Osteopetrorickets: two contradictory patterns-one unifying diagnosis.

A 5-month-old infant with bone findings on x-ray presented an apparent contradiction including findings of both diffusely dense bones and rickets in the context of a history and laboratory investigation that suggested leukemia. Next generation gene panel sequencing revealed a TCIRG1 mutation which is consistent with autosomal recessive osteopetrosis. The paradoxical x-ray findings underscore a recently elucidated mechanism for the pathogenesis of a TCIRG mutation. This case highlights the importance of recognizing this radiographic, seeming contradictory, association in the context of a confusing clinical presentation. Failure to recognize this pattern promptly may lead to a delay in diagnosis, thus potentially permanent organ failure.

Maxillary osteomyelitis in a young female with osteopetrosis: unveiling an uncommon connection.

Osteopetrosis encompasses a spectrum of conditions marked by heightened bone density due to faulty osteoclast-mediated bone resorption, leading to an accumulation of immature bone and thickened cortical structures. This condition gives rise to bone fragility, blood cell irregularities, nerve entrapment and growth challenges, all stemming from disrupted bone remodelling. Craniofacial distinctiveness, encompassing anomalies in the skull and jaw, is a frequent occurrence. Osteopetrosis presents a range of clinical signs, including facial and dental anomalies. The diagnostic process involves thorough clinical and radiological assessments, often obviating the need for genetic testing. Interestingly, few prior reports have delved into the specifics of craniofacial and dental issues in osteopetrosis. The presented case showcases rare occurrence of maxillary osteomyelitis. The diagnosis was established through a combination of history, clinical, radiographic and laboratory findings. The patient declined surgical intervention, leading to the implementation of conservative management involving regular irrigation alongside systemic antibiotic therapy.

Osteopetrosis with Arnold Chiari malformation type I.

Osteopetrosis is a rare genetic disorder resulting in increased bone density and decreased bone remodelling. Bone expansion results in the crowding of neural foramina causing cranial nerve compression. Here, we describe a female infant in her mid infancy presented with no eye contact since birth, and abdominal distension for 2 months. On CT evaluation, sclerotic bones with bilateral optic canal narrowing were present. A crowded posterior fossa with Arnold Chiari type I malformation was seen on MRI evaluation, suggesting a rare association of osteopetrosis with Arnold Chiari's malformation.

Total hip arthroplasty for the treatment of a hip disorder complicated by autosomal dominant osteopetrosis: a case report.

Autosomal dominant osteopetrosis (ADOP) is an extremely rare congenital bone disease. We report a case of a hip disorder in combination with ADOP, which was treated by total hip arthroplasty, resulting in a good recovery and a significant improvement in the patient's ability to perform daily activities.

Severe hypophosphataemia can be an early sign of osteopetrorickets: a case report.

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

Autosomal dominant osteopetrosis.

Autosomal dominant osteopetrosis (ADO) is the most common form of osteopetrosis. ADO is characterized by generalized osteosclerosis along with characteristic radiographic features such as a "bone-in-bone" appearance of long bones and sclerosis of the superior and inferior vertebral body endplates. Generalized osteosclerosis in ADO typically results from abnormalities in osteoclast function, due most commonly to mutations in the chloride channel 7 (CLCN7) gene. A variety of debilitating complications can occur over time due to bone fragility, impingement of cranial nerves, encroachment of osteopetrotic bone in the marrow space, and poor bone vascularity. There is a wide spectrum of disease phenotype, even within the same family. Currently, there is no disease specific treatment for ADO, so clinical care focuses on monitoring for disease complications and symptomatic treatment. This review describes the history of ADO, the wide disease phenotype, and potential new therapies.

Osteopetrosis: Discovery and early history of "marble bone disease".

Discovery in 1904 of the disorder initially called "marble bones", then in 1926 more appropriately referred to as "osteopetrosis", is attributed to Heinrich E. Albers-Schönberg (1865-1921), the first radiologist. He used the new technique of "Röntgenographie" to report in a young man the radiographic hallmarks of this osteopathy. Clinical descriptions of lethal forms of osteopetrosis had apparently been published earlier by others. In 1926, "osteopetrosis" (stony or petrified bones) replaced "marble bone disease" because the skeletal fragility resembled limestone more than marble. In 1936, despite fewer than 80 reported patients, a fundamental defect in hematopoiesis, secondarily impacting the entire skeleton, was hypothesized. By 1938, the signature histopathological finding of osteopetrosis was recognized -- persistence of unresorbed calcified growth plate cartilage. Also, it was apparent that besides lethal autosomal recessive osteopetrosis a less severe form was "handed down directly from generation to generation". In 1965, quantitative, but also qualitative, defects in osteoclasts became apparent. Here, I review the discovery and early understanding of osteopetrosis. Characterization of this disorder commencing at the beginning of the past century would support the aphorism of Sir William Osler (1849-1919): "Clinics Are Laboratories; Laboratories Of The Highest Order". As featured in this special issue of Bone, the osteopetroses would prove remarkably informative about the formation and function of the cells responsible for skeletal resorption.

