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Hereditary Noninflammatory Arthropathies
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Hereditary Noninflammatory Arthropathies Mariko L Ishimori Division of Rheumatology, Cedar-Sinai Medical Center, Los Angeles, CA, USA This article is a revision of the previous edition article by Peter H Beighton, volume 3, pp 3865–3871, © 2007, Elsevier Ltd.
163.1 INTRODUCTION Noninflammatory arthropathy is a major manifestation of a number of genetic disorders. There is a great variety of phenotypes, which present a diagnostic challenge in the clinical setting. In some of these conditions this arthropathy is generalized, while in others it predominates in the hip joints, with or without significant involvement of the spine. Degenerative osteoarthropathy (OA) is the end result of a number of different pathologic processes that culminate in cartilage degeneration, with remodeling and proliferation of new bone. The underlying mechanisms may involve disturbances in skeletal development; minor abnormalities of the cartilage matrix itself, notably, genetic defects of type II collagen; infiltration, as in certain storage disorders; and aseptic necrosis, as in the hemoglobinopathies. In addition, neuropathic joints develop in some hereditary neurologic conditions. Environmental factors may also play a role, and the interaction of primary defects in cartilage and abnormal external forces may be the pathogenetic determinants in some bone dysplasias and hypermobility syndromes. The pathogenetic situation was summed up by Mitchell and Crues (1), who stated “articular disease may result from either an abnormal concentration of force across a joint with normal cartilage matrix or a normal concentration of force across an abnormal joint.” The general categories of hereditary noninflammatory arthropathy are listed in Table 163-1. Degenerative OA, especially of the weight-bearing joints, is a common complication in a large number of genetic skeletal dysplasias and disorders (2). Many of these conditions have been reviewed elsewhere in this book, but those that have not been covered in the context of OA are outlined in this chapter.
163.2 SPONDYLOEPIPHYSEAL DYSPLASIAS In the 1997 version of the International Nomenclature and Classification of Osteochondrodysplasias (3),
several conditions in the spondyloepiphyseal dysplasia (SED) category, in which the underlying defect has been elucidated, were listed as type II collagenopathies. This category was further refined in the 2002 update (4), the 2006 update (5) and most recently, in the 2010 update (6). Other disorders in this group, such as Langer– Saldino dysplasia (achondrogenesis type II), platyspondylic dysplasia, Torrance type, and hypochondrogenesis, present as lethal neonatal dwarfism and do not enter into a discussion of degenerative arthropathy. Equally, Kniest and Stickler syndromes, which are also linked to type II collagen in some affected families (7), and in which degenerative OA occurs together with other significant manifestations, have been fully reviewed in a previous chapter and are not considered further in this section. SEDs are characterized by predominant involvement of the vertebral bodies and epiphyses of the proximal joints, as well as considerable phenotypic and genetic heterogeneity; in some forms dwarfism with a characteristic shortened trunk is severe, while in others stature approaches normality. Myopia and hearing loss are variable syndromic components. The classical severe form of SED congenita (SEDC) is inherited as an autosomal dominant trait, and is recognizable at birth, but other, milder, autosomal dominant forms may only become evident in late childhood or early adulthood. Osteoarthropathy of the hip joint, which may be an end result of coxa vara of the hip and/or avascularnecrosis-like changes in the capital femoral epiphysis, is a major cause of handicap in several of these disorders, to the extent that prosthetic joint replacement may be necessary at a comparatively young age. This complication is also of considerable diagnostic significance as it may be the presenting feature of an otherwise mild generalized skeletal dysplasia. Genu valgum and increased laxity of the medial collateral ligament may also be present resulting in pain and degenerative changes in the knee. Linkage to the type II collagen gene (COL2A1) has been demonstrated in some families with classical SEDC
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TA B L E 1 6 3 - 1 The Hereditary Noninflammatory Arthropathies Defects of the Cartilage Matrix SED group of disorders, including Kniest and Stickler syndromes, and the familial hip joint dysplasias (Proven or possible defects of type II collagen) Alkaptonuria (Abnormal binding of polymers of homogentisic acid to cartilage collagen) Gout and pseudogout (Deposition of calcium pyrophosphate and hydroxyapatite crystals in the cartilage matrix) Infiltration and/or Aseptic Necrosis (Femoral Head) Storage disorders Wilson disease Hemochromatosis Gaucher, Fabry, and Farber diseases Hemoglobinopathies Mechanical Collapse due to Interaction of Primary Defects in Cartilage and External Forces (notably the femoral head) Skeletal dysplasias Hypermobility syndromes Primary Hip Joint Dysplasias Perthes disease Slipped femoral capital epiphyses Neuropathic Arthropathy Amyloidosis Charcot–Marie–Tooth syndrome Déjérine–Sottas syndrome Familial dysautonomia SED = spondyloepiphyseal dysplasia.
