- Email: [email protected]
Common Skeletal Deformities
Common Skeletal Deformities WA Horton, Oregon Health and Science University, Portland, OR, USA ã 2014 Elsevier Inc. All rights reserved.
Familial aggregation occurs frequently among common skeletal deformities even after simply inherited syndromes have been excluded. Environmental factors have been implicated in some cases, but genetic factors are also thought to contribute as well. Advances in genomic technologies have begun to identify chromosomal regions and even specific genes that may contribute to these disorders, although in most cases the mechanisms through which they act remain elusive. The genetics of several common conditions are examined in this chapter. The incidence of idiopathic scoliosis – curvature of the spine – varies from 2% to 8% in the population. It usually becomes evident during periods of rapid growth, and is divided into a juvenile form that occurs most often in infant boys, and an adolescent form that occurs typically in girls during their pubertal growth spurt. Twin studies have shown a substantially higher rate of concordance for monozygotic compared to dizygotic twins. Similarly, family surveys have revealed a higher incidence of scoliosis in first-degree relatives, especially girls. Most evidence to date supports a multifactorial model for genetic predisposition to scoliosis. It also suggests female gender is a strong determinant in converting the genetic predisposition to clinical disease. Recent genome-wide linkage and association studies have pointed to several different chromosomal locations and gene loci that may contribute to the predisposition; however, none have been firmly established in this role. Spondylolisthesis refers to slippage of a vertebral body over another, most often in the lumbar spine. It is thought to be preceded by a defect in the posterior inferior process of the relevant vertebral arch, spondylolysis, which occurs in 4–8% of the population. Spondylolysis with and without slippage sometimes aggregates within families, and radiographic surveys of family members have detected spondylolysis in as many as 27% of near relatives. Type IX collagen has been implicated in spondylolisthesis based on detection of genetic polymorphisms in type IX collagen genes in patients undergoing surgery for spinal stenosis with spondylolisthesis. Congenital dislocation of the hip (CDH), sometimes referred to as developmental dysplasia of the hip, is characterized by the displacement of the femoral head outside the acetabulum before or slightly after birth. CDH is a common birth defect and many predisposing factors have been identified including time of birth in the year, intrauterine posture and especially female gender. Familial aggregation of CDH has long been recognized. Twin studies have consistently shown a higher concordance rate for monozygotic than for dizygotic twins and family surveys have revealed a higher incidence of CDH in close relatives. The genetic predisposition is thought to have two components. The first involves the configuration of the acetabulum or pelvic socket into which the femoral head fits. Multiple genes determine the acetabular shape including depth. The shallow end of the depth range is called acetabular dysplasia; it predisposes to CDH. The other factor is generalized joint laxity, which is inherited mainly as a polygenic trait. Genome-wide investigations have identified two candidate genes for CDH predisposition, TBX4 and GDF5, both of which are regulators of early skeletal development. Idiopathic isolated clubfoot is a common birth defect. Three different forms are recognized and all three exhibit familial aggregation. The most common form, talipes equinovarus, is characterized by adduction of the forefoot, inversion of the heel, and plantar flexion of the forefoot and ankle. It occurs more often in boys than in girls and in first-degree relatives compared to secondand third-degree relatives. Genetic analyses have suggested that both Mendelian and non-Mendelian factors influence the predisposition. There is recent evidence for contributions from TBX4 and HOX genes, although the nature of these contributions is unknown. In the second form of clubfoot, talipes calcaneovalgus, there is dorsal flexion of the forefoot and the plantar surface of the foot faces laterally. It is mild, often correcting spontaneously, and it occurs more commonly in girls often in first-born infants suggesting that uterine constraint might be an etiologic factor. The incidence of affected sibs is 4.5%, suggesting multifactorial inheritance. Inversion and adduction of the forefoot are found alone in metatarsus varus. It resembles talipes calcaneovalgus, is often mild, and may go unnoticed. It has been postulated that it could represent the very mild end of the diastrophic dysplasia clinical spectrum, but this notion is controversial. The juvenile osteochondroses are a group of disorders in which localized noninflammatory arthropathies result from regional disturbances of skeletal growth. There is ischemic necrosis of either primary or secondary endochondral ossification centers. Most of the abnormalities occur sporadically, but familial forms have