Long‐term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7

Abstract

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.

Adult Osteosclerotic Metaphyseal Dysplasia With Progressive Osteonecrosis of the Jaws and Abnormal Bone Resorption Pattern Due to a LRRK1 Splice Site Mutation

“…(38) Interestingly, also osteoclasts from Clcn7-deficient mice and a patient with CLCN7-related autosomal recessive osteopetrosis have a larger diameter for an unknown reason. (30,39,40) Lrrk1 −/− mice were resistant to ovariectomy (OVX)-induced bone loss at the spine, femur, and tibia and showed elevated total bone mass density (BMD) at all three skeletal sites at time of OVX. (7) LRRK1 has hence been contemplated as a potential target for osteoanabolic therapy.…”

Omi, a recessive mutation on chromosome 10, is a novel allele of Ostm1

“…This does not exclude the possibility that other hypomorphic OSTM1 mutations could lead to a mild osteopetrotic phenotype in humans. The recent identification of a similar mutation in CLC7 (Kantaputra et al 2012) confirms the idea that many more subtle mutations may be identified in the human population. Therapy for osteopetrosis is presently unsatisfactory and much work needs to done to unravel the gene defects and to identify new treatments to improve symptoms.…”

“…Various forms of recessive osteopetrosis have been reported, some of which are associated with the most severe phenotypes (including those caused by mutations in the TCIRG1 , CLC7 , and OSTM1 genes), whereas mutations in other genes ( CAII and PLEKHM1 ) give a milder osteopetrotic phenotype. Recently, long-term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7 was described (Kantaputra et al 2012). Interestingly, the phenotype of omi mice greatly overlaps the description of a case study of recessive mild osteopetrosis (Kahler et al 1984).…”

Identification of potential microRNA–target pairs associated with osteopetrosis by deep sequencing, iTRAQ proteomics and bioinformatics

“…Hsa-miR-23a is among several miRNAs currently miRNA-target pairs associated with osteopetrosis M Ou et al considered as suppressors of osteoblast differentiation, upregulated hsa-miR-23a in PBMCs may be involved in the abnormal osteoclasts found in osteopetrosis-specific PBMC-induced osteoclasts. 20 Hsa-miR-29b-3p in the miR-29abcd family was among the most significantly downregulated miRNAs in osteopetrosis library. This is consistent with a putative role of downregulation of hsa-miR-29b-3p in decreased osteoclastogenesis in osteopetrosis-specific PBMCinduced osteoclasts.…”