but not in others (8–14,81). This gene is situated on chromosome 12.q13.1–q13.2. In the same way, some of the milder, late-onset forms of autosomal dominant SED have been shown to be linked to type II collagen. For instance, in Namaqualand hip dysplasia, which has been diagnosed in 45 persons in five generations of a South African family (Figures 163-1–163-4), a logarithm of the odds (LOD) score of 7.98 indicates linkage to COL2A1 (15). More recently, a three-generation family in the United States with mild SEDC was reported with a novel Y-position proline substitution in the triple helical domain (Gly-X-Y) of the proα1(II) in COL2A1 (12). Conversely, a family of British stock with SEDC and generalized OA, living in Kimberly, does not show linkage (LOD 2.26) (16). The determinant gene in this kindred has been reported to be a null mutation in aggrecan (17,18). A mutation in aggrecan was also described in an autosomal recessive form of spondyloepimetaphyseal dysplasia (SEMD), aggrecan type (19). This was a missense mutation affecting the C-type lectin domain of the protein, and was detected in a Mexican family distinguished by severe short stature and a novel group of radiographic findings (19). A similar mutation was recently reported in a Swedish family with autosomal
dominant familial osteochondritis dissecans with mild short stature and early-onset osteoarthritis (20). Characterization of mutations in COL2A1 has been undertaken, and the Cardiff University Human Gene mutation database (21) lists at least 33 human mutations that have been described. There is great phenotypic variation in SED, making genotype–phenotype correlations more challenging (22) and it is possible that there are hot spots in this gene associated with some forms of mild SED in which OA occurs (23). Degenerative OA of the hip joint predominates in other dominant mild chondrodysplasias of SED type. In South Africa, Beukes hip dysplasia (Figure 163-5), named after a family of Dutch stock in which 47 persons in six generations are affected, is a disorder of this type (24). This condition has distinctive radiologic stigmata, and there is little doubt concerning its syndromic identity. Beukes hip dysplasia was shown to be not linked to COL2A1 (25), and the disease-associated gene was subsequently mapped to chromosome 4q35 (26). The osteochondrodysplasias that are of special importance in South Africa have been reviewed by Beighton (27). In the context of SED, it is noteworthy that in pseudoachondroplasia (PSACH) and some forms of multiple epiphyseal dysplasia (AD-MED), the disease-associated genes are allelic on chromosome 19. The phenotype in these conditions is the result of defective cartilage oligomeric matrix protein (COMP). Considerable intragenic heterogeneity is present, but the phenotypes are fairly consistent (28,29). AD-MED may also result from mutations in matrillin-3 (MAT3) and type IX collagen (30). It has now been shown that an unstable trinucleotide expansion in the COMP gene may be the causative mechanism (31). Contraction as well as expansion can occur in the PSACH/MED disorders, with either process producing the disease phenotype. Previously, expansions of this type had largely been recognized in genetic neurologic disorders, and the fact that they can also underlie skeletal disorders has important implications.
163.3 FAMILIAL OSTEOARTHROPATHY The major problems in the elucidation of the genetic determinants of OA are the considerable heterogeneity of the disorder and the great difficulty in precise phenotypic delineation of autonomous entities within this general category. Although OA is common, large families with apparent mendelian transmission of the condition are few and far between. Primary OA, or degenerative arthropathy, is a very common disorder of middle and old age. More than 80% of all persons over the age of 65 years have radiologic stigmata; of these individuals, about 25% are symptomatic. Risk factors include obesity and trauma, but it is not solely an age-related disorder and there is some evidence for a genetic component (32). The findings of the large-scale Framingham offspring investigation (33), and
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FIGURE 163-1 Namaqualand hip dysplasia in a branch of an affected South African family. The major manifestations are premature degenerative osteoarthropathy of the hip joint.
FIGURE 163-3 Namaqualand hip dysplasia. Anteroposterior radioFIGURE 163-2 Namaqualand hip dysplasia. Anteroposterior radio-
graphic view of an affected adult. The hips show advanced osteoarthropathy, with loss of joint space, irregularity, and distortion of the femoral heads, and patchy sclerosis and lucency.
the Baltimore longitudinal study (34) have also indicated that genetic factors are involved. Twin studies have been suggestive of a significant genetic component in OA of the hand and knee (35). It is possible, though unproven, that some “normal polymorphisms” of type II collagen might convey an increased propensity to the development of OA. It is also possible that subchondral bone may be primarily involved in the pathogenesis (36). The best example of familial OA is probably Heberden’s arthropathy. The influence of heredity in hand OA has been observed and studied in a variety of ways, including the assessment of relative risk in siblings, aggregation in families, and disease concordance in twins. Stecher in 1941 noted a hereditary disposition for
hand OA expression, with a twofold excess of disease in mothers and a threefold excess in sisters of patients with Heberden’s nodes compared with unrelated controls. (37). It is of historical interest that William Heberden (1710–1801), an English physician, gave the following account of the characteristic “nodi digitorum”: What are those little hard knobs, about the size of a small pea, which are frequently seen upon the fingers, particularly a little below the top, near the joint? They have no connexion with the gout, being found in persons who never had it; they continue for life; and being hardly ever attended with pain, or disposed to become sores, are rather unsightly, than inconvenient, though they must be some little hindrance to the free use of the fingers.
graphic view of an affected girl, showing early flattening and fragmentation of the femoral capital epiphyses.
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FIGURE 163-5 Beukes hip dysplasia. Anteroposterior radiographic view of an affected adult. The hips show gross osteoarthropathy and a valgus deformity of the femoral necks.
FIGURE 163-4 Namaqualand hip dysplasia. Lateral radiographic
view of the spine of a girl aged 10 years. The vertebral bodies show mild flattening and end-plate irregularity.
The form of generalized OA that is accompanied by Heberden’s nodes may represent a sex-influenced or sex-limited autosomal dominant trait (34). It has been suggested that females have a greater genetic liability to OA in general than men (38). A study by Jonsson et al. noted that sisters of patients with interphalangeal joint and first carpometacarpal (CMC1) joint OA have relative risks of 5.0 and 6.9, respectively, to develop OA in the same joint (39). The results of familial aggregation and twin studies provide strong evidence for an inherited predisposition to hand OA. The exact mode of inheritance remains unclear and multiple studies have resulted in reports of association or linkage with a variety of genetic loci (40).
Although this condition is common, the comparatively late onset poses difficulties for family studies and for linkage investigations with respect to the COL2A1 locus on chromosome 12 (41). An association between an aggrecan polymorphic allele and OA of the fingers has been proposed by Horton et al. (42), and the heritability of OA of the peripheral joints has been discussed by Bijkerk and associates (43). Kalichman et al. (44) undertook a clinical and radiologic investigation of OA of the hands in 1190 persons in 295 nuclear families in a homogenous population of Russian stock. In a sophisticated statistical analysis of their findings, the authors found some evidence of the activity of a major genetic determinant in OA. They could not, however, provide confirmation for a putative gene at 11q12 (45). Associations with MATN3 mutations have been reported for CMC1 joint involvement in an Icelandic population with familial hand osteoarthritis and also in a separate population with CMC1 OA of the hand with spine OA (46,47). Mutations in MATN3 have also been reported in AD-MED (48) and matrillin-3 polymorphisms have been associated with spinal disc degeneration and hand osteoarthritis (47). OA at the distal interphalangeal (DIP) and CMC1 joints can occur independently or in the same patient, and it has been suggested that CMC1 OA may need to be treated distinctly from interphalangeal joint OA, as susceptibility linkages may be joint-specific (39,49,50). A genetic linkage study by Hunter et al. found the highest heritabilities at CMC1 and DIP joints as well as the highest LOD scores (51). These investigators also concluded that a joint-specific approach to hand OA genetics may provide greater linkage, as evaluating hand OA as a general entity may decrease the strength of association (51).
