Osteoclast-poor osteopetrosis.

Osteopetrosis (OPT) is a rare inherited bone disease characterized by a bone resorption defect, due to osteoclast malfunction (in osteoclast-rich, oc-rich, OPT forms) or absence (in oc-poor OPT forms). This causes severe clinical abnormalities, including increased bone density, lack of bone marrow cavity, stunted growth, macrocephaly, progressive deafness, blindness, hepatosplenomegaly, and severe anemia. The oc-poor subtype of OPT is ultra-rare in humans. It is caused by mutations in either the tumor necrosis factor ligand superfamily member 11 (TNFSF11) gene, encoding RANKL (Receptor Activator of Nuclear factor-kappa B [NF-κB] Ligand) which is expressed on cells of mesenchymal origin and lymphocytes, or the TNFRSF member 11A (TNFRSF11A) gene, encoding the RANKL functional receptor RANK which is expressed on cells of myeloid lineage including osteoclasts. Clinical presentation is usually severe with onset in early infancy or in fetal life, although as more patients are reported, expressivity is variable. Phenotypic variability of RANK-deficient OPT sometimes includes hypogammaglobulinemia or radiological features of dysosteosclerosis. Disease progression is somewhat slower in RANKL-deficient OPT than in other 'malignant' subtypes of OPT. While both RANKL and RANK are essential for normal bone turnover, hematopoietic stem cell transplantation (HSCT) is the treatment of choice only for patients with the RANK-deficient form of oc-poor OPT. So far, there is no cure for RANKL-deficient OPT.

Hallazgos radiológicos en la osteopetrosis infantil autosómica recesiva / Radiological findings in autosomal recessive infantile osteopetrosis

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Osteopetrotic induced pluripotent stem cells derived from patients with different disease-associated mutations by non-integrating reprogramming methods.

BACKGROUND: Autosomal recessive osteopetrosis is a genetically and phenotypically heterogeneous disease, caused by defects in osteoclast formation and function. The only available treatment is allogeneic stem cell transplantation that has still high morbidity and mortality. The goal of the present study was to generate iPSCs from bone marrow-derived MSCs of osteopetrosis patients with three most common mutations by using two different integration-free gene transfer methods and compare their efficiencies. The secondary objective was to select the most appropriate integration-free production method for our institutional iPSC bank using this rare disease as a prototype. METHODS: Two different integration-free gene transfer methods (episomal and Sendai viral vectors) were tested and compared on the same set of patient samples exhibiting three different mutations associated with osteopetrosis. Generated iPSCs were characterized by standard assays, including immunophenotyping, immunocytochemistry, RT-PCR, embryoid body, and teratoma assays. Karyotype analyses were performed to evaluate genetic stability. RESULTS: iPSC lines exhibiting typical ESC-like colony morphology were shown to express pluripotency markers by immunofluorescence staining. Over 90% of the cells were found positive for SSEA-4 and OCT3/4 and negative/weak positive for CD29 by flow cytometry. Immunohistochemical staining of teratoma and spontaneously differentiated embryoid body sections confirmed their trilineage differentiation potential. All iPSC lines expressed pluripotency-related genes. Karyotype analyses were found normal. Direct sequencing of PCR-amplified DNA showed that disease-related mutations were retained in the patient-specific iPSCs. CONCLUSION: Generation of iPSC using SeV and episomal DNA vectors have several advantages over other methods like the ease of production, reliability, high efficiency, and safety, which is required for translational research. Furthermore, owing to the pluripotency and self-renewal capacity, patient-specific iPSCs seem to be ideal cell source for the modeling of a rare genetic bone disease like osteopetrosis to identify osteoclast defects, leading to clinical heterogeneity in osteopetrosis patients, especially among those with different mutations in the same gene.

Comparison of Optic Canal Diameter in Children With Malignant Infantile Osteopetrosis and Normal Children and the Effects of Hematopoietic Stem Cell Transplantation on the Optic Canal Diameter.

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.].

Autosomal recessive osteopetrosis type I: description of pathogenic variant of TCIRG1 gene.

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.

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.

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.

Novel mutations of the SERPINF1 and FKBP10 genes in Chinese families with autosomal recessive osteogenesis imperfecta.

