomal dominant and the recessive. It is very uncommon disease, it has a poor prognosis in the early stages of life. It is an autosomal recessive hereditary bone pathology characterized by increased bone density caused by an abnormality in osteoclast function. Children can be diagnosed immediately at birth due to their low stature, the presence of pathological fractures, osteomyelitis in long bones and recurrent infections. In most cases, there is multisystemic involvemen. The diagnosis of MIO is mainly given by the clinical manifestations, laboratory tests and radiological images. The confirmatory test is by molecular genetic analysis. The most severe complication of osteopetrosis is bone marrow suppression. The most effective therapeutic option for this pathology is hematopoietic stem cell transplantation., La osteopetrosis maligna infantil, también llamada Enfermedad de Albers- Schönberg o Huesos de Mármol comprende un síndrome que provoca un tejido óseo duro y quebradizo, huesos anchos y cortos, propensos a fracturas difíciles de tratar. Se clasifican en dos grandes grupos: Autosómica Dominante y Recesiva. Es muy infrecuente, presenta un mal pronóstico en las primeras etapas de la vida. Es una patología ósea hereditaria autosómica recesiva que se caracteriza por el aumento de la densidad ósea causada por una anomalía en la función de los osteoclastos. Los niños se pueden diagnosticar inmediatamente al nacer por su corta estatura, por la presencia de fracturas patológicas, osteomielitis en huesos largos e infecciones a repetición. En la mayoría de los casos existe afectación multisistémica. El diagnóstico de la OMI es principalmente dado por la clínica, exámenes de laboratorio e imágenes radiológicas. La prueba confirmatoria es mediante el análisis genético molecular. La complicación más severa de la Osteopetrosis corresponde la supresión de la médula ósea. La opción terapéutica más efectiva para esta patología es el trasplante de células progenitoras hematopoyéticas.

Objective: To describe Albers Schomberg disease (osteopetrosis) from a case report. Methods: Descriptive observational case report. Results and Conclusions: Children are usually diagnosed immediately or shortly after birth; it is characterized by hematologic problems such as anemia, thrombocytopenia, and granulocytopenia; splenomegaly; cranial nerve compression resulting in blindness and deafness; pathologic fractures; and infections. This disease is genetically recessive and there is bone marrow failure. Despite treatment, the infantile or malignant forms remain the most severe because of anemia, hemorrhages and complicated infections, often resulting in death within the first ten years of life. In contrast, adult patients have a higher survival rate., Objetivo: Describir la enfermedad de Albers Schomberg (osteopetrosis) desde un reporte de un caso. Método: Descriptiva observacional de caso clínico. Resultados y conclusiones: Por lo general, los niños son diagnosticados inmediatamente o poco después del nacimiento; se caracteriza por problemas hematológicos como anemia, trombocitopenia y granulocitopenia; esplenomegalia; la compresión de los nervios craneales que produce ceguera y sordera; fracturas patológicas e infecciones. Esta enfermedad es genéticamente recesiva existiendo hay falla de la médula ósea. A pesar del tratamiento, las formas infantiles o malignas siguen siendo las más graves por la anemia, las hemorragias y las infecciones complicadas, suelen provocar la muerte en los primeros diez años de vida. Por el contrario, los pacientes adultos tienen una tasa de supervivencia más alta.

Introduction and importance Osteopetrosis is a poorly known and probably underdiagnosed pathology. It is caused by various genetic abnormalities resulting in osteoclast dysfunction. Functional and aesthetic consequences have a major impact on the patient’s quality of life. Ten percent of osteopetrosis cases develop osteomyelitis that usually involves the mandible. Management of this complication remains complex and often unsatisfactory. Case presentation We report a case of a 62-year-old woman with osteopetrosis, complicated by mandibular osteomyelitis with intra-oral bone exposure and submental fistulas. Management was performed with antibiotic therapy and surgical necrotic resection. This cured the fistulas but the bone exposure persisted. Discussion This case report highlights the difficulty of achieving complete healing of osteomyelitis in osteopetrosis. Antibiotic therapy, surgical management, or even hyperbaric oxygen therapy are required, but must be adapted to the case. A free flap procedure is undesirable but, when it is necessary, a bone marrow transplant could be considered to restore osteoclast function. Conclusion The management of mandibular osteomyelitis in patients with osteopetrosis must adapt to the situation and severity. To avoid most cases of osteomyelitic complications in patients suffering from osteopetrosis, we propose that a preventive strategy of better dental care should be considered.