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The type II collagen gene is a good candidate for the basic defect in primary OA, and linkage was reported more than a decade ago (52,53). This observation would have been of immense importance, in view of the very high frequency of OA in the population as a whole. On further study, however, it emerged that the condition in question was a mild chondrodysplasia with involvement of the vertebrae and epiphyses, and it could thus be categorized in the SED group of disorders (54,55). The pathogenesis of primary OA is still the subject of intensive investigation. A candidate gene approach to autosomal dominant nonsyndromic OA in a large Dutch family involved 14 collagen or collagen-related candidate genes, of which 10 were excluded (56). Following a radiographic survey in middle-aged persons in Holland, these authors undertook haplotype analysis and identified associations between generalized OA and three polymorphisms in the COL2A1 gene (57). Loughlin et al. (50) carried out a genomic screen and identified possible OA-related loci on chromosomes 4, 6, and 16. In a subsequent investigation that was focused on chromosome 6, they demonstrated linkage in females but not in males between primary OA of the hip and a locus at 6p12.3–q13, close to the COL9A1 gene. Further studies of this region using single nucleotide polymorphisms (SNPs) did not support the contention that COL9A1 was associated with primary OA (58). Possible linkage of OA to a locus on chromosome 2q has been reported (45,59,60). In an investigation in 69 persons in 22 Tasmanian families with digital OA and Heberden’s nodes, no linkage with the putative locus on 2q could be demonstrated (61). It is apparent that there is considerable nonallelic heterogeneity in generalized OA and that the genes that are involved differ in the degree to which they confer susceptibility. In view of the rapid progress in molecular genetics and the importance of OA, however, it seems very likely that determinant genes will be identified in the foreseeable future.
twins, concordance of OA hip was greater in the monzygous twins. The severity of OA was also greater in the monozygous pairs. The authors concluded that genetic factors made a significant contribution to OA of the hip in females (65). Populations of different genetic stock living in the same environment may provide clues; for instance, in Hawaii, total hip replacement rates are higher in whites than in Asians (66). Similarly, there is a very low prevalence of primary OA of the hip in Asian, black, and East Indian populations (67). In a large investigation in Iceland, using a database of total hip joint replacements undertaken between 1972 and 1996, family clustering was identified (68). Thereafter, a susceptibility locus on chromosome 16p was identified in a large family (LOD 2.58) (69). At the clinical, radiologic, histologic, and phenotypic levels, this familial OA of the hip was indistinguishable from the idiopathic, nonfamilial OA of the hip (70). The determinant genes for the α1 chain of type II collagen and the vitamin D receptor are adjacent loci on 12q. Granchi et al. (71) investigated polymorphic sites in these genes in 143 persons in whom hip joint replacement had been undertaken for primary or secondary OA. The findings were interpreted as providing evidence for a genetic component for the risk of OA in persons with severe hip dysplasia. Part of the heritability of hip OA may be explained by the hip morphology produced by many of the identified susceptibility genes, which are active during skeletal development (72). On the other hand, as with generalized OA, it is possible that collagen polymorphisms might be involved in the pathogenesis of OA of the hip. The Genetics, Osteoarthritis and Progression (GARP) study identified the deiodinase, iodothyronine, type II (D2) gene (DIO2) as a susceptibility gene for hip OA, and found that a mutation in this gene is more likely to increase the vulnerability of cartilage to non-optimal hip morphology instead of causing these shapes (73).
163.4 PRIMARY OSTEOARTHROPATHY OF THE HIP
163.5 MSELENI JOINT DISEASE
In the context of primary OA, the question arises as to whether or not OA of the hip joint, in the absence of significant involvement of other joints, is an independent genetic entity. This common disorder in middle age and advancing years is important, as prosthetic joint replacement is often required. Risk factors such as trauma, obesity, and possibly sporting activities apply but are by no means absolute; there is no obvious simple mode of inheritance, but genealogic studies are difficult because of the late onset. Family clustering has been documented (32,62,63), and twin studies have yielded positive results (64). In a comparative study of pelvic radiographs of 135 monozygous and 277 dizygous sets of healthy female
Mseleni joint disease (MJD) is a remarkable disorder that presents with widespread generalized degenerative OA in late childhood and causes severe crippling handicap in adulthood (74). The condition occurs in high frequency in an isolated area in northern KwaZuluNatal, South Africa, near the border with Mozambique, and was first described in 1970 (75). Many persons are affected, and the condition has a major socioeconomic impact; the only option for management is prosthetic hip joint replacement. A condition very similar to MJD, Kasin–Beck disease, occurs in the Urov valley of Siberia, parts of China, and North Korea (76). Selenium deficiency, aflatoxins in foodstuffs, and hypoxia (13) have been incriminated in the latter, but despite more than
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CHAPTER 163 Hereditary Noninflammatory Arthropathies
FIGURE 163-6 Mseleni joint disease. An affected woman in her
home environment. (From Agarwal, S. S.; Phadke, S. R.; Fredlund, V., et al. Mseleni and Handigodu Familial Osteoarthropathies: Syndromic Identity? Am. J. Med. Genet. 1997, 72, 435–439.)