The aim of the present study was to characterize the clinical manifestations and identify the mutations of Serpin family F member 1 (SERPINF1) and FK506 binding protein 10 (FKBP10) genes in Chinese patients with osteogenesis imperfecta (OI). Using whole­exome sequencing in the first and third probands, a novel mutation was identified in SERPINF1 and a novel compound heterozygous mutation was revealed in FKBP10. Using Sanger sequencing, an additional novel mutation in SERPINF1 was identified in a proband of family 2. In family 1, the proband presented with a novel homozygous missense mutation of the SERPINF1 gene, c.1067T>A (V356E). In family 2, the proband had a novel homozygous deletion mutation of the SERPINF1 gene, c.283+473_643+104del (p.Ala96_Gly215del). Serum pigment­epithelium­derived factor concentration was not detected in probands with OI type VI. For both families, the proband's father was demonstrated to have a heterozygous mutation of SERPINF1, whereas no mutations was detected in the probands' mothers. An assessment of allelic copy numbers revealed a deletion of SERPINF1 in the mother of family 1. The results of the present study demonstrate that patients may have mild symptoms of OI with a large fragment deletion in the SERPINF1 gene. Thus, the phenotype of Chinese patients with type VI OI is milder than that of Caucasian and Korean patients. In family 3, the proband displayed a novel compound heterozygous mutation in FKBP10, c.813_814delGA (p.Glu271AspfsX101) and c.831delC (p.Gly278AlafsX20), and did not have Bruck syndrome. Codon 831 of the FKBP10 gene may represent a mutation hotspot for human OI. These results extend both the phenotypic and the genotypic contents of OI patients with SERPINF1 or FKBP10 mutations.

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

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

A novel mutation and a known mutation in the CLCN7 gene associated with relatively stable infantile malignant osteopetrosis in a Chinese patient.

Osteopetrosis is a group of heterogeneous disorders caused by the dysfunction of osteoclasts. The CLCN7 and TCIRG1 genes are the major obligate genes responsible for infantile malignant osteopetrosis (IMO). IMO patients usually die in infancy or before three years of age. In this study, we report a patient who was diagnosed with IMO at seven months of age. The patient presented with classical radiological features of IMO. She also exhibited erythropenia, thrombocytopenia, hepatosplenomegaly and neurodegeneration. The parents discontinued any medical treatment for the patient. Surprisingly, the patient's condition did not deteriorate when she was admitted a second time at the age of four years and nine months, despite not receiving any medical support during the untreated period. We sequenced the CLCN7 and TCIRG1 genes of the patient and her parents and identified a novel c.285+1G>A (IVS3+1G>A) mutation and the known c.896C>T (p.Ala299Val) mutation. The novel c.285+1G>A mutation occurred on the splice donor of the third intron of CLCN7. This mutation was predicted to interfere with normal splicing between exons 3 and 4, thereby truncating 711 amino acids from the C terminus and resulting in the loss of all of the functional domains of the encoded protein. The c.896C>T (p.Ala299Val) mutation was a previously known pathogenic mutation. We did not find any pathogenic mutations in the TCIRG1 gene. CLCN7-related osteopetrosis is known to have a high phenotype heterogeneity. Our study demonstrates a wide heterogeneity in the progression of the phenotypes and expanded the mutational spectrum for the CLCN7 gene.

Hematopoietic stem cell transplantation for infantile osteopetrosis.

We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty-four percent of transplants used grafts from HLA-matched siblings, 13% from HLA-mismatched relatives, 12% from HLA-matched, and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLA-mismatched related, HLA-matched unrelated, or mismatched unrelated donor transplantation. The 5- and 10-year probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (P = .01 and P = .002, respectively). Graft failure was the most common cause of death, accounting for 50% of deaths after HLA-matched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA-matched sibling and 61% after alternative donor transplantation (P = .49). The median age of surviving patients is 7 years. Of evaluable surviving patients, 70% are visually impaired; 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors >5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%. Though allogeneic transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed.

Radiologic resolution of malignant infantile osteopetrosis skeletal changes following hematopoietic stem cell transplantation.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is the only known curative treatment of malignant infantile osteopetrosis (MIOP). In this study, short-term serial bone surveys were used to assess radiologic evolution of skeletal changes after HSCT in MIOP. MATERIALS AND METHODS: Baseline whole-body bone survey was performed in all patients. HSCT was successful in 14 patients (11 with full chimerism, three with mixed chimerism) in whom follow-up bone surveys were carried out at 6 and 12 months after HSCT. RESULTS: Normal corticomedullary differentiation was evident in five (P = 0.06) and 12 (P < 0.005) patients at 6 and 12 months, respectively. Abnormal endobone appearance in long bones, present in 11 participants at baseline exam, disappeared in eight (P = 0.008) and all (P = 0.001) patients at 6 and 12 months, respectively. In 6-month follow-up, rachitic changes significantly disappeared (P < 0.01) in long bones; however, they were evident in ribs of 12 patients (P = 0.50). No patient had rickets in ribs or long bones after 12 months. CONCLUSION: We observed considerable resolution of MIOP skeletal changes after HSCT in all patients with either full or mixed chimerism. Rachitic changes in long bones, attenuated corticomedullary differentiation, and endobone appearance were the first to resolve. We propose using single long bone plain x-ray to demonstrate short-term skeletal response to HSCT.