Romosozumab, a humanized monoclonal antibody specific for sclerostin (SOST), has been approved for treatment of postmenopausal women with osteoporosis at a high risk for fracture. Previous work in sclerostin global knockout (Sost-/-) mice indicated alterations in immune cell development in the bone marrow (BM), which could be a possible side effect in romosozumab-treated patients. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young mice receiving sclerostin antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term Sost deficiency on wild-type (WT) long-term hematopoietic stem cells transplanted into older cohorts of Sost-/- mice. Our analyses revealed an increased frequency of granulocytes in the BM of Scl-Ab-treated mice and WT→Sost-/- chimeras, indicating myeloid-biased differentiation in Sost-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNFα, IL-1α, and MCP-1 in Sost-/- BM serum. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of Sost-/- mice. Taken together, our current study indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM.

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.

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.

Osteopetrosis is a hereditary disease with an autosomal recessive or autosomal dominant type of inheritance, caused by a disruption in the functional activity of osteoclasts due to gene mutation. The article systematizes data on etiology, classification, pathomorphology, gene disorders based on the analysis of 38 sources of literature, and deals with the modern approa­ches to the treatment of osteopetrosis. Three types of osteopetrosis with different severity degrees of skeletal disorders and pathological severity are described. The main pathomorphological changes in the structural organization of bone tissue are presented and features of the state of osteoclasts are shown depending on the mutation of genes controlling their functional activity. There are no protocols for the treatment of this pathology, but treatment me­thods based on the use of hematopoietic stem cells are under development. The paper presents with clinical case report of a patient with marble bone disease., Остеопетроз — наследственное заболевание с аутосомно-рецессивным или аутосомно-доминантным типом наследования, вызванное нарушением функциональной активности остеокластов за счет мутации генов. В статье на основе анализа литературных источников систематизированы данные об этиологии, классификации, патоморфологии, генных нарушениях и освещены современные подходы к лечению остеопетроза. Описаны три типа остеопетроза с различной степенью выраженности нарушений в скелете и тяжестью патологии. Представлены основные патоморфологические изменения в структурной организации костной ткани, отмечены особенности состояния остеокластов в зависимости от мутации генов, контролирующих их функциональную активность. Протоколов для лечения этой патологии не имеется, но ведется разработка методов лечения на основе использования гемопоэтических стволовых клеток. Представлен клинический пример пациентки с остеопетрозом., Остеопетроз — спадкове захворювання з автосомно-рецесивним чи автосомно-домінантним типом успадкування, спричинене порушенням функціональної активності остеокластів внаслідок мутації генів. У статті на основі аналізу літературних джерел систематизовані дані про етіологію, класифікацію, патоморфологію, генні порушення і висвітлені сучасні підходи до лікування остеопетрозу. Описано три типи остеопетрозу з різним ступенем вираженості порушень у скелеті та тяжкості патології. Подані основні патоморфологічні зміни у структурній організації кісткової тканини, відзначені особливості стану остеокластів залежно від мутації генів, які контролюють їх функціональну активність. Протоколів лікування цієї патології немає, але проводиться розробка методів лікування на основі використання гемопоетичних стовбурових клітин. Наведено клінічний приклад пацієнтки з остеопетрозом.