two decades of intensive investigations, no environmental determinants have been identified for MJD. It is of interest that a disorder that resembles MJD, bearing the geographic designation “Handigodu joint disease,” has been documented in several villages in the Shimoga district of Southern India (77). To date, extensive research has yet to uncover the etiology of MJD. There is no evidence for mendelian inheritance patterns and epigenetic changes in response to the environment have been postulated (78). Type VI collagen has been shown to be overabundant in hip joint cartilage in affected adults undergoing joint replacement, but this finding may represent a secondary phenomenon (79). Among affected persons are dwarfed individuals (Figures 163-6 and 163-7) with the characteristic clinical and radiographic stigmata in severe degree (80). These small persons do not represent a continuum with their affected relatives, in whom stature is essentially normal. Equally, genealogic data do not indicate that they are homozygous for the faulty
FIGURE 163-7 Mseleni joint disease. Two affected adults with severe stunting of stature. (From Agarwal, S. S.; Phadke, S. R.; Fredlund, V., et al. Mseleni and Handigodu Familial Osteoarthropathies: Syndromic Identity? Am. J. Med. Genet. 1997, 72, 435–439.)
gene. The status of the brachydactylous dwarfs of Mseleni thus remains uncertain. By the end of 2004, there was anecdotal evidence that the incidence of MJD in the Mseleni region was diminishing rapidly. This observation, if substantiated, would be suggestive of the fluctuation of the influence of an unrecognized environmental agent.
ACKNOWLEDGMENTS I would like to thank Dr Beighton for writing the earlier editions of this chapter and for the use of his figures. I would like to express my appreciation for the mentorship and guidance of Professor Michael Weisman, Professor Jerome Rotter, and Professor Dan Cohn. I would also like to acknowledge the assistance of Alisa Wilson in the organization of the literature review. This work was supported in part by NIH grant 5K23AR056996 and NIH NCRR CTSI grant UL1RR033176.
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20. Stattin, E. -L.; Wiklund, F.; Lindblom, K., et al. A Missense Mutation in the Aggrecan C-Type Lectin Domain Disrupts Extracellular Matrix Interactions and Causes Dominant Familial Osteochondritis Dissecans. Am. J. Hum. Genet. 2010, 86, 126–137. 21. Institute of Medical Genetics in Cardiff. The Human Gene Mutation Database. http://www.hgmd.org 22. Kannu, P.; Bateman, J.; Savarirayan, R. Clinical Phenotypes Associated with Type II Collagen Mutations. J. Paediatr. Child. Health. 2011. 10.1111/j.1440–1754.2010.01979.x, Epub ahead of print. 23. Bleasel, J. F.; Holderbaum, D.; Mallock, V., et al. Hereditary Osteoarthritis with Mild Spondyloepiphyseal Dysplasia: Are there “Hot Spots” on COL2AI? J. Rheumatol. 1996, 23, 1594–1598. 24. Cilliers, H. J.; Beighton, P. Beukes Familial Hip Dysplasia: An Autosomal Dominant Entity. Am. J. Med. Genet. 1990, 36, 386–390. 25. Beighton, P.; Cilliers, H. J.; Ramesar, R. Autosomal Dominant (Beukes) Premature Degenerative Osteoarthropathy of the Hip Joint Unlinked to COL2A1. Am. J. Med. Genet. 1994, 53, 348–351. 26. Roby, P.; Eyre, S.; Worthington, J., et al. Letter to the Editor. Autosomal Dominant (Beukes) Premature Degenerative Osteoarthropathy of the Hip Joint Maps to an 11-cM Region on Chromosome 4q35. Am. J. Hum. Genet. 1999, 64, 904–908. 27. Beighton, P. Osteochondrodysplasias in South Africa. Am. J. Med. Genet. 1996, 63, 7–11. 28. Ballo, R.; Briggs, M. D.; Cohn, D. H., et al. Multiple Epiphyseal Dysplasia, Ribbing Type: A Novel Point Mutation in the COMP Gene in a South African Family. Am. J. Med. Genet. 1997, 69, 396–400. 29. Briggs, M. D.; Mortier, G. R.; Cole, W. G., et al. Diverse Mutations in the Gene Cartilage Oligomeric Matrix Protein in Pseudoachondroplasia–Multiple Epiphyseal Dysplasia Disease Spectrum. Am. J. Hum. Genet. 1998, 62, 311–319. 30. Jackson, G. C.; Mittaz-Crettol, L.; Taylor, J. A. Pseudoachondroplasia and Multiple Epiphyseal Dysplasia: A 7-Year Comprehensive Analysis of the Known Disease Genes Identifies Novel and Recurrent Mutations and Provides an Accurate Assessment of their Relative Contribution. Hum. Mutat. 2011. 10.1002/humu.21611, Epub ahead of print. 31. Delot, E.; King, L. M.; Briggs, M. D., et al. Trinucleotide Expansion Mutations in the Cartilage Oligomeric Matrix Protein (COMP) Gene. Hum. Mol. Genet. 1999, 8, 123–128. 32. Chitnavis, J.; Sinsheimer, J. S.; Clipsham, K., et al. Genetic Influences in End-Stage Osteoarthritis: Sibling Risks of Hip and Knee Replacement for Idiopathic Osteoarthritis. J. Bone. Joint. Surg. Br. 1997, 79, 660–664. 33. Felson, D. T.; Couropmitree, N. N.; Chaisson, C. E., et al. Evidence for a Mendelian Gene in a Segregation Analysis of Generalized Radiographic Osteoarthritis: The Framingham Study. Arthritis Rheum. 1998, 41, 1064–1071. 34. Hirsch, R.; Lethbridge-Cejku, M.; Hanson, R., et al. Familial Aggregation of Osteoarthritis: Data from the Baltimore Longitudinal Study on Ageing. Arthritis Rheum. 1998, 41, 1227–1232. 35. Spector, T. D.; Cicuttini, F.; Baker, J., et al. Genetic Influences on Osteoarthritis in Women: A Twin Study. BMJ 1996, 312, 940–943. 36. Dieple, P. Editorial. Osteoarthritis: Time to Shift the Paradigm. BMJ 1999, 318, 1299–1300. 37. Stecher, R. M. Heberden’s Nodes: Heredity in Hypertrophic Arthritis of the Finger Joints. Am. J. Med. Sci. 1941, 201, 801–809. 38. Kaprio, J.; Kujala, U. M.; Peltonen, L.; Koskenvuo, M. Genetic Liability to Osteoarthritis May Be Greater in Women than Men. BMJ 1996, 313, 232.