been described. Dominant inheritance of Legg–Perthes disease, osteonecrosis of the capital femoral epiphysis, has been observed; however, most of these cases have turned out to be mild multiple epiphyseal dysplasia (Ribbing type). When the latter cases are excluded, this condition appears to not be inherited. Blount disease, a growth disturbance of the medial aspect of the proximal tibial growth plate, has also been reported to show autosomal dominant inheritance. But most evidence suggests that common environmental factors are largely responsible for the familial aggregation. Osteochondritis dissecans involving multiple sites, especially the knees, hips, elbows, and ankles, appears to behave as an autosomal dominant trait in some families. There also appears to be a poorly defined genetic predisposition to Scheuermann disease, which affects the spine.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.05633-6
1
2
Common Skeletal Deformities
Further Reading Damborg F, Engell V, Andersen M, Kyvik KO, and Thomsen K (2006) Prevalence, concordance, and heritability of Scheuermann kyphosis based on a study of twins. The Journal of Bone and Joint Surgery. American Volume 88(10): 2133–2136. Dietz FR, Cole WG, Tosi LL, Carroll NC, Werner RD, Comstock D, et al. (2005) A search for the gene(s) predisposing to idiopathic clubfoot. Clinical Genetics 67(4): 361–362. Engesaeter LB (2006) Increasing incidence of clubfoot: Changes in the genes or the environment? Acta Orthopaedica 77(6): 837–838. Kruse LM, Dobbs MB, and Gurnett CA (2008) Polygenic threshold model with sex dimorphism in clubfoot inheritance: The carter effect. The Journal of Bone and Joint Surgery. American Volume 90(12): 2688–2694. Lee MC and Eberson CP (2006) Growth and development of the child’s hip. The Orthopedic Clinics of North America 37(2): 119–132, v. Matsui Y, Mirza SK, Wu JJ, Carter B, Bellabarba C, Shaffrey CI, et al. (2004) The association of lumbar spondylolisthesis with collagen IX tryptophan alleles. Journal of Bone and Joint Surgery (British) 86(7): 1021–1026. Miller NH (2007) Genetics of familial idiopathic scoliosis. Clinical Orthopaedics and Related Research 462: 6–10. Ogilvie J (2010) Adolescent idiopathic scoliosis and genetic testing. Current Opinion in Pediatrics 22(1): 67–70. Osarumwense D, Popple D, Kershaw IF, Kershaw CJ, and Furlong AJ (2007) What follow-up is required for children with a family history of developmental dysplasia of the hip? Journal of Pediatric Orthopaedics. Part B 16(6): 399–402. Stevenson DA, Mineau G, Kerber RA, Viskochil DH, Schaefer C, and Roach JW (2009) Familial Predisposition to developmental dysplasia of the hip. Journal of Pediatric Orthopaedics 29(5): 463–466.
Familial aggregation occurs frequently among common skeletal deformities even after simply inherited syndromes have been excluded. Environmental factors have been implicated in some cases, but genetic factors are also thought to contribute as well. Advances in genomic technologies have begun to identify chromosomal regions and even specific genes that may contribute to these disorders, although in most cases the mechanisms through which they act remain elusive. The genetics of several common conditions are examined in this chapter. The incidence of idiopathic scoliosis – curvature of the spine – varies from 2% to 8% in the population. It usually becomes evident during periods of rapid growth, and is divided into a juvenile form that occurs most often in infant boys, and an adolescent form that occurs typically in girls during their pubertal growth spurt. Twin studies have shown a substantially higher rate of concordance for monozygotic compared to dizygotic twins. Similarly, family surveys have revealed a higher incidence of scoliosis in first-degree relatives, especially girls. Most evidence to date supports a multifactorial model for genetic predisposition to scoliosis. It also suggests female gender is a strong determinant in converting the genetic predisposition to clinical disease. Recent genome-wide linkage and association studies have pointed to several different chromosomal locations and gene loci that may contribute to the predisposition; however, none have been firmly established in this role. Spondylolisthesis refers to slippage of a vertebral body over another, most often in the lumbar spine. It is thought to be preceded by a defect in the posterior inferior process of the relevant vertebral arch, spondylolysis, which occurs in 4–8% of the population. Spondylolysis with and without slippage sometimes aggregates within families, and radiographic surveys of family members have detected spondylolysis in as many as 27% of near relatives. Type IX collagen has been implicated in spondylolisthesis based on detection of genetic polymorphisms in type IX collagen genes in patients undergoing surgery for spinal stenosis with spondylolisthesis. Congenital dislocation of the hip (CDH), sometimes referred to as developmental dysplasia of the hip, is characterized by the displacement of the femoral head outside the acetabulum before or slightly after birth. CDH is a common birth defect and many predisposing factors have been identified including time of birth in the year, intrauterine