Hearing Loss in Osteogenesis Imperfecta: Characteristics and Treatment Considerations

SAGE-Hindawi Access to Research Genetics Research International Volume 2011, Article ID 983942, 6 pages doi:10.4061/2011/983942 Review Article Hearing Loss in Osteogenesis Imperfecta: Characteristics and Treatment Considerations Joseph P. Pillion,1, 2 David Vernick,3 and Jay Shapiro2, 4 1 Department of Audiology, Kennedy Krieger Institute, Baltimore, MD 21205, USA 2 Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 3 Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, USA 4 Bone and Osteogenesis Imperfecta Department, Kennedy Krieger Institute, Baltimore, MD 21205, USA Correspondence should be addressed to Joseph P. Pillion, Received 2 June 2011; Accepted 4 October 2011 Academic Editor: Ignacio Del Castillo Copyright © 2011 Joseph P. Pillion et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Osteogenesis imperfecta (OI) is the most common heritable disorder of connective tissue. It is associated with fractures following relatively minor injury, blue sclerae, dentinogenesis imperfecta, increased joint mobility, short stature, and hearing loss. Structures in the otic capsule and inner ear share in the histologic features common to other skeletal tissues. OI is due to mutations involving several genes, the most commonly involved are the COL1A1 or COL1A2 genes which are responsible for the synthesis of the proalpha-1 and proalpha-2 polypeptide chains that form the type I collagen triple helix. A genotype/phenotype relationship to hearing loss has not been established in OI. Hearing loss is commonly found in OI with prevalence rates ranging from 50 to 92% in some studies. Hearing loss in OI may be conductive, mixed, or sensorineural and is more common by the second or third decade. Treatment options such as hearing aids, stapes surgery, and cochlear implants are discussed. 1. Introduction Osteogenesis imperfecta (OI) is the most common of the heritable disorders of bone as first defined by McKusick in 1956 [1]. Approximately 25,000 individuals with this condition live in the US. However, the real incidence may be twice that number because of persons with mild OI who experience a small number of fractures and in whom no diagnosis is made. Hearing loss is a significant complication of OI. The hallmark of OI is the occurrence of fractures with relatively minor injury. Blue sclerae, dentinogenesis imperfecta, increased joint mobility, and short stature are common to the 8 phenotypes that are currently recognized (Table 1). As shown in Table 1, these vary considerably in their relative incidence and clinical severity. It is not commonly appreciated, however, that OI is a systemic disorder of connective tissue due to the wide distribution of type I collagen in multiple organs. Type I collagen is the most abundant protein in the body. OI is the result of mutations involving several genes responsible for the synthesis or intracellular processing of type I collagen (COL1). To date, 7 genes have been implicated as causative in OI [2, 3]. Ninety-five percent of OI cases are due to dominantly transmitted mutations involving COL1A1 or COL1A2 genes which are responsible for the synthesis of the proalpha-1 and proalpha-2 polypeptide chains that form the type I collagen triple helix. Approximately 3–5% of cases involve mutations which are transmitted recessively and are associated with severe or lethal OI. These genes modify the intracellular processing of type I collagen: CRTAP (collagenrelated protein), P3H1/LEPRE1 (prolyl 3-hydroxylase 1), and PPIB (Cytophyllin B protein) and several chaperone proteins such as HSP-47 in the endoplasmic reticulum [4–6]. CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER) which 3-hydroxylates the Pro986 residue of collagen proalpha1 (1) and proalpha (2I) chains [7]. Mutations in these genes lead to severe or lethal skeletal disease (OI types VII and VIII) [8]. No correlation has been established to date between mutations affecting the COL1A1 and COL1A2 genes and hearing loss in OI [9]. 2 Genetics Research International Table 1: Types of osteogenesis imperfecta (adapted from [18]). Type Inheritance∗∗ I AD II AD, AR III AD, AR IV AD V AD VI unknown VII AR VIII AR ∗∗ Clinical Mild, blue sclerae fractures with little or no deformity hearing loss, DI Lethal, pulmonary insufficiency, beaded ribs, rhizomelic hearing loss Progressive deforming intrauterine fractures, deformed limbs, scoliosis white or blue sclerae hearing loss, DI Moderately severe, limb deformity, sclerae blue early and lighten with age scoliosis Variable phenotype like IV hyperplastic callus, dislocated radial head calcified interosseous membrane More fractures than IV mineralization defect on biopsy, vertebral fractures, no DI First nations family, Quebec congenital fractures white sclerae, severe rhizomelia Severe or lethal similar to OI type II (Sillence) Incidence++ 60% 10% 10% 15% 5% Unknown ++ ++ Mutations Type I collagen COL1A1, COL1A2 Type I collagen COL1A1, COL1A2 Type I collagen COL1A1, COL1A2 Type I collagen COL1A1, COL1A2 Unknown Type I collagen SERPINF1 (chaperone protein) CRTAP, LEPRE1, PPIB (prolyl-3 hydroxylation) CRTAP, LEPRE1 SERPINH1 AD = autosomal dominant. ∗∗ AR = autosomal recessive. ++ : the incidence of OI types I–IV is reasonably established. However, for the less common types, OI types VI, VII, and VIII, the incidence is not clearly defined. However, it is estimated that the recessively inherited forms (VII and VIII) constitute approximately 3–5% of the total OI population. As noted above, disordered type I collagen synthesis affects multiple organs in addition to bone. Blue sclerae result from altered light reflectance in the presence of abnormal scleral collagen [10]. Corneal defects occur because collagen is the dominant corneal protein. Tendon and ligament involvement leads to hyperextensible joints. Dentinogenesis imperfecta is the result of abnormal collagen in dental pulp which leads to enamel breakage. Type I collagen in vascular structures leads to mitral and aortic valve involvement as well as aortic dilatation in some cases. Finally, disordered type I collagen in the ear involves each of the auditory structures, both hard and soft tissues, leading to early-onset hearing loss. There is limited information about the histopathology of the temporal bone in OI. Berger et al. examined the histopathologic findings in 8 temporal bones from 5 patients with type III osteogenesis imperfecta [11]. Evidence of both deficient and abnormal ossification was found in the bony walls of middle ear and ossicles. Microfractures were found in the otic capsule and in the anterior process and handle the malleus and at the crura of the stapes. T (...truncated)