Chapter 692 Osteogenesis Imperfecta Joan C. Marini Osteoporosis, a feature of both inherited and acquired disorders, classically demonstrates fragility of the skeletal system and a susceptibility to fractures of the long bones or vertebral compressions from mild or inconsequential trauma. Osteogenesis imperfecta (OI) (brittle bone disease), the most common genetic cause of osteoporosis, is a generalized disorder of connective tissue. The spectrum of OI is extremely broad, ranging from forms that are lethal in the perinatal period to a mild form in which the diagnosis may be equivocal in an adult. Etiology Structural or quantitative defects in type I collagen cause the full clinical spectrum of OI. Type I collagen is the primary component of the extracellular matrix of bone and skin. Ten percent of cases clinically indistinguishable from OI do not have a molecular defect in type I collagen. Some of these cases have biochemically normal collagen and unknown genetic defects. Other cases have overmodified collagen and severe or lethal OI-like bone dysplasia. These cases are caused by recessive null mutations in a collagen-modifying enzyme, prolyl 3-hydroxylase 1 (coded by the LEPRE1 gene on chromosome 1p34.1) or its associated protein, CRTAP. Epidemiology The autosomal dominant forms of OI occur equally in all racial and ethnic groups, and recessive forms occur predominantly in ethnic groups with consanguineous marriages. The West African founder mutation for type VIII OI has a carrier frequency of 1/200-300 among African Americans. The incidence of OI detectable in infancy is about 1/20,000. There is a similar incidence of the mild form OI type I. Pathology The collagen structural mutations cause OI bone to be globally abnormal. The bone matrix contains abnormal type I collagen fibrils and relatively increased levels of types III and V collagen. Several noncollagenous proteins of bone matrix are also reduced. The hydroxyapatite crystals deposited on this matrix are poorly aligned with the long axis of fibrils. Pathogenesis Type I collagen is a heterotrimer composed of two α1(I) chains and one α2(I) chain. The chains are synthesized as procollagen molecules with short globular extensions on both ends of the central helical domain. The helical domain is composed of uninterrupted repeats of the sequence Gly-X-Y, where Gly is glycine, X is often proline, and Y is often hydroxyproline. The presence of glycine at every 3rd residue is crucial to helix formation because its small side chain can be accommodated in the interior of the helix. The chains are assembled at their carboxyl ends; helix formation then proceeds linearly in a carboxyl to amino direction. Concomitant with helix assembly and formation, helical proline and lysine residues are hydroxylated by prolyl 4-hydroxylase and lysyl hydroxylase and some hydroxylysine residues are glycosylated. Collagen structural defects are predominantly of two types: 80% are point mutations causing substitutions of helical glycine residues or crucial residues in the C-propeptide by other amino acids, and 20% are single exon splicing defects. The clinically mild OI type I has a quantitative defect, with null mutations in one α1(I) allele leading to a reduced amount of normal collagen. The glycine substitutions in the two α chains have distinct genotype-phenotype relationships. One third of mutations in the α1 chain are lethal, and those in α2(I) are predominantly nonlethal. Two lethal regions in α1(I) align with major ligand binding regions of the collagen helix. Lethal mutations in α2(I) occur in 8 regularly spaced clusters along the chain that align with binding regions for matrix proteoglycans in the collagen fibril. Classic OI is an autosomal dominant disorder. Some familial recurrences of OI are caused by parental mosaicism for dominant collagen mutations. Recessive OI (types VII and VIII) accounts for 5-7% of new OI in North America. These types are caused by null mutations in the genes coding for two of the components of the collagen prolyl 3-hydroxylation complex in the endoplasmic reticulum, LEPRE1, which encodes P3H1, or CRTAP. This complex is responsible for post-translational modification of a single proline residue, P986, on the α1(I) chains. It is not yet clear whether absence of the complex or the modification is the crucial feature of recessive OI. Clinical Manifestations OI has the triad of fragile bones, blue sclerae, and early deafness. OI was once divided into “congenita,” the forms detectable at birth, and “tarda,” the forms detectable later in childhood; this did not account for the variability of OI. The Sillence classification divides OI into four types based on clinical and radiographic criteria. Additional types have been proposed based on histologic distinctions. Osteogenesis Imperfecta Type I (Mild) OI type I is sufficiently mild that it is often found in large pedigrees. Many type I families have blue sclerae, recurrent fractures in childhood, and presenile hearing loss (30-60%). Both types I and IV are divided into A and B subtypes, depending on the absence (A) or presence (B) of dentinogenesis imperfecta. Other possible connective tissue abnormalities include easy bruising, joint laxity, and mild short stature compared with family members. Fractures result from mild to moderate trauma and decrease after puberty. Osteogenesis Imperfecta Type II (Perinatal Lethal) Only gold members can continue reading. 