Hematopoietic stem cell transplantation in a patient with osteopetrosis and mutation in CLCN7: long-term follow-up / Trasplante de células progenitoras hematopoyéticas en un paciente con osteopetrosis y mutación en CLCN7: seguimiento a largo plazo

Abstract Background: Osteopetrosis is a rare hereditary bone dysplasia characterized by insufficient osteoclast activity that results in increased bone mineral density. Hematopoietic stem cell transplantation (HSCT) can reverse skeletal abnormalities and restore hematopoiesis. Case report: We present the case of a 3-year and 2-month-old male patient with the diagnosis of osteopetrosis. The patient underwent allogeneic HSCT (Allo-HSCT) using 100% compatible bone marrow from a related donor and received a myeloablative conditioning regimen and a CD34 cell dose (4.7 × 107/kg). In the early post-transplant, frequent complications such as pneumonitis, hypercalcemia, and hyperphosphatemia ocurred. With a suitable granulocytic graft and chimerism of 100%, it was considered a successful transplant. However, the patient showed a delayed platelet graft treated with a platelet-stimulating factor for 6 months. The patient is currently disease-free, outpatient follow-up, with no data on graft-versus-host disease, and no progressive neurological damage. Conclusions: Osteopetrosis is a childhood disease that requires clinical suspicion and early diagnosis. HSCT is necessary at an early age to prevent disease progression and sensorineural, hematological, and endocrinological functions damage that can lead to death.

Resumen Introducción: La osteopetrosis es una displasia ósea hereditaria poco común, caracterizada por una actividad osteoclástica deficiente que aumenta la densidad mineral ósea. Se considera que el trasplante de células progenitoras hematopoyéticas (TCPH) puede revertir las anormalidades esqueléticas y restaurar la hematopoyesis. Caso clínico: Se presenta el caso de un paciente de sexo masculino, de 3 años y 2 meses de edad, con diagnóstico tardío de osteopetrosis. Se realizó un TCPH alogénico de donador relacionado 100% compatible con médula ósea. Se utilizaron un régimen de acondicionamiento mieloablativo y una dosis celular de CD34 de 4.7 × 107/kg de peso. En el postrasplante temprano, el paciente desarrolló complicaciones como neumonitis, hipercalcemia e hiperfosfatemia. Con un injerto granulocítico adecuado y quimerismo del 100% se consideró un trasplante exitoso. Sin embargo, el paciente presentó retraso en el injerto plaquetario, por lo que se administró factor estimulante de plaquetas por 6 meses. Actualmente el paciente se encuentra libre de enfermedad, en seguimiento ambulatorio, sin datos de enfermedad del injerto contra el hospedero y con pruebas de neurodesarrollo sin deterioro neurológico progresivo. Conclusiones: La osteopetrosis es una enfermedad infantil que requiere una sospecha clínica y un diagnóstico temprano, ya que es necesario un TCPH a corta edad como tratamiento para evitar la progresión de la enfermedad y el deterioro de las funciones neurosensoriales, hematológicas y endocrinológicas que puede derivar en la defunción del paciente.

Osteopetrosis autosómica dominante benigna: Reporte de caso / Autosomal dominant osteopetrosis: Case report

La osteopetrosis es una enfermedad infrecuente, se caracteriza por el incremento de la densidad ósea observada en las radiografías, resultado de anormalidades en la diferen- ciación y función de los osteoclastos que les incapacita para la resorción ósea y cartilaginosa, formándose huesos más densos, pero más frágiles. Objetivo: describir la Osteopetrosis Auto- sómica Dominante mostrando nuestra experiencia el método de tratamiento. Con un amplio conocimiento de esta patología, los hallazgos radiográficos característicos y los manejos tera- péuticos adecuados podremos lograr un diagnóstico precoz certero y una mejor sobrevida de los pacientes. Reporte de caso: Paciente femenina de 13 años, con historia de fracturas espontáneas a repetición en los antebrazos principalmente, la madre niega antecedentes de trauma; asimismo refiere observar retraso en el crecimiento de la paciente, por lo cual acude al hospital regional de occidente, Quetzaltenango, Guatemala, para evaluación. Se le realizan radiografías en proyección anteroposterior (AP) y lateral de cráneo, de extremidades superio- res e inferiores y de columna dorsal evidenciando en las radiografías de cráneo aumento de la densidad ósea y aumento de grosor de la misma, en la columna dorsal se observó aumento de la esclerosis a nivel de las placas terminales superiores e inferiores de los cuerpos vertebrales, dando la típica apariencia de "vertebra en sándwich", signo patognomónico de esta enferme- dad. La paciente recibió tratamiento con prednisolona, vitamina D y calcio en dosis de acuerdo a las medidas antropométricas de la paciente y control médico por año para evaluar estado clínico...(AU)