[Minimally Invasive Direct Coronary Artery Bypass in a Patient with Osteopetrosis and Symptomatic Ischemic Heart Disease:Report of a Case].

Osteopetrosis is a heterogeneous group of heritable conditions. It varies greatly in severity, and fracture treatment remains a matter of controversy due to altered responses to fixation and the risk of osteomyelitis. Therefore, sternotomy outcomes in this condition are unclear. We report the case of a patient with osteopetrosis and coronary artery disease (CAD). A 78-year-old man with osteopetrosis presented with frequent chest pain. Coronary angiography revealed two-vessel CAD. Percutaneous coronary intervention was contraindication because of coronary aneurysm in the left main trunk. Considering risks in median sternotomy, we performed minimally invasive cardiac surgery through left minithoracotomy for coronary artery bypass grafting( CABG). But we needed to break the left fourth rib to obtain sufficient surgical views. To the best of our knowledge, this is the first case report on CABG for a patient with osteopetrosis and endoscopic surgery without rib retractor is recommended.

Genome sequencing identifies a large non-coding region deletion of SNX10 causing autosomal recessive osteopetrosis.

Autosomal recessive osteopetrosis (ARO) is a rare genetic disorder caused by impaired osteoclast activity. In this study, we describe a 4-year-old boy with increased bone density due to osteopetrosis, autosomal recessive 8. Using genome sequencing, we identified a large deletion in the 5'-untranslated region (UTR) of SNX10 (sorting nexin 10), where the regulatory region of this gene is located. This large deletion resulted in the absence of the SNX10 transcript and led to abnormal osteoclast activity. SNX10 is one of the nine genes known to cause ARO, shown to interact with V-ATPase (vacuolar type H( + )-ATPase), as it plays an important role in bone resorption. Our study highlights the importance of regulatory regions in the 5'-UTR of SNX10 for its expression while also demonstrating the importance of genome sequencing for detecting large deletion of the regulatory region of SNX10.

Osteopetrosis: Gene-based nosology and significance Dysosteosclerosis.

Dysosteosclerosis (DSS) refers to skeletal dysplasias that radiographically feature focal appendicular osteosclerosis with variable platyspondyly. Genetic heterogeneity is increasingly reported for the DSS phenotype and now involves mutations of SLC29A3, TNFRSF11A, TCIRG1, LRRK1, and CSF1R. Typical radiological findings are widened radiolucent long bones with thin cortices yet dense irregular metaphyses, flattened vertebral bodies, dense ribs, and multiple fractures. However, the radiographic features of DSS evolve, and the metaphyseal and/or appendicular osteosclerosis variably fades with increasing patient age, likely due to some residual osteoclast function. Fractures are the principal presentation of DSS, and may even occur in infancy with SLC29A3-associated DSS. Cranial base sclerosis can lead to cranial nerve palsies such as optic atrophy, and may be the initial presentation, though not observed with SLC29A3-associated DSS. Gene-specific extra-skeletal features can be the main complication in some forms of DSS such as CSF1R- associated DSS. Further genetic heterogeneity is likely, especially for X-linked recessive DSS and cases currently with an unknown genetic defect. Distinguishing DSS can be challenging due to variable clinical and radiological features and an evolving phenotype. However, defining the DSS phenotype is important for predicting complications, prognosis, and instituting appropriate health surveillance and treatment.

A successful implant-supported fixed prosthesis in a patient with osteopetrosis: A clinical report.

Osteopetrosis (marble bone disease) is a family of rare genetic disorders characterized by impaired osteoclast function leading to hyperdense, hypovascular, brittle bone. Typical imaging shows increased bone mass and thickened cortical and trabecular bone. Bones are more prone to fracture and osteomyelitis may develop. When considering dental implant placement in a patient with osteopetrosis, the potential for bony fracture and/or osteomyelitis should be considered along with the decreased likelihood of successful osseointegration because of hypovascularity. This clinical report describes an unusual imaging presentation and successful osseointegration of multiple dental implants supporting an implant-supported fixed mandibular prosthesis with long-term survival.

Spectrum of Skeletal Imaging Features in Osteopetrosis: Inheritance Pattern and Radiological Associations.

