Infantile Malignant Osteopetrosis Research Articles

Malignant Infantile Osteopetrosis Masquerading as Isolated Fetal Femoral Fracture: First Indian Case Report and Review of Literature

AbstractMalignant infantile osteopetrosis is a rare case of isolated fetal femoral fracture, a scarcely documented phenomenon in medical literature. Through detailed examination and genetic testing, it unveils malignant infantile osteopetrosis as an unexpected etiology, challenging existing diagnostic paradigms. This groundbreaking case emphasizes the critical role of genetic testing in unraveling complex fetal anomalies and underscores the necessity for comprehensive approaches in prenatal diagnostics, offering new insights into prenatal manifestations of skeletal dysplasias.

Osteopetrosis and related osteoclast disorders in adults: A review and knowledge gaps On behalf of the European calcified tissue society and ERN BOND

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.

Osteopetrosis in the pediatric patient: what the radiologist needs to know.

Osteopetrosis describes several types of rare sclerosing bone dysplasias of varying clinical and radiographic severity. The classic autosomal dominant subtype emerges most often in adolescence but can present from infancy through adulthood. The autosomal recessive osteopetrosis, or "malignant infantile osteopetrosis," presents in infancy with a grimmer prognosis, though the autosomal dominant forms (often mislabeled as "benign") actually can have life-threatening consequences as well. Often osteopetrosis is detected due to skeletal findings on radiographs performed to evaluate injury or as an incidental finding during evaluation for illness. Given the varied phenotypic severity and presentations at different ages, radiologists play an integral role in the care of these patients both in diagnosis and in clinical evaluation and monitoring. A deeper understanding of the underlying genetic basis of the disease can aid in the radiologist in diagnosis and in anticipation of unique complications. An overview of current clinical management is also discussed.

Generation of an induced pluripotent stem cell line (SYSUSCi004-A) from a patient with Infantile Malignant Osteopetrosis

Infantile Malignant Osteopetrosis (IMO) is a rare, severe autosomal recessive form of osteopetrosis. Here, the peripheral blood mononuclear cells (PBMCs) extracted from a patient with IMO carrying a compound heterozygous mutation in T cell immune regulator 1, ATPase H + transporting V0 subunit a3 (TCIRG1) gene (c.242delC; c.1114C > T) were successfully reprogrammed using Sendai virus encoding the four Yamanaka factors. The generated hiPSCs, IMO-hiPSCs, displayed typical embryonic stem cell-like morphology and were verified by expression of pluripotency markers such as OCT4, SOX2, NANOG, TRA-1–60 and SSEA4, as well as in vivo and in vitro differentiation into derivatives of three germ layers.

Analysis of clinical presentation and genetic characteristics of malignant infantile osteopetrosis

Objective: To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. Methods: This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Results: Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) vs. 0.4 (0.2, 0.6) years, Z=-2.60, P=0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) vs. 1.1 (0.8, 1.6) mmol/L, Z=-2.59, P=0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) vs. 56 (37, 82) U/L, Z=-3.38, P=0.001) and the level of neutrophils (14.0 (9.9, 18.1) vs. 9.2 (6.7, 11.1) ×109/L, Z=-2.07, P=0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) vs. 6.3 (2.5, 9.7) μg/L, Z=2.83, P=0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% vs. 83.3%±7.6%, χ²=0.56, P=0.456). Conclusions: TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.

Management of perinatal cervical spine injury using custom-fabricated external orthoses: design considerations, narrative literature review, and experience from the Hospital for Sick Children. Illustrative cases.

Cervical spine injuries in neonates are rare and no guidelines are available to inform management. The most common etiology of neonatal cervical injury is birth-related trauma. Management strategies that are routine in older children and adults are not feasible due to the unique anatomy of neonates. Here, the authors present 3 cases of neonatal cervical spinal injury due to confirmed or suspected birth trauma, 2 of whom presented immediately after birth, while the other was diagnosed at 7 weeks of age. One child presented with neurological deficits due to spinal cord injury, while another had an underlying predisposition to bony injury, infantile malignant osteopetrosis. The children were treated with a custom-designed and manufactured full-body external orthoses with good clinical and radiographic outcomes. A narrative literature review further supplements this case series and highlights risk factors and the spectrum of birth-related spinal injuries reported to date. The current report highlights the importance of recognizing the rare occurrence of cervical spinal injury in newborns and provides pragmatic recommendations for management of these injuries. Custom orthoses provide an alternate option for neonates who cannot be fitted in halo vests and who would outgrow traditional casts.

299 - Bone Marrow Transplantation in Malignant Infantile Osteopetrosis: Reporting 25 Years of Experience from a Tertiary Care Hospital

299 - Bone Marrow Transplantation in Malignant Infantile Osteopetrosis: Reporting 25 Years of Experience from a Tertiary Care Hospital

Concurrent Malignant Infantile Osteopetrosis and Hypophosphatasia in a Six-year-old Boy: A Case Report

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.