SNX10 gene mutation in infantile malignant osteopetrosis: A case report and literature review / 中南大学学报(医学版)

A case of SNX10 gene mutation in a patient with infantile malignant osteopetrosis (IMO) was admitted to Department of Pediatrics, Third Xiangya Hospital, Central South University. The patient had the symptom of anemia, hepatosplenomegaly and growth retardation. The X-ray examination suggested extensive increase of bone density throughout the body, which was clinically diagnosed as IMO. The homozygous mutation of SNX10 gene c.61C>T was found via gene sequencing. We reviewed the relevant literatures and found that anemia, visual and hearing impairment, hepatosplenomegaly are the main clinical symptoms of IMO, SNX10 gene mutation is a rare cause of IMO, and hematopoietic stem cell transplantation is an effective treatment.

Osteopetrosis: Presentación de dos casos / Osteopetrosis: two case reports

Las osteopetrosis (enfermedad de Albers-Schönberg) comprende 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 osteopetrosis es 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 una deformidad previa. Nivel de Evidencia: IV

Osteopetrosis, also known as Albers-Schönberg disease, is a disorder that is divided into four types and characterized by bone dysplasia and lack of bone resorption due to abnormal osteoclastic activity, resulting in the development of brittle and denser bone tissue that is prone to fractures that are difficult to treat surgically. On this paper, we discuss the cases of two patients with osteopetrosis and humeral shaft fractures, both of whom received conservative management. The objectives of our paper are to discuss our experience in the management of these cases and to review the available literature. Conservative management provides the best outcome for humeral shaft fractures in patients with osteopetrosis, given that bone quality in these patients excludes osteosynthesis. In addition, the use of implants may lead to complications such as infections, delayed fracture healing and pseudarthrosis, among others. Surgery should be reserved for certain patients, such as those with delayed fracture healing, pseudarthrosis, history of recurrent fractures, pre-existing fracture deformity, and those at risk of developing disabling deformities or that do not respond to conservative management. Level of Evidence: IV

Osteopetrosis: presentación de un caso clínico / Osteopetrosis: presentation of a clinical case

La osteopetrosis, en particular la variante autosómica recesiva, es una patología con alta mortalidad de muy baja incidencia, lo cual conlleva al retraso de su diagnóstico perdiendo la posibilidad de un tratamiento oportuno para mejorar su pronóstico. Esta enfermedad se produce por una falla en la función o diferenciación osteoclástica con reabsorción ósea defectuosa.Presentamos un caso clínico motivados por la necesidad de agudizar su sospecha ante la presencia de los siguientes signos clínicos (hipocalcemia, alteraciones hematológicas, disfunción de pares craneales) y radiológicos característicos (engrosamiento cortical con colapso medular, esclerosis difusa afectando cráneo, huesos largos y columna, esclerosis focal, líneas escleróticas y radiolucidas que se alternan). Es necesario estar alertas a esta entidad para dar la posibilidad de un pronto estudio genético para arribar más rápido al transplante de medula ósea mejorando la sobrevida de estos pacientes

The osteopetrosis, including autosomal recessive variant is a disease with high mortality of very low incidence which leads to delay in diagnosis losing the possibility of early treatment to improve their prognosis. This disease is caused by a failure to function or osteoclastic differentiation with defective bone resorption. We report a case motivated by the need to sharpen their suspicion in the presence of the following clinical signs (hypocalcemia, blood disorders, cranial nerve dysfunction) and radiological characteristic (core collapse cortical thickening, diffuse sclerosis affecting skull, long bones and spine, focal sclerosis, sclerotic and radiolucent lines alternating).You need to be alert to this organization to give the possibility of a genetic study soon to arrive faster by improving bone marrow transplant survival in these patients

