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.
Child ; Male ; Female ; Humans ; Osteopetrosis/therapy* ; Retrospective Studies ; Prognosis ; Genes, Recessive ; Phosphorus ; Chloride Channels/genetics* ; Vacuolar Proton-Translocating ATPases/genetics*

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.
Bone Density ; Child ; Hematopoietic Stem Cell Transplantation ; Humans ; Mutation ; Osteopetrosis/genetics* ; Sorting Nexins/genetics*

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.
Femoral Fractures ; Fracture Fixation, Internal ; Hip Fractures ; Hip ; Humans ; Male ; Osteopetrosis ; Retrospective Studies ; Surgeons

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.
Anemia, Sickle Cell ; Arthritis, Infectious ; Cleidocranial Dysplasia ; Diagnosis ; Gardner Syndrome ; Hyperparathyroidism ; Klippel-Feil Syndrome ; Marfan Syndrome ; Neurofibromatosis 1 ; Osteopetrosis ; Pentalogy of Cantrell ; Poland Syndrome ; Polychondritis, Relapsing ; Retrospective Studies ; Rickets ; Scleroderma, Systemic ; Spondylitis, Ankylosing ; Sternoclavicular Joint ; Thalassemia ; Thoracic Wall ; Tuberculosis

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.
Bone Density ; Cranial Nerves ; Crowding ; Dental Care ; Dental Caries ; Denture, Partial, Removable ; Female ; Follow-Up Studies ; Humans ; Immune System ; Incisor ; Infant ; Molar ; Oral Hygiene ; Osteoclasts ; Osteomyelitis ; Osteopetrosis ; Pancytopenia ; Pediatric Dentistry ; Sepsis ; Skeleton ; Tooth ; Tooth, Deciduous ; Wound Healing

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.
Aged ; Exome ; Female* ; Humans ; Korea ; Leukocytes ; Mutation, Missense ; Osteoclasts ; Osteopetrosis* ; Osteosclerosis ; Pelvis ; Skeleton ; Skull ; Spine

OBJECTIVETo detect potential mutation of the TCIRG1 gene in a boy with infantile malignant osteopetrosis.

METHODSTarget 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.

RESULTSThe 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.

CONCLUSIONThe 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.

Adult ; Asian Continental Ancestry Group ; Base Sequence ; Humans ; Infant ; Infant, Newborn ; Infant, Newborn, Diseases ; genetics ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation ; Osteopetrosis ; genetics ; Pedigree ; Vacuolar Proton-Translocating ATPases ; genetics

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.
Arthritis, Rheumatoid ; Bone and Bones ; Bone Resorption ; Cytokines* ; Homeostasis ; Osteoclasts* ; Osteogenesis ; Osteopetrosis ; Osteoporosis

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.
Anemia ; Bone Resorption ; Brain ; Congenital, Hereditary, and Neonatal Diseases and Abnormalities ; Cytomegalovirus Infections* ; Cytomegalovirus* ; Deafness ; Humans ; Hypocalcemia ; Immunosuppression ; Infant ; Infant, Newborn* ; Osteopetrosis* ; Plasma ; Radiography ; Real-Time Polymerase Chain Reaction ; Rickets ; Sclerosis ; Thrombocytopenia ; Vision Disorders

OBJECTIVETo explore the application of preimplantation genetic diagnosis (PGD) for infantile malignant osteopetrosis (IMO).

METHODSFor 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.

RESULTSPrenatal 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.

CONCLUSIONThe study demonstrated the advantage of PGD over prenatal diagnosis when natural pregnancies have repeatedly produced IMO children/fetuses.

Adult ; Base Sequence ; Female ; Fertilization in Vitro ; Fetus ; Genetic Carrier Screening ; Humans ; Infant ; Male ; Microsatellite Repeats ; Molecular Sequence Data ; Osteopetrosis ; diagnosis ; embryology ; genetics ; prevention & control ; Pedigree ; Point Mutation ; Pregnancy ; Preimplantation Diagnosis ; Vacuolar Proton-Translocating ATPases ; genetics