Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019214 (hepatosplenomegaly)
 4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal recessive malignant infantile osteopetrosis (ARO) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia. The pathophysiological basis is inadequate bone resorption due to osteoclast dysfunction. In the majority of cases, mutations in either of two human genes cause this fatal disorder: TCIRG1, encoding a subunit of the osteoclast H(+)-ATPase, and the voltage-gated chloride channel gene CLCN7. We excluded both genes in a small inbred family with malignant infantile osteopetrosis and undertook linkage analysis of several candidate loci that are involved in murine osteopetrosis. A region spanning more than 20 cM between the markers D6S1717 and D6S1608 on chromosome 6q21 was found to be homozygous in the affected child. This locus is syntenic to the genomic region harboring the gene for the osteopetrotic mutant mouse grey-lethal (gl). Recently, mutations in a novel gene of unknown function were described in the grey-lethal mouse and in one human patient. Mutation screening of the grey-lethal gene (OSTM1), revealed a homozygous 2-bp deletion in exon 2 (c.415_416delAG) in the affected child. No mutations could be found in six independent ARO patients who had tested negative for mutations in TCIRG1 and CLCN7. In summary, we describe the identification of a novel mutation in the coding sequence of the human grey-lethal gene, which is the second OSTM1 mutation found in human ARO, confirming the involvement of this gene in the pathogenesis of this severe bone disease.
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PMID:Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis. 1510 79

Infantile malignant autosomal recessive osteopetrosis (ARO; OMIM 259700) has been reported to be associated with mutations in TCIRG1, CLCN7, or OSTM1. ARO caused by homozygous (or compound heterozygous) mutations in CLCN7, as described here, is usually diagnosed at birth or early in infancy due to generalized osteosclerosis and severe hematologic deficits. The maximal life expectancy of patients with ARO in the absence of bone marrow transplantation is thought to be 10 years. We report on a 25-year-old Thai man who is affected with ARO. Clinical features include proportionate short stature, vision impairment, esotropia, exophthalmos, mild hearing loss, and hepatosplenomegaly. Pancytopenia was present and the patient had frequent illnesses. Radiographs showed generalized osteosclerosis with almost no visible of bone marrow spaces. Dense maxilla and mandible with impacted and malformed teeth were observed. Multiple fractures were reported. He developed osteomyelitis of the mandible on four separate occasions, and partial mandibulectomy was performed. Molecular studies showed that there were no pathogenic mutations in TCIRG1. However, mutation analysis of CLCN7 revealed a homozygous missense mutation (p.Arg526Gln). This patient is, it appears, the longest lived individual with ARO ever reported. Evaluation of osteoclastogenesis in our patient demonstrated very large immature osteoclasts with a high number of nuclei.
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PMID:Long-term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7. 2241 46

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.
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PMID:A novel mutation and a known mutation in the CLCN7 gene associated with relatively stable infantile malignant osteopetrosis in a Chinese patient. 2647 79

Malignant infantile osteopetrosis is a rare congenital disease characterized by a dysfunction of osteoclasts followed by an abnormal bone densification. We report the case of a 5-month-old infant in whom this disease was suspected because of the clinical (hepatosplenomegaly, gingival hypertrophy), hematological (pancytopenia and hypocalcemia), and radiological criteria (abnormal bone density, periosteal reaction). The genetic investigation confirmed the diagnosis. Compound heterozygous mutations in the CLCN7 gene were identified, including an as yet undescribed mutation. The second mutation had already been described as being responsible for severe and irreversible neurological damage in patients with osteopetrosis. Since this patient presented severely delayed development, he was not eligible for bone marrow transplantation.
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PMID:[Malignant infantile osteopetrosis: Case report of a 5-month-old boy]. 2685 Jan 55

The osteopetroses and related sclerosing bone dysplasias can have a broad range of manifestations. Especially in the milder forms, sandwich vertebrae are an easily recognizable and reliable radiological hallmark. We report on four patients from three families presenting with sandwich vertebrae and platyspondyly. The long bone phenotypes were discordant with one patient showing modeling defects and patchy osteosclerosis, while the second displayed only metaphyseal sclerotic bands, and the third and fourth had extreme metaphyseal flaring with uniform osteosclerosis. Two of the four patients had experienced pathological fractures, two had developmental delay, but none showed cranial nerve damage, hepatosplenomegaly, or bone marrow failure. According to these clinical features the diagnoses ranged between intermediate autosomal recessive osteopetrosis and dysosteosclerosis. After exclusion of mutations in CLCN7 we performed gene panel and exome sequencing. Two novel mutations in SLC29A3 were found in the first two patients. In the third family a TCIRG1 C-terminal frameshift mutation in combination with a mutation at position +4 in intron 2 were detected. Our study adds two cases to the small group of individuals with SLC29A3 mutations diagnosed with dysosteosclerosis, and expands the phenotypic variability. The finding that intermediate autosomal recessive osteopetrosis due to TCIRG1 splice site mutations can also present with platyspondyly further increases the molecular heterogeneity of dysosteosclerosis-like sclerosing bone dysplasias.
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PMID:Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1. 3156 Oct 10