Osteopetrosis infantil maligna / Malignant Infantile osteopetrosis

INTRODUCCIÓN: Osteopetrosis Infantil Maligna (OIM) es un grave e inusual desorden genético debi do a una actividad osteoclástica anormal. OBJETIVO: Reportar lactante en quien se documentó una Osteopetrosis Infantil Maligna, revisando aspectos diagnósticos y terapéuticos más relevantes. CASO CLÍNICO: Reportamos un lactante de 10 meses de sexo masculino en quien se confirmó OIM tras presentar plaquetopenia y visceromegalias. En su historial destacó ser primer hijo de padres no consanguíneos, y entre sus hallazgos presentó hepatoesplenomegalia, plaquetopenia y anemia graves, compromiso sensorial visual y auditivo e infecciones a repetición. El diagnóstico fue confirmado mediante estudio genético, el cual identificó 2 mutaciones heterocigotas en el gen TCIRG1. Se rea lizó trasplante de precursores hematopoyéticos, sin haber presentado recuperación hematológica, falleciendo por enfermedad veno oclusiva. DISCUSIÓN: La OIM es una enfermedad inusual, grave y de inicio temprano, siendo necesario un elevado índice de sospecha ante hepatoesplenomegalia y falla medular. El diagnóstico temprano y el trasplante de precursores hematopoyéticos son las únicas intervenciones potencialmente curativas de esta entidad letal.

INTRODUCCIÓN: 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 impairment, 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 hepatosplenomegaly and bone marrow failure. Early diagnosis and hematopoietic stem cells transplanta tion are the only potentially therapeutic interventions of this lethal entity.

Lessons Learned from Long-Term Management of Hip Fracture in Patients with Osteopetrosis: A Report of Nine Hips in Five Patients

BACKGROUND: Treating patients with osteopetrosis is very challenging even in very skilled surgeons with many experiences. We present an account of 5 patients treated for hip fracture related problems occurring throughout their life due to this disease. Difficulties encountered during their treatment prompted us to present some general management principles. METHODS: From January 2003 to December 2016, 5 patients with osteopetrosis (9 hips; 3 men, 2 women), who underwent operative or conservative treatment were retrospectively reviewed. We evaluated their clinical features and rate of union, malunion and post-operative infection. RESULTS: Four of 5 patients (80%) suffered bilateral fracture, and 8 of 9 fractures (89%) are transverse and occurred at subtrochanteric area resulted from minor trauma. Among 9 hips, surgery was performed in seven hips. Nonunion were found in 3 hips (33%), malunion in 1 hip (11%) and oteomyelitis was developed in 2 hips (22%) at a median of 8.1 years. CONCLUSIONS: Clinical features of hip fracture in osteopetrosis are very similar to atypical subtrochanteric femoral fractures. Patients should be informed of the possibilities of several anticipated complications including the risk of nonunion and infection after surgery.

Imaging of Thoracic Wall Abnormalities

Identification of certain abnormalities of the chest wall can be extremely helpful in correctly diagnosing a number of syndromic conditions and systemic diseases. Additionally, chest wall abnormalities may sometimes constitute diagnoses by themselves. In the present pictorial essay, we review a number of such conditions and provide illustrative cases that were retrospectively identified from our clinical imaging database. These include pentalogy of Cantrell, Klippel-Feil syndrome, cleidocranial dysplasia, Poland syndrome, osteopetrosis, neurofibromatosis type 1, Marfan syndrome, Gardner syndrome, systemic sclerosis, relapsing polychondritis, polymyositis/dermatomyositis, ankylosing spondylitis, hyperparathyroidism, rickets, sickle cell anemia, thalassemia, tuberculosis, septic arthritis of the sternoclavicular joint, elastofibroma dorsi, and sternal dehiscence.

Experiencia de una década en niños sometidos a esplenectomía en el Hospital Nacional de Niños / Experience on children's splenectomy: a ten year single center retrospective study