A rare cause of anemia and hepatosplenomegaly-marble bone disease

Abstract Marble bone disease (“osteopetrosis”) is a rare, heritable disorder of the skeleton due to a defective function of the osteoclasts and characterized by increased bone density on radiographs. It is an uncommon disease with an unknown etiology. The presentation and severity of osteopetrotic conditions vary greatly, from neonatal onset with potentially fatal complications such as bone marrow failure (e.g., classic or “malignant” or autosomal recessive osteopetrosis) to the incidental discovery of osteopetrosis on radiographs (e.g., osteopoikilosis), susceptibility to infections, growth failure, and generalized osteosclerosis. If left untreated most of the cases of infantile form osteopetrosis die as a result of bone marrow suppression in the first decade of life. Normocytic anemia is caused either by hypoproliferation of hemopoietic tissue or increased destruction of red cells. Osteopetrosis is a rare cause of anemia. We are presenting here an unusual case that was diagnosed clinically and radiologically as malignant infantile osteopetrosis and was referred to us for the evaluation of anemia and hepatosplenomegaly.

A RARE CAUSE OF HEPATOSPLENOMEGALY –MALIGNANT INFANTILE OSTEOPETROSIS

Osteopetrosis (“marble bone disease”) is a descriptive term that refers to a group of rare, heritable disorders of skeleton characterized by increased bone density on radiographs. It is an uncommon disease of unknown cause. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure , to the incidental nding of osteopetrosis on radiographs . Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental nding of osteopetrosis on radiographs (e.g. osteopoikilosis). The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the rst decade as a complication of bone marrow suppression. A 4 month old male child presented with anemia and hepatosplenomegaly was diagnosed clinically and radiologically as Malignant Infantile Osteopetrosis.

The clinical features of OSTM1-associated malignant infantile osteopetrosis: A retrospective, single-center experience over one decade.

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

Three-Year Dentition Follow-up of a Paediatric Case with Malignant Infantile Osteopetrosis: A Review of the Literature

Three-Year Dentition Follow-up of a Paediatric Case with Malignant Infantile Osteopetrosis: A Review of the Literature

Cutaneous vesicles in an infant after bone marrow transplantation.

Eight-month-old infant who recently received a matched unrelated donor transplant for malignant infantile osteopetrosis was admitted on T+48 for the evaluation of fevers. Her complete blood count (CBC) on admission showed a neutrophil count of 8940 × 109/L and Hb of 7.1 g/dl. Patient was started on cefepime and vancomycin while awaiting results of blood culture that grew methicillin-susceptible Staphylococcus aureus. She continued treatment with cefepime and had her central line removed. On T+50 parents reported the appearance of a new blistering rash on her hands. Skin examination demonstrated multiple 1–2 mm deep seated noninflammatory vesicles located on the distal digits and metacarpophalangeal joints of both hands and pad of the right thumb (Figure 1). During this admission, our patient's Epstein–Barr virus (EBV) polymerase chain reaction (PCR) test in whole blood became positive and she also had diarrhea that tested positive for norovirus. In an early posttransplant (<100 days) patient, our major concern was acute graft versus host disease (GVHD). Due to the limited distribution of rash and the lack of systemic symptoms, it became less likely. Although GVHD can present as bullous skin lesions, it is associated with severe disease presentation. Second in our list were infectious causes. There are reports of norovirus-related urticaria presenting with generalized erythematous wheals associated with pruritus. Dermatologic manifestations of EBV are reported more commonly in patients with infectious mononucleosis (IM). IM patients more commonly develop a faint erythematous macular rash early in the course or a maculopapular rash associated with the inappropriate use of amoxicillin. There are reports of IM presenting with erythematous papulovesicules, but it is uncommon. Vesicular lesions associated with Herpes simplex 1 or 2 infection are characterized by grouped vesicles on an erythematous base ring. In severely immunocompromised patients with deficient cellular immunity, the risk of extensive mucocutaneous disease and disseminated infection is higher. Transplant patients are at risk of developing herpes simplex virus (HSV) infection due to reactivation. Lastly, sucking blisters are noninflammatory vesicles with thick walls that contain sterile fluid. Lesions are usually located on dorsal areas of fingers, hands or wrists and can be bilateral. The observation of the infant sucking the involve areas helped guiding with the diagnosis. In the absence of lesions in other areas and with lack of systemic symptoms sucking blisters became the most likely diagnosis. No biopsy was performed due to well apearing baby. Fever subsided and antibiotics were stopped after 10 days with negative blood culture. Rash is persistent with a healthy looking infant without other manifestations. Kristen Nagle, PNP; Linda Cabral, PA. The authors declare they have no conflicts of interest. The authors received no specific funding for this work. A written informed consent was obtained from the parents of the patient to publish the case and images in a medical journal.

Assessing the Efficacy of Alkylating Agent Regimens in the Treatment of Infantile Malignant Osteopetrosis: Cyclophosphamide, Busulfan, or Thiotepa.