Osteopetrosis (also known as Albers-Schönberg disease) is a syndrome that includes four classic types and is characterized by bone dysplasia and lack of bone resorption due to abnormal osteoclastic activity and consequent development of brittle and hard bone that is prone to fractures that are difficult to treat surgically. Herein we present two cases of osteopetrosis with diaphyseal fractures of the humerus, both managed with non-surgical treatment. The objectives of our manuscript are to document our experience in the management of these cases and review the literature. The non-invasive treatment provides the best outcome for dyaphyseal fractures on the humerus in patients with osteopetrosis, given that the quality of the bone in these patients impairs the implementation of osteosynthesis. In addition, the placement of implants can lead to complications such as infections, delayed consolidation and pseudoarthrosis, among others. Surgical treatment should reserved for certain patients such as those with delayed consolidation, pseudoarthrosis, a history of repeated fractures, pre-existing deformity and those who are at risk for the development of disabling deformities or do not respond to non-surgical treatment, Las osteopetrosis (enfermedad de Albers-Schönberg) es un síndrome con cuatro tipos clásicos e instituye una displasia ósea secundaria a la falta de resorción de hueso por anormalidad de los osteoclastos, lo cual provoca un tejido óseo duro y quebradizo,propenso a fracturas difíciles de tratar quirúrgicamente. Se han publicado escasos artículos sobre el tema; por este motivo, decidimos presentar a dos pacientes con fracturas diafisarias de húmero con osteopetrosis, ambas tratadas en forma incruenta.Los objetivos son comunicar nuestra experiencia y el método de tratamiento de dicha afección y realizar una revisión bibliográfica acerca del tema. Creemos que el tratamiento de elección para las fracturas diafisarias de húmero en pacientes con osteopetrosises el incruento, ya que su tipo de tejido óseo dificulta la implementación de cualquier osteosíntesis. Además, la colocación de implantes puede provocar algunas complicaciones, como infecciones, retraso de la consolidación y seudoartrosis. La cirugía se reserva para ciertos casos, como en pacientes con riesgo de desarrollar deformidades incapacitantes, aquellos que han sufrido fracturas repetidas, con retraso de la consolidación, seudoartrosis, quienes no responden al tratamiento incruento o con unadeformidad previa.

Osteoclasts are derived from hematopoietic stem cells (HSCs) and form upon stimulation of osteoclast precursors by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κΒ ligand (RANKL). Osteoclasts resorb bone by secreting hydrochloric acid, matrix metalloproteinases (MMPs) and cathepsin K. Failure of bone resorption or bone formation results in metabolic bone diseases. Osteopetrosis (excess bone) is caused by mutations impairing osteoclastogenesis or osteoclast function, and can only be treated with a hematopoietic stem cell (HSC) transplant (HSCT). Infantile malignant osteopetrosis (IMO) is typically lethal without HSCT. 50% of IMO patients have mutations in TCIRG1, a component of the osteoclast V-ATPase that is crucial for acidification. The first aim of this dissertation was to develop a clinically applicable TCIRG1-targeting gene therapy, to circumvent the need for HSC donors, and assess its efficacy and safety.Osteoclasts have also been implicated as mediators of bone and cartilage degradation in rheumatic diseases. The increased bone degradation in rheumatoid arthritis and osteoarthritis has been strongly linked to increased osteoclast presence and activity, but the role of osteoclasts in the pathological degradation of cartilage—and type II collagen, its main component—remains unclear. Therefore, the second aim of this dissertation was to develop novel models and biomarkers for the investigation of osteoclast-mediated cartilage degradation.In Paper I, we demonstrated that a proof-of-concept lentiviral vector, with a viral promoter, used to transduce IMO HSCs only induces TCIRG1 expression in osteoclasts, not in precursors or macrophages, and that a small percentage of treated cells is sufficient to restore resorption. In Paper II, we developed a clinically applicable vector, with a human promoter, and demonstrated that transduced human IMO HSCs transplanted into mice maintained the ability to generate functional osteoclasts