Osteopetrosis autosómica dominante: a propósito de 3 casos y una mutación / Autosomal dominant osteopetrosis: A presentation of 3 cases and a new gene mutation

La osteopetrosis (OP) es una rara enfermedad ósea congénita producida por una alteración funcional en los osteoclastos con incapacidad para la reabsorción ósea normal, produciéndose un aumento de la densidad mineral ósea y esclerosis ósea. Puede clasificarse en autosómica recesiva (OPTB) o autosómica dominante (OPTA1-2). Existe una gran variabilidad clínica de la enfermedad, desde asintomática a letal en los primeros meses de vida, con expresividad variable en los miembros de una familia. Su diagnóstico es principalmente clínico con confirmación genética, y el tratamiento es sintomático. Se presentan una serie de casos de OP, con el hallazgo de una nueva mutación en el gen LRP5 causante de OPTA1 en uno de ellos

Osteopetrosis (OP) is a congenital bone disease which is caused by a functional disorder in osteoclasts with inability for normal bone resorption, leading to increased bone mineral density and bone sclerosis. It can be classified into different groups according to their clinical and their genetic characteristics: autosomal recessive with several subtypes (OPTB) or autosomal dominant type 1 or 2 (OPTA1-2). There is a wide clinical variability of the disease, from asymptomatic to lethal in the first months of life, with variable expressivity in the family members. Diagnosis is mainly clinical with genetic confirmation of the OP, and treatment is symptomatic. Three cases of OP are presented, with the discovery of a new gene mutation in LRP5 which caused OPTA1 in one of them

Structure of human SNX10 reveals insights into its role in human autosomal recessive osteopetrosis.

Sorting nexin 10 (SNX10), the unique member of the SNX family having vacuolation activity in cells, was shown to be involved in the development of autosomal recessive osteopetrosis (ARO) in recent genetic studies. However, the molecular mechanism of the disease-related mutations affecting the biological function of SNX10 is unclear. Here, we report the crystal structure of human SNX10 to 2.6 Å resolution. The structure reveals that SNX10 contains the extended phox-homology domain we previously proposed. Our study provides the structural details of those disease-related mutations. Combined with the vacuolation study of those mutations, we found that Tyr32 and Arg51 are important for the protein stability and both play a critical role in vacuolation activity, while Arg16Leu may affect the function of SNX10 in osteoclast through protein-protein interactions.

RANK receptor oligomerisation in the regulation of NFκB signalling.

The interaction of receptor activator of NFκB (RANK), a member of the tumour necrosis factor receptor superfamily, with RANK ligand is crucial for the formation, function and survival of osteoclasts. The role of the cytoplasmic oligomerisation domain (pre-ligand assembly domain; PLAD or 'IVVY' motif) in the ligand-dependent activation of downstream NFκB signalling has not been studied previously. The discovery of truncating mutations of TNFRSF11A (W434X and G280X that lack the PLAD) as the cause of rare cases of osteoclast-poor osteopetrosis offered the opportunity for functional study of this region. Recapitulating the W434X mutation by transcription activator-like effector nuclease (TALEN)-mediated targeted disruption of Tnfrsf11a within the region homologous to W434X in the mouse macrophage-like cell line RAW264.7 impaired formation of osteoclast-like cells. Using overexpression studies, we demonstrated that, in contrast to WT-RANK, the absence of the PLAD in G280X-RANK and W434X-RANK prevented ligand-independent but not ligand-dependent oligomerisation. Cells expressing W434X-RANK, in which only two of the three TRAF6-binding motifs are present, continued to exhibit ligand-dependent NFκB signalling. Hence, the absence of the PLAD did not prevent ligand-induced trimerisation and subsequent NFκB activation of RANK, demonstrating that therapeutic targeting of the PLAD in the prevention of osteoporosis may not be as effective as proposed previously.