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39. Jonsson, H.; Manolescu, I.; Stefansson, S. E., et al. The Inheritance of Hand Osteoarthritis in Iceland. Arthritis Rheum. 2003, 48, 391–395. 40. Livshits, G.; Kalichman, L.; Cohen, Z.; Kobyliansky, E. Mode of Inheritance of Hand Osteoarthritis in Ethnically Homogenous Pedigrees. Hum. Biol. 2002, 74, 849–860. 41. Ritvanieme, P.; Korkko, J.; Bonaventure, J., et al. Identification of COL2A1 Gene Mutations in Patients with Chondrodysplasias and Familial Osteoarthritis. Arthritis Rheum. 1995, 38, 999–1004. 42. Horton, W. E., Jr.; Lethbridge-Cejku, M.; Hochberg, M. C., et al. An Association between an Aggrecan Polymorphic Allele and Bilateral Hand Osteoarthritis in Elderly White Men. Osteoarthr. Cartil. 1998, 6, 245–251. 43. Bijkerk, C.; Houwing-Duistermaat, J. J.; Valkenburg, H. A., et al. Heritabilities of Radiologic Osteoarthritis in Peripheral Joints and of Disc Degeneration of the Spine. Arthritis Rheum. 1999, 42, 1729–1735. 44. Kalichman, L.; Kobyliansky, E.; Malkin, I., et al. Search for Linkage between Hand Osteoarthritis and 11q12–13 Chromosomal Segment. Osteoarthr. Cartil. 2003, 11, 561–568. 45. Chapman, K.; Mustafa, Z.; Irven, C., et al. Osteoarthritis Susceptibility Locus on Chromosome 11q, Detected by Linkage. Am. J. Hum. Genet. 1999, 65, 167–174. 46. Stefansson, E.; Jonsson, H.; Ingvarsson, T., et al. GenomeWide Scan for Hand Osteoarthritis: A Novel Mutation in Matrillin-3. Am. J. Hum. Genet. 2003, 72, 1448–1459. 47. Min, J. L.; Meulenbelt, I.; Riyazi, N., et al. Association of Matrillin-3 Polymorphisms with Spinal Disc Degeneration and Osteoarthritis of the First Carpometacarpal Joint of the Hand. Ann. Rheum. Dis. 2006, 65, 1060–1066. 48. Chapman, K. L.; Mortier, G. R.; Chapman, K., et al. Mutations in the Region Encoding the von Willebrand Factor A Domain of Matrillin-3 Are Associated with Multiple Epiphyseal Dysplasia. Nat. Genet. 2001, 28, 393–396. 49. Demissie, S.; Cupples, L. A.; Myers, R., et al. Genome Scan for Quantity of Hand Osteoarthritis: The Framingham Study. Arthritis Rheum. 2002, 46, 946–952. 50. Loughlin, J.; Mustafa, Z.; Irven, C., et al. Stratification Analysis of an Osteoarthritis Genome Screen—Suggestive Linkage to Chromosomes 4, 6 and 16 [Letter]. Am. J. Hum. Genet. 1999, 65, 1795–1798. 51. Hunter, D. J.; Demissie, S.; Cupples, L. A., et al. A Genome Scan for Joint-Specific Hand Osteoarthritis Susceptibility: The Framingham Study. Arthritis Rheum. 2004, 50, 2489–2496. 52. Bleasel, J. F.; Poole, A. R.; Heinegarad, D., et al. Changes in Serum Cartilage Marker Levels Indicate Altered Cartilage Metabolism in Families with the Osteoarthritis-Related Type II Collagen Gene COL2A1 Mutation. Arthritis Rheum. 1999, 42, 39–45. 53. Palotie, A.; Ott, J.; Elima, K., et al. Predisposition to Familial Osteoarthritis Linked to Type II Collagen Gene. Lancet 1989, 1, 924–927. 54. Ala-Kokko, L.; Baldwin, C. T.; Moskowitz, R. W.; Prockop, D. J. Single Base Mutation in the Type II Procollagen Gene (COL2A1) as a Cause of Osteoarthritis Associated with Mild Chondrodysplasia. Proc. Natl. Acad. Sci. U.S.A 1990, 87, 6565–6568. 55. Knowlton, R. G.; Katzenstein, P. L.; Moskowitz, R. W., et al. Genetic Linkage of a Polymorphism in the Type II Procollagen Gene (COL2A1) to Primary Osteoarthritis Associated with Mild Chondrodysplasia. N. Engl. J. Med. 1990, 322, 526–530. 56. Meulenbelt, I.; Bijkerk, C.; Breedveld, F. C.; Slagboom, P. E. Genetic Linkage Analysis of 14 Candidate Gene Loci in a Family with Autosomal Dominant Osteoarthritis Without Dysplasia. J. Med. Genet. 1997, 34, 1024–1027.