posture and especially female gender. Familial aggregation of CDH has long been recognized. Twin studies have consistently shown a higher concordance rate for monozygotic than for dizygotic twins and family surveys have revealed a higher incidence of CDH in close relatives. The genetic predisposition is thought to have two components. The first involves the configuration of the acetabulum or pelvic socket into which the femoral head fits. Multiple genes determine the acetabular shape including depth. The shallow end of the depth range is called acetabular dysplasia; it predisposes to CDH. The other factor is generalized joint laxity, which is inherited mainly as a polygenic trait. Genome-wide investigations have identified two candidate genes for CDH predisposition, TBX4 and GDF5, both of which are regulators of early skeletal development. Idiopathic isolated clubfoot is a common birth defect. Three different forms are recognized and all three exhibit familial aggregation. The most common form, talipes equinovarus, is characterized by adduction of the forefoot, inversion of the heel, and plantar flexion of the forefoot and ankle. It occurs more often in boys than in girls and in first-degree relatives compared to secondand third-degree relatives. Genetic analyses have suggested that both Mendelian and non-Mendelian factors influence the predisposition. There is recent evidence for contributions from TBX4 and HOX genes, although the nature of these contributions is unknown. In the second form of clubfoot, talipes calcaneovalgus, there is dorsal flexion of the forefoot and the plantar surface of the foot faces laterally. It is mild, often correcting spontaneously, and it occurs more commonly in girls often in first-born infants suggesting that uterine constraint might be an etiologic factor. The incidence of affected sibs is 4.5%, suggesting multifactorial inheritance. Inversion and adduction of the forefoot are found alone in metatarsus varus. It resembles talipes calcaneovalgus, is often mild, and may go unnoticed. It has been postulated that it could represent the very mild end of the diastrophic dysplasia clinical spectrum, but this notion is controversial. The juvenile osteochondroses are a group of disorders in which localized noninflammatory arthropathies result from regional disturbances of skeletal growth. There is ischemic necrosis of either primary or secondary endochondral ossification centers. Most of the abnormalities occur sporadically, but familial forms have been described. Dominant inheritance of Legg–Perthes disease, osteonecrosis of the capital femoral epiphysis, has been observed; however, most of these cases have turned out to be mild multiple epiphyseal dysplasia (Ribbing type). When the latter cases are excluded, this condition appears to not be inherited. Blount disease, a growth disturbance of the medial aspect of the proximal tibial growth plate, has also been reported to show autosomal dominant inheritance. But most evidence suggests that common environmental factors are largely responsible for the familial aggregation. Osteochondritis dissecans involving multiple sites, especially the knees, hips, elbows, and ankles, appears to behave as an autosomal dominant trait in some families. There also appears to be a poorly defined genetic predisposition to Scheuermann disease, which affects the spine.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.05633-6
1
2
Common Skeletal Deformities
Further Reading Damborg F, Engell V, Andersen M, Kyvik KO, and Thomsen K (2006) Prevalence, concordance, and heritability of Scheuermann kyphosis based on a study of twins. The Journal of Bone and Joint Surgery. American Volume 88(10): 2133–2136. Dietz FR, Cole WG, Tosi LL, Carroll NC, Werner RD, Comstock D, et al. (2005) A search for the gene(s) predisposing to idiopathic clubfoot. Clinical Genetics 67(4): 361–362. Engesaeter LB (2006) Increasing incidence of clubfoot: Changes in the genes or the environment? Acta Orthopaedica 77(6): 837–838. Kruse LM, Dobbs MB, and Gurnett CA (2008) Polygenic threshold model with sex dimorphism in clubfoot inheritance: The carter effect. The Journal of Bone and Joint Surgery. American Volume 90(12): 2688–2694. Lee MC and Eberson CP (2006) Growth and development of the child’s hip. The Orthopedic Clinics of North America 37(2): 119–132, v. Matsui Y, Mirza SK, Wu JJ, Carter B, Bellabarba C, Shaffrey CI, et al. (2004) The association of lumbar spondylolisthesis with collagen IX tryptophan alleles. Journal of Bone and Joint Surgery (British) 86(7): 1021–1026. Miller NH (2007) Genetics of familial idiopathic scoliosis. Clinical Orthopaedics and Related Research 462: 6–10. Ogilvie J (2010) Adolescent idiopathic scoliosis and genetic testing. Current Opinion in Pediatrics 22(1): 67–70. Osarumwense D, Popple D, Kershaw IF, Kershaw CJ, and Furlong AJ (2007) What follow-up is required for children with a family history of developmental dysplasia of the hip? Journal of Pediatric Orthopaedics. Part B 16(6): 399–402. Stevenson DA, Mineau G, Kerber RA, Viskochil DH, Schaefer C, and Roach JW (2009) Familial Predisposition to developmental dysplasia of the hip. Journal of Pediatric Orthopaedics 29(5): 463–466.