Osteopetrosis: genetics, treatment and new insights into osteoclast function.

Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal dominant forms exist, but this Review focuses on autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis. The genetic basis of this disease is now largely uncovered: mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function), whereas mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO. In osteoclast-rich ARO, impaired endosomal and lysosomal vesicle trafficking results in defective osteoclast ruffled-border formation and, hence, the inability to resorb bone and mineralized cartilage. ARO presents soon after birth and can be fatal if left untreated. However, the disease is heterogeneous in clinical presentation and often misdiagnosed. This article describes the genetics of ARO and discusses the diagnostic role of next-generation sequencing methods. The management of affected patients, including guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined. Finally, novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are also discussed.

Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1.

Autosomal recessive osteopetrosis (ARO, MIM 259700) is a genetically heterogeneous rare skeletal disorder characterized by failure of osteoclast resorption leading to pathologically increased bone density, bone marrow failure, and fractures. In the neuronopathic form neurological complications are especially severe and progressive. An early identification of the underlying genetic defect is imperative for assessment of prognosis and treatment by hematopoietic stem cell transplantation. Here we describe for the first time homozygous microdeletions of different sizes affecting the OSTM1 gene in two unrelated consanguineous families with children suffering from neuronopathic infantile malignant osteopetrosis. Patients showed an exceptionally severe phenotype with variable CNS malformations, seizures, blindness, and deafness. Multi-organ failure due to sepsis led to early death between six weeks and five months of age in spite of intensive care treatment. Analysis of the breakpoints revealed different mechanisms underlying both rearrangements. Microdeletions seem to represent a considerable portion of OSTM1 mutations and should therefore be included in a sufficient diagnostic screening.

A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation.

Osteopetrosis is a rare genetic disorder characterized by increased bone mineral density (BMD) due to osteoclast failure. T-cell immune regulator 1 (TCIRG1) plays crucial roles on osteoclast function, and its mutation causes autosomal recessive osteopetorosis. However, mutations in TCIRG1 have never been identified in autosomal dominant osteopetrosis (ADO). A 3-year-old boy was first presented to the clinic because of spontaneous radius and femur fractures. He has optic atrophy. The areal BMD at the lumbar spine was 1274 g/cm2 (233% of normal). Laboratory tests revealed no remarkable abnormal findings, including anemia, except for extremely elevated serum tartrate-resistant acid phosphatase-5b (14,600 mU/dL). Radiographically, the skull base, pelvis, and vertebrae showed a focal sclerosis. Genetic analysis revealed a novel de novo heterozygous missense mutation (His242Arg). Taken together with the mutation, his mild clinical features were diagnosed as ADO. This case implies that TCIRG1 could become a genetic candidate for ADO in addition to malignant forms such as ARO.

Successful staged hip replacement in septic hip osteoarthritis in osteopetrosis: a case report.

BACKGROUND: Osteopetrosis is a rare, inherited, bone disorder, characterized by osteosclerosis, obliteration of the medullary cavity and calcified cartilage. The autosomal dominant form is compatible with a normal life span, although fractures often result from minimal trauma, due to the pathologic nature of bone. Osteomyelitis is common in patients with osteopetrosis because of a reduced resistance to infection, attributed to the lack of marrow vascularity and impairment of white cell function. Only one case of osteomyelitis of the proximal third of the femur has been previously reported, treated with several repeated debridements and finally with femoral head resection. Here we present for the first time a case of a staged implant of a cementless total hip prosthesis for the treatment of a septic hip in femoral neck nonunion in osteopetrosis. CASE PRESENTATION: A 36-years-old woman, affected by autosomal dominant osteopetrosis was referred to our department because of a septic hip arthritis associated with femoral neck septic non-union, with draining fistulas. The infection occurred early after a plate osteosynthesis for a closed perthrocanteric fracture of the femur and persisted in spite of osteosynthesis removal, surgical debridement and external fixation. In our hospital the patient underwent accurate debridement, femoral head and greater trochanter resection, preparation of the diaphyseal intramedullary canal and implant of an antibiotic-loaded cement spacer. The spacer was exchanged after one month, due to infection recurrence and four months later, a cementless total hip arthroplasty was implanted, with no clinical and laboratory signs of infection recurrence at two years follow-up. CONCLUSIONS: In case of hip septic arthritis and proximal femur septic non-union, femoral head resection may not be the only option available and staged total hip arthroplasty can be considered.