57. Meulenbelt, I.; Bijkerk, C.; De Wildt, S. C.M., et al. Haplotype Analysis of Three Polymorphisms of the COL2A1 Gene and Association with Generalised Radiological Osteoarthritis. Ann. Hum. Genet. 1999, 63, 393–400. 58. Loughlin, J.; Mustafa, Z.; Dowling, B., et al. Finer Linkage Mapping of a Primary Hip Osteoarthritis Susceptibility Locus on Chromosome 6. Eur. J. Hum. Genet. 2002, 10, 562–568. 59. Leppsvuori, J. K.; Kujula, U. M.; Kaprio, J., et al. Genome Scan for Predisposing Loci of Distal Interphalangeal Joint Osteoarthritis. Am. J. Hum. Genet. 1998, 63, A297. 60. Wright, G. D.; Hughes, A. E.; Regan, M., et al. Association of Two Loci on Chromosome 2q with Nodal Osteoarthritis. Ann. Rheum. Dis. 1996, 55, 317–319. 61. Stankovich, J.; Sale, M. M.; Colley, H. M., et al. Investigation of Chromosome 2q in Osteoarthritis of the Hand: No Significant Linkage in a Tasmanian Population. Ann. Rheum. Dis. 2002, 61, 1081–1084. 62. Lanyon, P.; Doherty, S.; Muir, K.; Doherty, S. Strong Genetic Predisposition to Hip Osteoarthritis. Arthritis Rheum. 1998, 41, S351. 63. Lindberg, H. Prevalence of Primary Coxarthritis in Siblings of Patients with Primary Coxarthritis. Clin. Orthop. 1986, 203, 273–275. 64. MacGregor, A. J.; Spector, T. D. Twins and the Genetic Architecture of Osteoarthritis. Rheumatology (Oxford) 1999, 38, 583–588. 65. MacGregor, A. J.; Antoniades, L.; Matson, M., et al. The Genetic Contribution to Radiographic Hip Osteoarthritis in Women: Results of a Classic Twin Study. Arthritis Rheum. 2000, 43, 2410–2416. 66. Oishi, C. S.; Hoaglund, F. T.; Gordon, L.; Ross, P. D. Total Hip Replacement Rates Are Higher Among Caucasians than Asians in Hawaii. Clin. Orthop. 1998, 353, 166–174. 67. Hoaglund, F. T.; Steinbach, L. S. Primary Osteoarthritis of the Hip: Etiology and Epidemiology. J. Am. Acad. Orthop. Surg. 2001, 9, 320–327. 68. Ingvarsson, T.; Stefansson, S. E.; Hallgrimsdottir, I. B., et al. The Inheritance of Hip Osteoarthritis in Iceland. Arthritis Rheum. 2000, 43, 2785–2792. 69. Ingvarsson, T.; Stefansson, S. E.; Gulcher, J. R., et al. A Large Icelandic Family with Early Osteoarthritis of the Hip Associated with a Susceptibility Locus on Chromosome 16p. Arthritis Rheum. 2001, 44, 2548–2555. 70. Ingvarsson, T. Prevalence and Inheritance of Hip Osteoarthritis in Iceland. Acta. Orthop. Scand. Suppl. 2000, 298, 1–46. 71. Granchi, D.; Stea, S.; Sudanese, A., et al. Association of Two Gene Polymorphisms with Osteoarthritis Secondary to Hip Dysplasia. Clin. Orthop. 2002, 403, 108–117. 72. Slagboom, E.; Meulenbelt, I. Genetics of Osteoarthritis: Early Developmental Clues to an Old Disease. Nat. Clin. Pract. Rheumatol. 2008, 4, 563. 73. Waarsing, J. H.; Kloppenburg, M.; Slagboom, P. E., et al. Osteoarthritis Susceptibility Genes Influence the Association Between Hip Morphology and Osteoarthritis. Arthritis Rheum. 2011, 63, 1349–1354. 74. Du Toit, G. T. Hip Disease of Mseleni. Clin. Orthop. 1979, 141, 223–236. 75. Wittman, W.; Fellingham, S. A. Unusual Hip Disease in Remote Part of Zululand. Lancet 1970, 295, 852–853. 76. Sokoloff, L. Endemic Forms of Osteoarthritis. Clin. Rheum. Dis. 1985, 11, 187–202. 77. Agarwal, S. S.; Phadke, S. R.; Fredlund, V., et al. Mseleni and Handigodu Familial Osteoarthropathies: Syndromic Identity? Am. J. Med. Genet. 1997, 72, 435–439. 78. Gibbon, V. E.; Harington, J. S.; Penny, C. B.; Fredlund, V. Mseleni Joint Disease: A Potential Model of Epigenetic Chondrodysplasia. Joint Bone Spine 2010, 77, 399–404.
CHAPTER 163 Hereditary Noninflammatory Arthropathies 79. Ballo, R.; Viljoen, D.; Machado, M., et al. Mseleni Joint Disease—A Molecular Genetic Approach to Defining the Aetiology. S. Afr. Med. J. 1996, 86, 956–958. 80. Viljoen, D.; Fredlund, V.; Ramesar, R.; Beighton, P. Brachydactylous Dwarfs of Mseleni. Am. J. Med. Genet. 1993, 46, 636–640.
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81. Xia, X.; Cui, Y.; Huang, Y., et al. A First Familial G504S Mutation of COL2A1 Gene Results in Distinctive Spondyloepiphyseal Dysplasia Congenita. Clin. Chim. Acta. 2007, 382, 148–150.
Biography Mariko L Ishimori, MD, is currently Assistant Professor of Medicine at Cedars-Sinai Medical Center in Los Angeles, CA, and Assistant Health Sciences Clinical Professor of Medicine at the David Geffen School of Medicine at UCLA. Dr Ishimori’s research interest involves the genetic study of osteoarthritis and lupus nephritis as well as clinical studies in hand osteoarthritis and systemic lupus erythematosus. She has received funding from the General Clinical Research Centers (now Clinical and Translational Science Institute (CTSI)), the American College of Rheumatology, the Arthritis Foundation, and the National Institutes of Health for her research.
163
Hereditary Noninflammatory Arthropathies Mariko L Ishimori Division of Rheumatology, Cedar-Sinai Medical Center, Los Angeles, CA, USA This article is a revision of the previous edition article by Peter H Beighton, volume 3, pp 3865–3871, © 2007, Elsevier Ltd.