Resumen Objetivo: describir las características clínicas y la evolución de los pacientes sometidos a esplenectomía en el Hospital Nacional de Niños, de enero de 1996 a diciembre del 2006. Métodos: este es un estudio descriptivo retrospectivo que analiza un periodo de 10 años, de pacientes sometidos a esplenectomías en el Hospital Nacional se Niños. Se realizó una revisión de 107 expedientes con el diagnóstico en cuestión. De estos expedientes se obtuvieron: datos clínicos, epidemiológicos, indicaciones para el procedimiento y su respectiva evolución, complicaciones y mortalidad asociada. Se analiza además el seguimiento de las recomendaciones con respecto a profilaxis antibiótica y vacunación. Resultados: se analizó una muestra total de 107 casos. Entre los resultados se encontró que la edad promedio de intervención fue de 6,4 años. Los diagnósticos más comunes fueron hemoglobinopatías (59,8 %), púrpura trombocitopénica idiopática (16,8 %) y osteopetrosis maligna (8,4 %). Entre las indicaciones para esplenectomías predominaron el tratamiento de enfermedad de base (39,9%), hiperesplenismo (26,2 %) y ausencia de respuesta al tratamiento médico (22,4 %). El procedimiento quirúrgico más común fue la laparotomía en el 87,9 % de los casos. La complicación quirúrgica inmediata más frecuente fue la hemorragia persistente (3,7 %), mientras que la complicación quirúrgica tardía más común fue la sepsis (16,8 %). La respuesta terapéutica en la mayoría de los pacientes fue completa (66,7 %). Hubo 5 pacientes fallecidos, de los cuales en dos se relacionó su mortalidad con sepsis. La edad promedio al momento de fallecimiento fue de 6,7 años. Conclusiones: la esplenectomía es una alternativa para el tratamiento de las enfermedades médicas, tras la cual se evidenció una respuesta satisfactoria en la mayoría de los casos del estudio.

Abstract Aim: to describe clinical characteristics and evolution of patients who underwent splenectomy in Costa Rica's National Children's Hospital during January 1996 through December 2006. Methods: This is a chart review study in a 10 year period including children who underwent splenectomy. A hundred and seven charts of children with ages between 0 and 18 years old were reviewed to obtain their clinical presentation, characteristics, indications for splenectomy, follow up, complications and mortality. Also the antibiotic prophylaxis and immunization schedule was analyzed based on international recommendations. Results: A total of 107 patients were included. Results showed that the mean age at which splenectomy was performed was 6.4 years. Most of the patients had their splenectomy due to hemoglobinophaties (59.8%), followed by immune thrombocytopenic purpura (16.8%) and malignant osteopetrosis (8.4%). The most common indications for splenectomy were treatment of the disease (39.9%), hyperesplenism (26.2%) and lack of responde to medical treatment (22.4%). Laparotomy was the most performed surgery (87.9%). Mainly sepsis and hemorrhage were found as complications due to procedure. Overall, complete response to surgical treatment was observed (66.7%). Five patients died during follow up. Conclusions: Splenectomy is an alternative for treating medical disease with predominantly good outcomes observed in our study.

Autosomal recessive osteopetrosis type I: description of pathogenic variant of TCIRG1 gene / Osteopetrosis infantil maligna: descripción de una nueva mutación patogénica de TCIRG1

Abstract 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_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.

Resumen Introducción: La osteopetrosis infantil maligna es una condición rara cuyo origen es la deficiente reabsorción ósea por parte de los osteoclastos. Su diagnóstico requiere un alto índice de sospecha. El tratamiento de elección es el trasplante alogénico de células hematopoyéticas. Los mejores desenlaces ocurren si el procedimiento se lleva a cabo antes de que ocurra daño a los nervios craneales. Caso clínico: Paciente masculino de 8 meses de edad fue referido a la consulta de hematología por citopenias, hepatomegalia y falla para crecer. Se diagnosticó osteopetrosis infantil maligna basándose en los hallazgos de la exploración física, la alteración del metabolismo del calcio y el fósforo y la hiperdensidad del hueso. Se obtuvo ADN del paciente y ambos padres; se demostró un heterocigosidad compuesta del gen TCIRG1 con una deleción (c.1809_1818del) no descrita previamente. Conclusiones: Una nueva mutación patogénica de TCIRG1 se identificó en un paciente mexicano con osteopetrosis. Se ofreció trasplante de células progenitoras hematopoyéticas como el mejor tratamiento disponible, pero fue rechazado por los padres. Se necesita un reconocimiento temprano y la implementación del acceso generalizado a este procedimiento.