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Chapter 692 Osteogenesis Imperfecta Joan C. Marini Osteoporosis, a feature of both inherited and acquired disorders, classically demonstrates fragility of the skeletal system and a susceptibility to fractures of the long bones or vertebral compressions from mild or inconsequential trauma. Osteogenesis imperfecta (OI) (brittle bone disease), the most common genetic cause of osteoporosis, is a generalized disorder of connective tissue. The spectrum of OI is extremely broad, ranging from forms that are lethal in the perinatal period to a mild form in which the diagnosis may be equivocal in an adult. Etiology Structural or quantitative defects in type I collagen cause the full clinical spectrum of OI. Type I collagen is the primary component of the extracellular matrix of bone and skin. Ten percent of cases clinically indistinguishable from OI do not have a molecular defect in type I collagen. Some of these cases have biochemically normal collagen and unknown genetic defects. Other cases have overmodified collagen and severe or lethal OI-like bone dysplasia. These cases are caused by recessive null mutations in a collagen-modifying enzyme, prolyl 3-hydroxylase 1 (coded by the LEPRE1 gene on chromosome 1p34.1) or its associated protein, CRTAP. Epidemiology The autosomal dominant forms of OI occur equally in all racial and ethnic groups, and recessive forms occur predominantly in ethnic groups with consanguineous marriages. The West African founder mutation for type VIII OI has a carrier frequency of 1/200-300 among African Americans. The incidence of OI detectable in infancy is about 1/20,000. There is a similar incidence of the mild form OI type I. Pathology The collagen structural mutations cause OI bone to be globally abnormal. The bone matrix contains abnormal type I collagen fibrils and relatively increased levels of types III and V collagen. Several noncollagenous proteins of bone matrix are also reduced. The hydroxyapatite crystals deposited on this matrix are poorly aligned with the long axis of fibrils. Pathogenesis Type I collagen is a heterotrimer composed of two α1(I) chains and one α2(I) chain. The chains are synthesized as procollagen molecules with short globular extensions on both ends of the central helical domain. The helical domain is composed of uninterrupted repeats of the sequence Gly-X-Y, where Gly is glycine, X is often proline, and Y is often hydroxyproline. The presence of glycine at every 3rd residue is crucial to helix formation because its small side chain can be accommodated in the interior of the helix. The chains are assembled at their carboxyl ends; helix formation then proceeds linearly in a carboxyl to amino direction. Concomitant with helix assembly and formation, helical proline and lysine residues are hydroxylated by prolyl 4-hydroxylase and lysyl hydroxylase and some hydroxylysine residues are glycosylated. Collagen structural defects are predominantly of two types: 80% are point mutations causing substitutions of helical glycine residues or crucial residues in the C-propeptide by other amino acids, and 20% are single exon splicing defects. The clinically mild OI type I has a quantitative defect, with null mutations in one α1(I) allele leading to a reduced amount of normal collagen. The glycine substitutions in the two α chains have distinct genotype-phenotype relationships. One third of mutations in the α1 chain are lethal, and those in α2(I) are predominantly nonlethal. Two lethal regions in α1(I) align with major ligand binding regions of the collagen helix. Lethal mutations in α2(I) occur in 8 regularly spaced clusters along the chain that align with binding regions for matrix proteoglycans in the collagen fibril. Classic OI is an autosomal dominant disorder. Some familial recurrences of OI are caused by parental mosaicism for dominant collagen mutations. Recessive OI (types VII and VIII) accounts for 5-7% of new OI in North America. These types are caused by null mutations in the genes coding for two of the components of the collagen prolyl 3-hydroxylation complex in the endoplasmic reticulum, LEPRE1, which encodes P3H1, or CRTAP. This complex is responsible for post-translational modification of a single proline residue, P986, on the α1(I) chains. It is not yet clear whether absence of the complex or the modification is the crucial feature of recessive OI. Clinical Manifestations OI has the triad of fragile bones, blue sclerae, and early deafness. OI was once divided into “congenita,” the forms detectable at birth, and “tarda,” the forms detectable later in childhood; this did not account for the variability of OI. The Sillence classification divides OI into four types based on clinical and radiographic criteria. Additional types have been proposed based on histologic distinctions. Osteogenesis Imperfecta Type I (Mild) OI type I is sufficiently mild that it is often found in large pedigrees. Many type I families have blue sclerae, recurrent fractures in childhood, and presenile hearing loss (30-60%). Both types I and IV are divided into A and B subtypes, depending on the absence (A) or presence (B) of dentinogenesis imperfecta. Other possible connective tissue abnormalities include easy bruising, joint laxity, and mild short stature compared with family members. Fractures result from mild to moderate trauma and decrease after puberty. Osteogenesis Imperfecta Type II (Perinatal Lethal) Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Rumination, Pica, and Elimination (Enuresis, Encopresis) Disorders Adolescent Pregnancy Neisseria gonorrhoeae (Gonococcus) Blastomycosis (Blastomyces dermatitidis) Stay updated, free articles. Join our Telegram channel Join Tags: Nelson Textbook of Pediatrics Expert Consult Jun 18, 2016 | Posted by admin in PEDIATRICS | Comments Off on Osteogenesis Imperfecta Full access? Get Clinical Tree
