Exploring genetic mutations in a 7-month-old male infant with osteopetrosis
Keywords:
osteopetrosis, CLCN7 mutationAbstract
Osteopetrosis (marble bone disease) is a group of rare inheritable metabolic bone diseases. The clinical presentation is heterogeneous due to multiple organ involvement. Severity of the disease depends on genetic mutations and modes of inheritance causing autosomal dominant, autosomal recessive as well as X-linked osteopetrosis. In this report, we described a 7-month-old male infant presenting anemia, hepatosplenomegaly and thrombocytopenia. Bone x-ray showed typical radiologic features of osteopetrosis. Mutation analysis was performed using a whole exome sequencing (WES) technique. We found that the patient harbored compound heterozygous mutations of the CLCN7 gene. The WES results were confirmed using Sanger sequencing technique. Each parent carried a CLCN7 mutation transmitted to the patient.
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References
Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009;4:5.
Wu CC, Econs MJ, DiMeglio LA, Insogna KL, Levine MA, Orchard PJ, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017;102:3111-23.
Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone. 2008;42:19-29.
Shamriz O, Shaag A, Yaacov B, NaserEddin A, Weintraub M, Elpeleg O, et al. The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis. Clin Genet. 2017;92:80-5.
Bollerslev J, Henriksen K, Nielsen MF, Brixen K, Van Hul W. Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol. 2013;169:R39-57.
Estévez R, Pusch M, Ferrer-Costa C, Orozco M, Jentsch TJ. Functional and structural conservation of CBS domains from CLC chloride channels. J Physiol. 2004;557:363-78.
Sobacchi C, Villa A, Schulz A, Kornak U. CLCN7-Related Osteopetrosis. 2007 Feb 12 [Updated 2016 Jun 9]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1127/
Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, et al. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J Bone Miner Res. 2003;18:1740-7.
Villa A, Guerrini MM, Cassani B, Pangrazio A, Sobacchi C. Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor. Calcif Tissue Int. 2009;84:1-12.
Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, et al. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Hum Mutat. 2010;31(1):E1071-80.
Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med. 2004;351:2839-49.
Orchard PJ, Fasth AL, Le Rademacher J, He W, Boelens JJ, Horwitz EM, et al. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood. 2015;126:270-6.
Fasth A, Porras O. Human malignant osteopetrosis: pathophysiology, management and the role of bone marrow transplantation. Pediatr Transplant. 1999;3(Suppl 1):102-7.
Tolar J, Bonfim C, Grewal S, Orchard P. Engraftment and survival following hematopoietic stem cell transplantation for osteopetrosis using a reduced intensity conditioning regimen. Bone Marrow Transplant. 2006;38:783-7.
Natsheh J, Drozdinsky G, Simanovsky N, Lamdan R, Erlich O, Gorelik N, Or R, Weintraub M, Stepensky P. Improved outcomes of hematopoietic stem cell transplantation in patients with infantile malignant osteopetrosis using fludarabine-based conditioning. Pediatric blood & cancer. 2016 Mar;63(3):535-40.