Genetic Analysis of CLCN7 in an Old Female Patient with Type II Autosomal Dominant Osteopetrosis

BACKGROUND: Type II autosomal dominant osteopetrosis (ADO II) is a rare genetically heterogeneous disorder characterized by osteosclerosis and increased bone mass, predominantly involving spine, pelvis, and skull. It is closely related to functional defect of osteoclasts caused by chloride voltage-gated channel 7 (CLCN7) gene mutations. In this study, we aimed to identify the pathogenic mutation in a Korean patient with ADO II using whole exome sequencing. METHODS: We evaluated the clinical, biochemical, and radiographic analysis of a 68-year-old woman with ADO II. We also performed whole exome sequencing to identify pathogenic mutation of a rare genetic disorder of the skeleton. Moreover, a polymorphism phenotyping program, Polymorphism Phenotyping v2 (PolyPhen-2), was used to assess the effect of the identified mutation on protein function. RESULTS: Whole exome sequencing using peripheral leukocytes revealed a heterozygous c.296A>G missense mutation in the CLCN7 gene. The mutation was also confirmed using Sanger sequencing. The mutation c.296A>G was regarded to have a pathogenic effect by PolyPhen-2 software. CONCLUSION: We detect a heterozygous mutation in CLCN7 gene of a patient with ADO II, which is the first report in Korea. Our present findings suggest that symptoms and signs of ADO II patient having a c.296A>G mutation in CLCN7 may appear at a very late age. The present study would also enrich the database of CLCN7 mutations and improve our understanding of ADO II.

Dental Management in a Patient with Infantile Osteopetrosis : A Case Report with a 7-Year follow-up / 대한소아치과학회지

Osteopetrosis is characterized by impaired osteoclast function and increased bone density. Infantile osteopetrosis is a severe form of the disease and has characteristics such as diffusely sclerotic skeleton, pancytopenia, cranial nerve entrapment, infection susceptibility, and abnormal craniofacial appearance. Patients with infantile osteopetrosis often experience developmental delay, and may have a short life span.A 14-month-old girl with osteopetrosis presented to the department of pediatric dentistry. Incipient caries on deciduous incisors were observed. The patient revisited 4 years of age. Besides medical problems, oral complications such as growth retardation, narrow upper arch, crowding, dental caries, and abnormal tooth development were observed. After consultation with her pediatrician, dental treatments were performed on the deciduous molars under sedation after a prophylactic antibiotic injection. At a periodic follow-up, multiple deciduous teeth were treated and extracted, and oral-rehabilitation with a removable partial denture was initiated.Patient with osteopetrosis are highly susceptible to infection because of their compromised immune system and problems associated with wound healing that lead to osteomyelitis or sepsis development.Active participation in dental care for sugar intake management and proper oral hygiene are obligatory.

Osteopetrosis con afectación de cuatro nervios craneales / Osteopetrosis with damage of four cranial nerves

Introducción: la osteopetrosis se caracteriza por una insuficiente resorción ósea, como consecuencia de un trastorno de la actividad de los osteoclastos, y provoca aumento de la densidad ósea, es decir, un hueso altamente calcificado, pero muy frágil; hay fracaso del potencial de la médula ósea, desencadenando la hematopoyesis secundaria, con manifestaciones de visceromegalia y pancitopenia. El engrosamiento de los huesos provoca estrechamiento de los forámenes del cráneo, por donde emergen los nervios craneales, se comprimen y provoca manifestaciones clínicas secundariamente. Presentación del caso: paciente femenina que a los 3 años de edad manifestó nistagmus horizontal, paresia de nervio motor ocular externo derecho, pérdida de respuesta al estímulo auditivo bilateral, parálisis facial periférica izquierda y atrofia bilateral del nervio óptico; radiológicamente mostró aumento de la densidad ósea, con importante engrosamiento de la base de cráneo y huesos largos. Conclusiones: el diagnóstico de la osteopetrosis es sencillo y depende principalmente de los estudios radiológicos, pero pasa inadvertido por su baja frecuencia y falta de sospecha clínica. El diagnóstico temprano del compromiso de múltiples nervios craneales, la atención multidisciplinaria y su tratamiento oportuno, contribuye a su mejor evolución(AU)

Introduction: osteopetrosis is characterized by insufficient bone resorption as a consequence of a disorder in the osteoclast activity and brings about increased bone density, that is, a highly calcified bone but very fragile. There is failed potential of the bone marrow, thus unleashing secondary hematopoiesis with visceromegalia and pancitopenia manifestations. The bone thickening provokes narrowing in cranium foramens where the cranial nerves pass, they compressed and cause secondary clinical manifestations. Case report: a female patient aged 3 years showed horizontal nistagmus, paresia in the right external ocular motor nerve, loss of response to bilateral hearing stimulus, peripheral facial palsy and bilateral atrophy of the optical nerve. The radiological tests showed increased bone density with significant thickening of the skull base and long bones. Conclusions: the diagnosis of osteopetrosis is simple and mainly depends on the radiological studies, but it is unnoticed because of its low frequency and the inexistent clinical suspicion. The early diagnosis of the damage of several cranial nerves, the multidisciplinary care and timely treatment may contribute to better evolution(AU)