163.1 INTRODUCTION Noninflammatory arthropathy is a major manifestation of a number of genetic disorders. There is a great variety of phenotypes, which present a diagnostic challenge in the clinical setting. In some of these conditions this arthropathy is generalized, while in others it predominates in the hip joints, with or without significant involvement of the spine. Degenerative osteoarthropathy (OA) is the end result of a number of different pathologic processes that culminate in cartilage degeneration, with remodeling and proliferation of new bone. The underlying mechanisms may involve disturbances in skeletal development; minor abnormalities of the cartilage matrix itself, notably, genetic defects of type II collagen; infiltration, as in certain storage disorders; and aseptic necrosis, as in the hemoglobinopathies. In addition, neuropathic joints develop in some hereditary neurologic conditions. Environmental factors may also play a role, and the interaction of primary defects in cartilage and abnormal external forces may be the pathogenetic determinants in some bone dysplasias and hypermobility syndromes. The pathogenetic situation was summed up by Mitchell and Crues (1), who stated “articular disease may result from either an abnormal concentration of force across a joint with normal cartilage matrix or a normal concentration of force across an abnormal joint.” The general categories of hereditary noninflammatory arthropathy are listed in Table 163-1. Degenerative OA, especially of the weight-bearing joints, is a common complication in a large number of genetic skeletal dysplasias and disorders (2). Many of these conditions have been reviewed elsewhere in this book, but those that have not been covered in the context of OA are outlined in this chapter.
163.2 SPONDYLOEPIPHYSEAL DYSPLASIAS In the 1997 version of the International Nomenclature and Classification of Osteochondrodysplasias (3),
several conditions in the spondyloepiphyseal dysplasia (SED) category, in which the underlying defect has been elucidated, were listed as type II collagenopathies. This category was further refined in the 2002 update (4), the 2006 update (5) and most recently, in the 2010 update (6). Other disorders in this group, such as Langer– Saldino dysplasia (achondrogenesis type II), platyspondylic dysplasia, Torrance type, and hypochondrogenesis, present as lethal neonatal dwarfism and do not enter into a discussion of degenerative arthropathy. Equally, Kniest and Stickler syndromes, which are also linked to type II collagen in some affected families (7), and in which degenerative OA occurs together with other significant manifestations, have been fully reviewed in a previous chapter and are not considered further in this section. SEDs are characterized by predominant involvement of the vertebral bodies and epiphyses of the proximal joints, as well as considerable phenotypic and genetic heterogeneity; in some forms dwarfism with a characteristic shortened trunk is severe, while in others stature approaches normality. Myopia and hearing loss are variable syndromic components. The classical severe form of SED congenita (SEDC) is inherited as an autosomal dominant trait, and is recognizable at birth, but other, milder, autosomal dominant forms may only become evident in late childhood or early adulthood. Osteoarthropathy of the hip joint, which may be an end result of coxa vara of the hip and/or avascularnecrosis-like changes in the capital femoral epiphysis, is a major cause of handicap in several of these disorders, to the extent that prosthetic joint replacement may be necessary at a comparatively young age. This complication is also of considerable diagnostic significance as it may be the presenting feature of an otherwise mild generalized skeletal dysplasia. Genu valgum and increased laxity of the medial collateral ligament may also be present resulting in pain and degenerative changes in the knee. Linkage to the type II collagen gene (COL2A1) has been demonstrated in some families with classical SEDC
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TA B L E 1 6 3 - 1 The Hereditary Noninflammatory Arthropathies Defects of the Cartilage Matrix SED group of disorders, including Kniest and Stickler syndromes, and the familial hip joint dysplasias (Proven or possible defects of type II collagen) Alkaptonuria (Abnormal binding of polymers of homogentisic acid to cartilage collagen) Gout and pseudogout (Deposition of calcium pyrophosphate and hydroxyapatite crystals in the cartilage matrix) Infiltration and/or Aseptic Necrosis (Femoral Head) Storage disorders Wilson disease Hemochromatosis Gaucher, Fabry, and Farber diseases Hemoglobinopathies Mechanical Collapse due to Interaction of Primary Defects in Cartilage and External Forces (notably the femoral head) Skeletal dysplasias Hypermobility syndromes Primary Hip Joint Dysplasias Perthes disease Slipped femoral capital epiphyses Neuropathic Arthropathy Amyloidosis Charcot–Marie–Tooth syndrome Déjérine–Sottas syndrome Familial dysautonomia SED = spondyloepiphyseal dysplasia.
but not in others (8–14,81). This gene is situated on chromosome 12.q13.1–q13.2. In the same way, some of the milder, late-onset forms of autosomal dominant SED have been shown to be linked to type II collagen. For instance, in Namaqualand hip dysplasia, which has been diagnosed in 45 persons in five generations of a South African family (Figures 163-1–163-4), a logarithm of the odds (LOD) score of 7.98 indicates linkage to COL2A1 (15). More recently, a three-generation family in the United States with mild SEDC was reported with a novel Y-position proline substitution in the triple helical domain (Gly-X-Y) of the proα1(II) in COL2A1 (12). Conversely, a family of British stock with SEDC and generalized OA, living in Kimberly, does not show linkage (LOD 2.26) (16). The determinant gene in this kindred has been reported to be a null mutation in aggrecan (17,18). A mutation in aggrecan was also described in an autosomal recessive form of spondyloepimetaphyseal dysplasia (SEMD), aggrecan type (19). This was a missense mutation affecting the C-type lectin domain of the protein, and was detected in a Mexican family distinguished by severe short stature and a novel group of radiographic findings (19). A similar mutation was recently reported in a Swedish family with autosomal
dominant familial osteochondritis dissecans with mild short stature and early-onset osteoarthritis (20). Characterization of mutations in COL2A1 has been undertaken, and the Cardiff University Human Gene mutation database (21) lists at least 33 human mutations that have been described. There is great phenotypic variation in SED, making genotype–phenotype correlations more challenging (22) and it is possible that there are hot spots in this gene associated with some forms of mild SED in which OA occurs (23). Degenerative OA of the hip joint predominates in other dominant mild chondrodysplasias of SED type. In South Africa, Beukes hip dysplasia (Figure 163-5), named after a family of Dutch stock in which 47 persons in six generations are affected, is a disorder of this type (24). This condition has distinctive radiologic stigmata, and there is little doubt concerning its syndromic identity. Beukes hip dysplasia was shown to be not linked to COL2A1 (25), and the disease-associated gene was subsequently mapped to chromosome 4q35 (26). The osteochondrodysplasias that are of special importance in South Africa have been reviewed by Beighton (27). In the context of SED, it is noteworthy that in pseudoachondroplasia (PSACH) and some forms of multiple epiphyseal dysplasia (AD-MED), the disease-associated genes are allelic on chromosome 19. The phenotype in these conditions is the result of defective cartilage oligomeric matrix protein (COMP). Considerable intragenic heterogeneity is present, but the phenotypes are fairly consistent (28,29). AD-MED may also result from mutations in matrillin-3 (MAT3) and type IX collagen (30). It has now been shown that an unstable trinucleotide expansion in the COMP gene may be the causative mechanism (31). Contraction as well as expansion can occur in the PSACH/MED disorders, with either process producing the disease phenotype. Previously, expansions of this type had largely been recognized in genetic neurologic disorders, and the fact that they can also underlie skeletal disorders has important implications.