Osteopetrosis (from the Greek "osteo": bone; "petrosis": stone) is a clinically and genetically heterogeneous group of rare diseases of the skeleton, sharing the same main characteristic of an abnormally increased bone density. Dense bones in radiological studies are considered the hallmark of these diseases, and the reason for the common term used: "Marble bone disease". Interestingly, a radiologist, Dr. Albers-Schonberg, described this disease for the first time in Germany in 1904. Indeed, radiology has a key role in the clinical diagnosis of osteopetrosis and is fundamental in assessing the disease severity and complications, as well as in follow-up controls and the evaluation of the response to treatment. Osteopetrosis includes a broad spectrum of genetic mutations with very different clinical symptoms, age onset, and prognosis (from mild to severe). This diversity translates into different imaging patterns related to specific mutations, and different disease severity. The main recognized types of osteopetrosis are the infantile malignant forms with autosomal recessive transmission (ARO-including the rarer X-linked recessive form); the intermediate autosomal recessive form (IAO); and the autosomal dominant ones ADO, type I, and type II, the latter being called 'Albers-Schonberg' disease. Imaging features may change among those distinct types with different patterns, severities, skeletal segment involvement, and speeds of progression. There are several classical and well-recognized radiological features related to osteopetrosis: increased bone density (all types with different degrees of severity assuming a 'Marble Bone Appearance' especially in the ARO type), different metaphyseal alterations/enlargement including the so-called 'Erlenmeyer flask deformity' (particularly of femoral bones, more frequent in ADO type 2, and less frequent in ARO and IAO), 'bone in bone' appearance (more frequent in ADO type 2, less frequent in ARO and IAO), and 'rugger-jersey spine' appearance (typical of ADO type 2). After conducting an overview of the epidemiological and clinical characteristic of the disease, this review article aims at summarizing the main radiological features found in different forms of osteopetrosis together with their inheritance pattern.

Phenotype-autosomal recessive osteopetrosis.

Osteopetrosis (OPT) is a life-threatening disease characterized by increased bone mass caused by diminished osteoclast function/differentiation. The autosomal recessive forms, caused by biallelic variants in implicated genes, usually present in infancy. Without treatment, autosomal recessive OPTs are usually fatal within the first 10 years of life [1]. Here, we review the clinical features and associated pathophysiology of the autosomal recessive OPT. A greater understanding of these rare disorders will advance early diagnosis and optimal management.

Malignant Infantile Osteopetrosis with Bone Marrow Involvement.

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

Imaging in osteopetrosis.

Imaging investigations are critical in the management of children with suspected and confirmed osteopetrosis. In severe cases, imaging can provide rapid confirmation of the diagnosis, whilst in milder cases, imaging findings may be the first or only indicators of the disease. Imaging can also identify major complications, including fractures and neurological compromise. We review the pathophysiological basis for the imaging findings in osteopetrosis, focusing on the impact of loss of various osteoclast functions leading to elevated bone density, hyperostosis, modelling abnormalities and bone fragility. We give an overview of the specific imaging findings, both skeletal and neuroradiological, in the spectrum of osteopetrotic disorders, including in the related entities of pyknodysostosis and dysosteosclerosis. We also explore potential radiological differential diagnoses.

Progressive skeletal defects caused by Kindlin3 deficiency, a model of autosomal recessive osteopetrosis in humans.

The cellular and molecular mechanisms of bone development and homeostasis are clinically important, but not fully understood. Mutations in integrins and Kindlin3 in humans known as Leukocyte adhesion deficiencies (LAD) cause a wide spectrum of complications, including osteopetrosis. Yet, the rarity, frequent misdiagnosis, and lethality of LAD preclude mechanistic analysis of skeletal abnormalities in these patients. Here, using inducible and constitutive tissue-specific Kindlin3 knockout (K3KO) mice, we show that the constitutive lack of embryonic-Kindlin3 in myeloid lineage cells causes growth retardation, edentulism, and skull deformity indicative of hydrocephaly. Micro-CT analysis revealed craniosynostosis, choanal stenosis, and micrognathia along with other skeletal abnormalities characteristic of osteopetrosis. A marked progression of osteosclerosis occurs in mature to middle-aged adults, resulting in the narrowing of cranial nerve foramina and bone marrow cavities of long bones. However, postnatal-Kindlin3 is less critical for bone remodeling and architecture. Thus, myeloid Kindlin3 is essential for skeletal development and its deficiency leads to autosomal recessive osteopetrosis (ARO). The study will aid in the diagnosis, management, and treatment choices for patients with LAD-III and ARO.