While management of appendicular fractures has been well described in the setting of osteopetrosis, there is limited information on managing fractures of the axial spine. Here we present an osteopetrotic patient with multiple traumatic multiple, comminuted, unstable cervical spinal fractures managed with non-operative stabilization, and provide a review of the pathophysiology, genetic characteristics, and special considerations that must be explored when determining operative versus non-operative management of spinal injury in osteopetrosis. A PubMed query was performed for English articles in the literature published up to June 2016, and used the following search terms alone and in combination: "osteopetrosis", "spine", "fractures", "osteoclasts", and "operative management". Within four months after initial injury, treatment with halo vest allowed for adequate healing. The patient was asymptomatic with cervical spine dynamic radiographs confirming stability at four months. On four-year follow up examination, the patient remained without neck pain, and CT scan demonstrated partially sclerotic fracture lines with appropriate anatomical alignment. In conclusion, external halo stabilization may be an effective option for treatment of multiple unstable acute traumatic cervical spine fractures in patients with osteopetrosis. Given the challenge of surgical stabilization in osteopetrosis, further research is necessary to elucidate the optimal form of treatment in this select patient population.

In osteopetrosis, osteoclast dysfunction can lead to deafness, blindness, bone marrow failure, and death. Hematopoietic cell transplantation (HCT) is currently the only curative treatment, but outcome remains disappointing. Although a rapid progression toward HCT is detrimental to prevent further progress of disease manifestations, 70% of cases lack an HLA-matched sibling and require alternative stem cell sources. We present two cases of osteopetrosis that successfully received an HCT with haploidentical TcRαβ-depleted cells from one of the parents. These cases showed no further disease progression, had restoration of functional osteoclasts, and illustrate this approach to enable prompt HCT with ready available parental donors and rapid and sustained hematological, including osteoclast, recovery.

La osteopetrosis es una rara y compleja enfermedad hereditaria ósea, caracterizada por la alteración de la resorción ósea debido a una deficiente función o pobre desarrollo de osteoclastos, produciendo un hueso altamente calcificado, pero con mayor fragilidad. Presentámos un caso clÍnico de un paciente de sexo masculino de 3 años de edad, que a los 11 días de vida debuta con convulsiones tónico clónicas generalizadas. Posteriormente presenta múltiples ingresos por neumonía y anemia. En la actualidad no existe un tratamiento médico efectivo, por lo que es necesario un abordaje multidisciplinario. El trasplante de médula ósea constituye una alternativa viable para el tratamiento de algunos casos de osteopetrosis severa.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most children with osteopetrosis (OP). Timing of HSCT is critical; therefore, umbilical cord blood transplantation (UCBT) is an attractive option. We analyzed outcomes after UCBT in 51 OP children. Median age at UCBT was 6 months. Seventy-seven percent of the cord blood grafts had 0 or 1 HLA disparity with the recipient. Conditioning regimen was myeloablative (mostly busulfan-based in 84% and treosulfan-based in 10%). Antithymocyte globulin was given to 90% of patients. Median number of total nucleated and CD34 cells infused was 14 × 10/kg and 3.4 × 10/kg, respectively. Median follow-up for survivors was 74 months. Cumulative incidence (CI) of neutrophil recovery was 67% with a median time to recovery of 23 days; 33% of patients had graft failure, 81% of engrafted patients had full donor engraftment, and 19% had mixed donor chimerism. Day 100 CI of acute graft-versus-host disease (grades II to IV) was 31% and 6-year CI of chronic graft-versus-host disease was 21%. Mechanical ventilation was required in 28%, and veno-occlusive disease was diagnosed in 16% of cases. Six-year overall survival rate was 46%. Comparative studies with other alternative donors should be performed to evaluate whether UCBT remains a valid alternative for children with OP without an HLA-matched donor.