Osteoporosis, hallazgos en radiología convencional. Reporte de un caso / Osteoporosis, findings in conventional radiology. Report of a case

Introducción El presente artículo hace una revisión sobre los hallazgos radiológicos mediante radiografía simple, así como también los hallazgos clínicos en el diagnóstico de la osteopetrosis una enfermedad poco común que afecta el desarrollo normal óseo, se trata de un caso clínico reportado en el Hospital Pediátrico Baca Ortiz de la Ciudad de Quito. Reporte de Caso: Nos apoyamos en la presentación de un caso clínico de una paciente que acude por consulta externa con cuadro de fatiga y decaimiento de 2 años de evolución, se realizan exámenes complementarios demostrando presencia de anemia así como los hallazgos característicos de osteopetrosis por imagen posteriormente detallados. Conclusiones: La osteopetrosis es una enfermedad poco común, compleja y por lo menos con cuatro subtipos que difieren en la forma de herencia o de las manifestaciones adicionales asociadas, sin embargo todas se caracterizan por presentarse clínicamente con fatiga debido a anemia crónica, puede presentar o no hepatoesplenomegalia, conjuntamente asociadas siempre a osteoesclerosis difusa con ensanchamiento óseo, fracturas patológicas.

Introduction This article reviews the radiological findings by simple radiography as well as the clinical findings in the diagnosis of osteopetrosis, a rare disease that affects normal bone development. This is a case report reported in the Hospital Pediátrico Baca Ortiz at Quito City. Case Report: We rely on the presentation of a clinical case of a patient who goes by external consultation with fatigue and decay of 2 years of evolution, complementary tests are performed demonstrating the presence of anemia as well as the characteristic findings of osteopetrosis by image later detailed. Conclusions: Osteopetrosis is an uncommon, complex disease and with at least four subtypes that differ in the form of inheritance or associated additional manifestations, however all are characterized by presenting clinically with fatigue due to chronic anemia, may present or not hepatosplenomegaly, Always associated with diffuse osteosclerosis with bone spreading, pathological fractures.

Analysis of TCIRG1 gene mutation in a Chinese family affected with infantile malignant osteopetrosis / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect potential mutation of the TCIRG1 gene in a boy with infantile malignant osteopetrosis.</p><p><b>METHODS</b>Target sequence capture and next-generation sequencing were applied for the proband and his parents to identify the causative mutation, and Sanger sequencing was used to verify the suspected mutation.</p><p><b>RESULTS</b>The proband manifested at 4 months of age with symptoms including anemia, thrombocytopenia, hepatosplenomegaly, and cephalus quadratus. X-ray revealed generalized increased bone density. A novel compound heterozygous mutation, c.796G to T (p.E266X) and c.1372G to A (p.G458S), were identified in the boy. His father and grandmother also carried the c.796G to T (p.E266X) mutation, and his mother carried the c.1372G to A (p.G458S) mutation. Neither mutation was found in the PubMed and ClinVar databases.</p><p><b>CONCLUSION</b>The novel compound heterozygous mutation c.796G to T (p.E266X) and c.1372G to A (p.G458S) probably underlies the disease in the proband. Above results may enrich the mutation spectrum of the TCIRG1 gene and provide new evidence for the molecular basis of infantile malignant osteopetrosis.</p>

Osteomielite mandibular refratária em paciente com osteopetrose: relato de caso / Refractory mandibular osteomyelitis in a young patient with osteopetrosis: Case report