Infantile malignant osteopetrosis is a debilitating disease that requires total bone marrow irradiation and transplant procedures for patients to survive. The major complication of this procedure is graft vs host disease (GVHD), followed by infections and end organ toxicity. Therefore, current research efforts into treatment mainly aim to reduce GVHD while limiting infections and organ toxicity. Different regimens of alkylating agents have been used to try to reduce GVHD. The most common regimen is cyclophosphamide (Cy) with busulfan (Bu), followed by Cy with Bu and thiotepa (Thio). This meta-analysis aimed to evaluate the efficacy of different treatments by comparing mortality and morbidity causes and rates across groups. The mean one-year survival rate for the Cy, Bu, Thio regimen studies in the human leukocyte antigen (HLA) unmatched group (45.01%) was statistically lower than the one-year survival rate for the studies using just a Cy, Bu regimen (70.8%) in the HLA unmatched studies (p<0.00142). The one-year survival in the studies which had HLA-matched donors was 80.56%, which is statistically higher (p<0.001) than the one-year survival in the HLA-unmatched studies (53.96%), indicating a benefit of finding HLA-matched donors. It seems that price and availability could be a factor in the widespread use of Cy.

Findings on Optical Coherence Tomography in Malignant Infantile Osteopetrosis.

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

Infantile malignant osteopetrosis caused by a new mutation of TCIRG1 gene： a case report

Infantile malignant osteopetrosis caused by a new mutation of TCIRG1 gene： a case report

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-month-old male infant diagnosed as malignant infantile osteopetrosis, who presented with bronchopneumonia, anemia, thrombocytopenia, hepatosplenomegaly, failure to thrive (FTT).

Clinical presentation and analysis of genotype-phenotype correlations in patients with malignant infantile osteopetrosis.

Malignant infantile osteopetrosis (MIOP) is the autosomal recessive, severe form of osteopetrosis. This rare genetic syndrome usually presents soon after birth and is often fatal if left untreated. Early diagnosis is key for proper management but clinical presentation is diverse, and oftentimes diagnosis may be challenging. In this study, we retrospectively collected data of genetic mutations and phenotypic characteristics at the initial presentation of 81 MIOP patients and analyzed genotype-phenotype correlations. The most common genetic mutation was in the TCIRG1 gene (n=46, 56.8%), followed by SNX10 (n=20, 25%). Other genetic mutations included RANK (n=7, 8.7%), CLCN7 (n=5, 6.2%) and CA2 (n=3, 3.7%). More than half of the patients presented with growth retardation (n=46, 56.8%). Twenty-one of the patients were blind (26%) and thirty-seven patients had other neurological deficits (45.7%) at the time of initial presentation. Most patients presented with hematological signs of bone marrow failure including anemia (n=69, 85.2%) and thrombocytopenia (n=33, 40.7%). Thrombocytopenia at initial presentation was significantly more prevalent in patients with mutations in the TCIRG1 gene (p=0.036). Other phenotypic presenting features were not found to be significantly correlated to specific gene mutations. In conclusion, the initial presentation of MIOP is variable, but some features are common such as growth retardation, visual impairment, and cytopenias. High awareness of MIOP presenting signs is essential for prompt diagnosis of this challenging disease.

Scapular Caffey’s disease: A masquerading swelling in an infant, a case report and review of literature

Caffey’s disease was characterized by a triad of symptoms, irritability, soft tissue swelling, and underlying cortical bone thickening. It mostly occurs before the first 5 months of life in infancy. The knowledge of this pathology was essential as it masquerades as wide range diseases including acute osteomyelitis, bone tumors, trauma, battered baby syndrome (child abuse), hypervitaminosis a, scurvy, infantile malignant osteopetrosis, neonatal tuberculosis, congenital syphilis, pseudoparalyis of infancy which was more common and require specific management including extensive surgery. Classically, infantile cortical hyperostosis disease occurs in the early part of the first year of life. Infantile cortical hyperostosis was characterized by a clinical triad (fever, soft-tissue swelling, hyperirritability) and a clinching radiographic picture of underlying cortical hyperostosis (thickening or bony expansion). We reported a case of scapular swelling in a 2 -month-old infant where a retrospective diagnosis of caffey’s disease was made. We proposed a high clinical suspicion for early diagnosis of Caffey’s disease and hence appropriate management.

Genetic analysis of osteopetrosis in Pakistani families identifies novel and known sequence variants

Osteopetrosis is a genetically heterogenous, fatal bone disorder characterized by increased bone density. Globally, various genetic causes are reported for osteopetrosis with all forms of inheritance patterns. A precise molecular diagnosis is necessary for prognosis and for prescribing treatment paradigms in osteopetrosis. Here we report on thirteen individuals diagnosed with infantile malignant osteopetrosis coming from ten unrelated Pakistani families; nine of whom are consanguineous. We performed whole exome sequencing and Sanger sequencing in all families and identified homozygous variants in genes previously reported for autosomal recessive inheritance of osteopetrosis. All the identified variants are expected to affect the stability or length of gene products except one nonsynonymous missense variant. TCIRG1 was found as a candidate causal gene in majority of the families. We report six novel variants; four in TCIRG1 and one each in CLCN7 and OSTM1. Our combined findings will be helpful in molecular diagnosis and genetic counselling of patients with osteopetrosis particularly in populations with high consanguinity.