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La osteopetrosis, es una displasia ósea hereditaria ligada al cromosoma X, conocida también como enfermedad de los huesos de mármol o enfermedad de Albers Schonberg, poco frecuente y consiste en la alteración de la resorción ósea por una disminución del número o actividad de los osteoclastos impidiendo la formación correcta de la cavidad medular, como consecuencia existen alteraciones hematológicas, inmunológicas, aumento en la densidad y deformidades óseas muy característica; la forma más severa es la osteopetrosis infantil o maligna de carácter autosómica recesiva; su aparición es precoz en la primera infancia y se caracteriza por una grave insuficiencia de la médula ósea que suele tener un mal pronóstico; el diagnóstico se basa en la valoración clínica y la forma radiológica característica, es la imagen de hueso en el interior del hueso, es confirmada por pruebas genéticas que permiten comprender la historia natural, el tratamiento específico, el asesoramiento en los riesgos de recurrencia y diagnóstico prenatal en las formas graves. El objetivo principal de este artículo es presentar un caso clínico de osteopetrosis, que corresponde a una enfermedad poco frecuente con elevada morbimortalidad. Se presenta el caso clínico de un lactante menor masculino que ingresa por cuadro clínico respiratorio compatible con bronquiolitis; al examen físico llama la atención palidez generalizada, malformaciones craneofaciales, retraso psicomotriz; sus estudios radiográficos evidencian aumento de la densidad ósea imagen sugestiva de osteopetrosis, debido a la similitud clínica de la enfermedad de los huesos de mármol con algunos trastornos hematológicos e inmunológicos, se concluye que debería ser incluida como parte del diagnóstico diferencial, de manera que pueda tener diagnóstico y tratamiento temprano para mejorar la calidad de vida de quienes la padecen.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most children with osteopetrosis (OP). Timing of HSCT is critical; therefore, umbilical cord blood transplantation (UCBT) is an attractive option. We analyzed outcomes after UCBT in 51 OP children. Median age at UCBT was 6 months. Seventy-seven percent of the cord blood grafts had 0 or 1 HLA disparity with the recipient. Conditioning regimen was myeloablative (mostly busulfan-based in 84% and treosulfan-based in 10%). Antithymocyte globulin was given to 90% of patients. Median number of total nucleated and CD34+ cells infused was 14 × 107/kg and 3.4 × 105/kg, respectively. Median follow-up for survivors was 74 months. Cumulative incidence (CI) of neutrophil recovery was 67% with a median time to recovery of 23 days; 33% of patients had graft failure, 81% of engrafted patients had full donor engraftment, and 19% had mixed donor chimerism. Day 100 CI of acute graft-versus-host disease (grades II to IV) was 31% and 6-year CI of chronic graft-versus-host disease was 21%. Mechanical ventilation was required in 28%, and veno-occlusive disease was diagnosed in 16% of cases. Six-year overall survival rate was 46%. Comparative studies with other alternative donors should be performed to evaluate whether UCBT remains a valid alternative for children with OP without an HLA-matched donor.

La osteopetrosis es un término que engloba a un grupo heterogéneo y poco frecuente de enfermedades heredables caracterizados por un aumento de la densidad ósea resultante de una anormal diferenciación o disfunción osteoclástica. Existen múltiples variantes de la enfermedad con presentación clínica heterogénea: desde el paciente asintomático hasta formas fatales en la infancia. En muchos casos el diagnóstico es guiado por los hallazgos característicos radiológicos, como en el caso que presentamos a continuación.

La osteopetrosis es un término que engloba a un grupo heterogéneo y poco frecuente de enfermedades heredables caracterizados por un aumento de la densidad ósea resultante de una anormal diferenciación o disfunción osteoclástica. Existen múltiples variantes de la enfermedad con presentación clínica hetero- génea: desde el paciente asintomático hasta formas fatales en la infancia. En muchos casos el diagnóstico es guiado por los hallaz- gos característicos radiológicos, como en el caso que presentamos a continuación.

The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis. (C) 2009 Wiley-Liss, Inc.

Autosomal recessive osteopetrosis (ARO) is a group of genetic disorders that involve defects that preclude the normal function of osteoclasts, which differentiate from hematopoietic precursors. In half of human cases, ARO is the result of mutations in the TCIRG1 gene, which codes for a subunit of the vacuolar proton pump that plays a fundamental role in the acidification of the cell-bone interface. Functional mutations of this pump severely impair the resorption of bone mineral. Although postnatal hematopoietic stem cell transplantation can partially rescue the hematological phenotype of ARO, other stigmata of the disease, such as secondary neurological and growth defects, are not reversed. For this reason, ARO is a paradigm for genetic diseases that would benefit from effective prenatal treatment. Using the oc/oc mutant mouse, a murine model whose osteopetrotic phenotype closely recapitulates human TCIRG1-dependent ARO, we report that in utero transplantation of adult bone marrow hematopoietic stem cells can correct the ARO phenotype in a limited number of mice. Here we report that in utero injection of allogeneic fetal liver cells, which include hematopoietic stem cells, into oc/oc mouse fetuses at 13.5 days post coitum produces a high level of engraftment, and the oc/oc phenotype is completely rescued in a high percentage of these mice. Therefore, oc/oc pathology appears to be particularly sensitive to this form of early treatment of the ARO genetic disorder