Osteopetrose é uma rara desordem óssea metabólica, de caráter hereditário, com diagnóstico firmado por vários achados clínicos e principalmente radiográficos. Caracteriza-se por uma disfunção osteoclástica, que gera a um aumento da densidade óssea esqueletal. Em pacientes acometidos por essa condição, um fator determinante é a reduzida vascularização óssea com quadro de anemia e neutropenia frequentemente presente, tornando-os muito susceptíveis a infecções. Três variantes da doença são reconhecidas na literatura: autossômica recessiva maligna infantil, autossômica recessiva branda e a forma autossômica dominante benigna do adulto, sendo a primeira a mais grave. Dessa forma, torna-se imperativo o cuidadoso manejo deste paciente pelo cirurgião-dentista no que se refere à extrações dentárias, haja vista que, em 10% dos casos, os pacientes podem desenvolver osteomielite nos maxilares após esse procedimento. Este trabalho ilustra o caso de um paciente de 15 anos de idade, com osteopetrose recessiva branda que, após a extração de um dente molar decíduo, desenvolveu infecção mandibular severa, sendo realizado tratamento cirúrgico-medicamentoso. Após alguns anos, o paciente retornou com quadro infeccioso refratário, demonstrando, ao exame clínico, fístulas submandibulares com drenagem espontânea e exteriorização de placa de reconstrução na região parassínfise da cirurgia anterior. O tratamento antibiótico não mostrou grandes melhorias, e assim, o paciente foi submetido a novo procedimento cirurgico por meio de mandibulectomia, com resolução final do processo de infecção... (AU)

Osteopetrosis is a rare hereditary metabolic bone disorder that has its diagnosis mainly based on several clinical and radiographic findings. It is characterized by an osteoclast dysfunction which leads to an increase in skeletal bone density. In patients suffering from this condition, a key factor is the reduced bone vascularization with anemia and neutropenia often present, making them very susceptible to infections. Three variants of the disease are recognized in the literature: severe infantile malignant autosomal recessive, intermediate mild autosomal recessive, and benign autosomal dominant, with the first being the most severe. Therefore, it becomes imperative a careful management of this patient by the dentist in regards to dental extractions, given that in 10% of cases, patients may develop osteomyelitis of the jaws after these procedures. This paper illustrates a case of a patient of 15 years old, with mild recessive osteopetrosis that after extraction of a deciduous molar tooth, developed severe mandible infection, surgery and medicamentous treatment were performed. After a few years, the patient returned with refractory infectious, demonstrating on clinical examination, submandibular fistula with spontaneous drainage and reconstruction plate externalization in parasymphysis region of previous surgery. Antibiotic treatment did not show major improvements, so the patient underwent new surgical procedure through mandibulectomy, with final resolution of the infection process... (AU)

A Case of Cytomegalovirus Infection in a Neonate with Osteopetrosis

Infantile osteopetrosis is a rare congenital disorder caused by abnormal bone resorption. Patients with osteopetrosis can have severe anemia, thrombocytopenia, hepatosplenomegaly, rickets, visual impairment, and deafness. Cytomegalovirus also can cause a congenital infection with anemia, thrombocytopenia, hepatosplenomegaly, and calcifications in the brain. We report a 38-day-old infant with severe hepatosplenomegaly, thrombocytopenia, hypocalcemia, and growth failure. Real time polymerase chain reaction detected cytomegalovirus in the plasma. Skeletal radiography revealed generalized bone sclerosis. He was diagnosed with osteopetrosis along with cytomegalovirus infection. Only the test for mutation of the CLCN7 gene, representing the most common and heterogeneous form of osteopetrosis, was available, and the result was negative. With supportive care and antiviral treatment, severe thrombocytopenia due to the cytomegalovirus infection almost normalized despite the possible immunosuppression caused by osteopetrosis. We present the first report of an infant who suffered from osteopetrosis and CMV infection which was successfully treated by long term antiviral agent therapy.

Pro-inflammatory Cytokines Modulating Osteoclast Differentiation and Function

In general, bone homeostasis is maintained through the balance between bone formation and resorption. Disruption in this balance results in bone-related diseases such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Often, enhanced osteoclastogenesis is followed by accelerated bone resorption that is induced by pro-inflammatory cytokines in osteoporosis or rheumatoid arthritis, and leads to bone destruction. In this review study, factors involved in osteoclast differentiation and function are discussed, and how the prevention of such factors is effective in ameliorating bone loss in osteoporosis or rheumatoid arthritis.

Preimplantation genetic diagnosis of infantile malignant osteopetrosis in a Chinese family / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the application of preimplantation genetic diagnosis (PGD) for infantile malignant osteopetrosis (IMO).</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSION</b>The study demonstrated the advantage of PGD over prenatal diagnosis when natural pregnancies have repeatedly produced IMO children/fetuses.</p>