Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1

• Published in: Bone (New York, N.Y.) Vol. 55; no. 2; pp. 292 - 297
• Main Authors: Ott, Claus-Eric, Fischer, Björn, Schröter, Phillipe, Richter, Reyk, Gupta, Neerja, Verma, Nishant, Kabra, Madhulika, Mundlos, Stefan, Rajab, Anna, Neitzel, Heidemarie, Kornak, Uwe
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.08.2013; Elsevier
• Subjects: Autosomal recessive osteopetrosis; Base Sequence; Biological and medical sciences; Consanguinity; Copy number variation; Diseases of the osteoarticular system; Female; Fundamental and applied biological sciences. Psychology; Gene Deletion; Homozygote; Humans; Infant; Infant, Newborn; Infantile malignant osteopetrosis type 5; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Membrane Proteins - genetics; Molecular Sequence Data; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); OPTB5; Orthopedics; Osteopetrosis - congenital; Osteopetrosis - genetics; Osteopetrosis - pathology; OSTM1; Pedigree; Real-Time Polymerase Chain Reaction; Skeletal dysplasia; Tumors; Ubiquitin-Protein Ligases - genetics; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Infantile malignant osteopetrosis type 5; OPTB5; Autosomal recessive osteopetrosis; Copy number variation; Skeletal dysplasia; OSTM1; Human; Dysplasia; Diseases of the osteoarticular system; Malignant tumor; Homozygosity; Genetic disease; Osteopetrosis; Morphology; Deletion; Skeleton; Bone; Osteochondrodysplasia; Child; Cancer
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2013.04.007

Abstract Autosomal recessive osteopetrosis (ARO, MIM 259700) is a genetically heterogeneous rare skeletal disorder characterized by failure of osteoclast resorption leading to pathologically increased bone density, bone marrow failure, and fractures. In the neuronopathic form neurological complications are especially severe and progressive. An early identification of the underlying genetic defect is imperative for assessment of prognosis and treatment by hematopoietic stem cell transplantation. Here we describe for the first time homozygous microdeletions of different sizes affecting the OSTM1 gene in two unrelated consanguineous families with children suffering from neuronopathic infantile malignant osteopetrosis. Patients showed an exceptionally severe phenotype with variable CNS malformations, seizures, blindness, and deafness. Multi-organ failure due to sepsis led to early death between six weeks and five months of age in spite of intensive care treatment. Analysis of the breakpoints revealed different mechanisms underlying both rearrangements. Microdeletions seem to represent a considerable portion of OSTM1 mutations and should therefore be included in a sufficient diagnostic screening.