比較的短期間に，右大腿骨骨折を3回発症した大理石骨病の症例を報告する.初回及び2回目の骨幹部骨折に対してエンダー釘を用いて骨接合を行ったが，髄腔狭小化のため充分な強度を持つ内固定はできなかった.3回目の骨折は遠位のエンダー釘刺入孔を含む大腿骨顆上骨折であった.治療はエンダー釘を抜去し，プレートによる骨接合を施行した.ドリリングに多少時間を要したがスクリュー刺入は可能であった.大理石骨病患者の骨折では，内固定材料が入っていても再骨折を生じる可能性や，骨孔作成部にも容易に骨折が生じることを念頭に置くべきと思われた.

The ubiquitous multisubunit vacuolar-type proton pump (H+- or V-ATPase) is essential for acidification of diverse intracellular compartments. It is also present in specialized forms at the plasma membrane of intercalated cells in the distal nephron, where it is required for urine acidification, and in osteoclasts, playing an important role in bone resorption by acid secretion across the ruffled border membrane. It was reported previously that, in human, several of the renal pump's constituent subunits are encoded by genes that are different from those that are ubiquitously expressed. These paralogous proteins may be important in differential functions, targeting or regulation of H+-ATPases. They include the d subunit, where d1 is ubiquitous whereas d2 has a limited tissue expression. This article reports on an investigation of d2. It was first confirmed that in mouse, as in human, kidney and bone are two of the main sites of d2 mRNA expression. d2 mRNA and protein appear later during nephrogenesis than does the ubiquitously expressed E1 subunit. Mouse nephron-segment reverse transcription-PCR revealed detectable mRNA in all segments except thin limb of Henle's loop and distal convoluted tubule. However, with the use of a novel d2-specific antibody, high-intensity d2 staining was observed only in intercalated cells of the collecting duct in fresh-frozen human kidney, where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern. In human bone, d2 co-localized with the a3 subunit in osteoclasts. This different subunit association in different tissues emphasizes the possibility of the H+-ATPase as a future therapeutic target.

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.

Osteoclasts are tissue-specific polykaryon bone-resorbing cells derived from the monocyte/macrophage hematopoietic lineage with specialized functions required for the adhesion of the cells to bone and the subsequent polarization of the cell membrane, secretion of acid to dissolve mineral crystals, and release of proteolytic enzymes to degrade the extracellular matrix proteins. Most pathological conditions in the skeleton lead to loss of bone due to excess osteoclastic bone resorption, including periodontal disease, rheumatoid arthritis, and osteoporosis. In rare cases, most of them genetic, patients with osteopetrosis exhibit sclerotic bone due either to a lack of osteoclasts or to non-functional osteoclasts. Mainly because of phenotypic findings in genetically manipulated mice or due to spontaneous mutations in humans, mice, and rats, several genes have been discovered as being crucial for osteoclast formation and activation. Recent breakthroughs in our understanding of osteoclast biology have revealed the critical roles in osteoclast differentiation played by RANKL, RANK, and OPG, three novel members of the tumor necrosis factor ligand and receptor superfamilies. The further study of these molecules and downstream signaling events are likely to provide a molecular basis for the development of new drugs for the treatment of diseases with excess or deficient osteoclastic bone resorption.

Autosomal dominant osteopetrosis II (ADOII) is a relatively benign disorder caused by a missense mutation in the ClCN7 gene. In this study, we characterize the osteoclasts from patients with ADOII, caused by a G215R mutation, and investigate the effect on osteoclast function in vitro. Osteoclasts from ADOII patients and healthy age- and sex-matched controls, were used to evaluate osteoclastogenesis, cell fusion, acidification, and resorptive activity. ADOII osteoclasts in vivo have increased number and size. However, in vitro we observed no significant changes in the osteoclast formation rate, the morphology, and the expression of markers, such as cathepsin K and tartrate-resistant acid phosphatase. When mature ADOII osteoclasts were investigated on mineralized bone, they degraded the bone material, however only to 10 to 20% of the level in controls. We show by acridine orange, that the reduced chloride transport leads to reduced acidification. We show that the residual activity is sensitive to inhibitors of cathepsins and chloride channels, confirming that resorption is reduced but present. In conclusion, this is the first functional in vitro study of human ADOII osteoclasts. We show normal osteoclastogenesis in ADOII osteoclasts. However, the residual activity of the ClC-7 channel in ADOII osteoclasts does not allow sufficient acidification and thereby resorption.

The thymi of op/op rats were investigated before and after bone marrow graft. Normal littermates were used as controls. The thymic involution and atrophy in non-treated op/op rats was characterized by the presence of pyknotic thymocytes (apoptosis) and numerous lipid-laden macrophages containing pleiomorphic lysosomes. This thymic atrophy is histologically very similar to the thymic involution induced by glucocorticoids or by stress in normal rats. In treated new born op/op rats, the osteopetrotic process began to be reversed 2 weeks after the graft. The thymus of treated op/op recovered a normal weight and its histology and ultrastructure were quite similar to that of normal littermates. These findings are discussed in relation to the defective macrophage function and cellular immunity impairment reported in osteopetrosis., SCOPUS: ar.j, info:eu-repo/semantics/published

The aim of the present work was to further characterize immunological defects in osteopetrosis. The op/op mutant mouse is of particular interest since a marrow cavity develops spontaneously in older animals. The interleukin production (IL-1, IL-2, IL-3, IL-4, IL-6), the presence of macrophage differentiation antigens and the evolution of the bone lesions were studied in osteopetrotic and normal mice. Low levels of IL-1, IL-3 and IL-4 were observed at the age of 6 weeks in the op/op mice. However, at 22 weeks of age, the level of IL-1 and IL-4 returned to normal value in these op/op mice whereas the level of IL-3 remained partially decreased at the same age. Furthermore, macrophage expression of MAC-2 antigen, reduced at 12 weeks of age was found to be normal 10 weeks later. These immunological defects and their recovery seems to be concomitant with the healing of the bone lesions. © 1993, Elsevier Scientific Publishers Ireland Ltd. All rights reserved. All rights reserved., SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, FLWNA, info:eu-repo/semantics/published

Background: Osteopetrosis is a rare skeletal disease characterized by increased bone density caused by a malfunction of osteoclasts. Case presentation: An 8-year-4-month-old girl with multiple primary and permanent tooth impaction was diagnosed with osteopetrosis. In spite of typical manifestations of osteopetrosis in early childhood, including visual and hearing impairments, short stature, and dental abnormalities, diagnosis was severely delayed. Conclusion: Multiple impacted teeth may indicate a possible diagnosis of osteopetrosis. Dentists should perform an orthopantomography examination when eruption disturbances are encountered and systemic disease should also be suspected, with referral to a pediatrician when necessary.

Background: Osteopetrosis is a rare skeletal disease characterized by increased bone density caused by a malfunction of osteoclasts. Case presentation: An 8-year-4-month-old girl with multiple primary and permanent tooth impaction was diagnosed with osteopetrosis. In spite of typical manifestations of osteopetrosis in early childhood, including visual and hearing impairments, short stature, and dental abnormalities, diagnosis was severely delayed. Conclusion: Multiple impacted teeth may indicate a possible diagnosis of osteopetrosis. Dentists should perform an orthopantomography examination when eruption disturbances are encountered and systemic disease should also be suspected, with referral to a pediatrician when necessary.