163.3 FAMILIAL OSTEOARTHROPATHY The major problems in the elucidation of the genetic determinants of OA are the considerable heterogeneity of the disorder and the great difficulty in precise phenotypic delineation of autonomous entities within this general category. Although OA is common, large families with apparent mendelian transmission of the condition are few and far between. Primary OA, or degenerative arthropathy, is a very common disorder of middle and old age. More than 80% of all persons over the age of 65 years have radiologic stigmata; of these individuals, about 25% are symptomatic. Risk factors include obesity and trauma, but it is not solely an age-related disorder and there is some evidence for a genetic component (32). The findings of the large-scale Framingham offspring investigation (33), and
CHAPTER 163 Hereditary Noninflammatory Arthropathies
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FIGURE 163-1 Namaqualand hip dysplasia in a branch of an affected South African family. The major manifestations are premature degenerative osteoarthropathy of the hip joint.
FIGURE 163-3 Namaqualand hip dysplasia. Anteroposterior radioFIGURE 163-2 Namaqualand hip dysplasia. Anteroposterior radio-
graphic view of an affected adult. The hips show advanced osteoarthropathy, with loss of joint space, irregularity, and distortion of the femoral heads, and patchy sclerosis and lucency.
the Baltimore longitudinal study (34) have also indicated that genetic factors are involved. Twin studies have been suggestive of a significant genetic component in OA of the hand and knee (35). It is possible, though unproven, that some “normal polymorphisms” of type II collagen might convey an increased propensity to the development of OA. It is also possible that subchondral bone may be primarily involved in the pathogenesis (36). The best example of familial OA is probably Heberden’s arthropathy. The influence of heredity in hand OA has been observed and studied in a variety of ways, including the assessment of relative risk in siblings, aggregation in families, and disease concordance in twins. Stecher in 1941 noted a hereditary disposition for
hand OA expression, with a twofold excess of disease in mothers and a threefold excess in sisters of patients with Heberden’s nodes compared with unrelated controls. (37). It is of historical interest that William Heberden (1710–1801), an English physician, gave the following account of the characteristic “nodi digitorum”: What are those little hard knobs, about the size of a small pea, which are frequently seen upon the fingers, particularly a little below the top, near the joint? They have no connexion with the gout, being found in persons who never had it; they continue for life; and being hardly ever attended with pain, or disposed to become sores, are rather unsightly, than inconvenient, though they must be some little hindrance to the free use of the fingers.
graphic view of an affected girl, showing early flattening and fragmentation of the femoral capital epiphyses.
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CHAPTER 163 Hereditary Noninflammatory Arthropathies
FIGURE 163-5 Beukes hip dysplasia. Anteroposterior radiographic view of an affected adult. The hips show gross osteoarthropathy and a valgus deformity of the femoral necks.
FIGURE 163-4 Namaqualand hip dysplasia. Lateral radiographic
view of the spine of a girl aged 10 years. The vertebral bodies show mild flattening and end-plate irregularity.
The form of generalized OA that is accompanied by Heberden’s nodes may represent a sex-influenced or sex-limited autosomal dominant trait (34). It has been suggested that females have a greater genetic liability to OA in general than men (38). A study by Jonsson et al. noted that sisters of patients with interphalangeal joint and first carpometacarpal (CMC1) joint OA have relative risks of 5.0 and 6.9, respectively, to develop OA in the same joint (39). The results of familial aggregation and twin studies provide strong evidence for an inherited predisposition to hand OA. The exact mode of inheritance remains unclear and multiple studies have resulted in reports of association or linkage with a variety of genetic loci (40).
Although this condition is common, the comparatively late onset poses difficulties for family studies and for linkage investigations with respect to the COL2A1 locus on chromosome 12 (41). An association between an aggrecan polymorphic allele and OA of the fingers has been proposed by Horton et al. (42), and the heritability of OA of the peripheral joints has been discussed by Bijkerk and associates (43). Kalichman et al. (44) undertook a clinical and radiologic investigation of OA of the hands in 1190 persons in 295 nuclear families in a homogenous population of Russian stock. In a sophisticated statistical analysis of their findings, the authors found some evidence of the activity of a major genetic determinant in OA. They could not, however, provide confirmation for a putative gene at 11q12 (45). Associations with MATN3 mutations have been reported for CMC1 joint involvement in an Icelandic population with familial hand osteoarthritis and also in a separate population with CMC1 OA of the hand with spine OA (46,47). Mutations in MATN3 have also been reported in AD-MED (48) and matrillin-3 polymorphisms have been associated with spinal disc degeneration and hand osteoarthritis (47). OA at the distal interphalangeal (DIP) and CMC1 joints can occur independently or in the same patient, and it has been suggested that CMC1 OA may need to be treated distinctly from interphalangeal joint OA, as susceptibility linkages may be joint-specific (39,49,50). A genetic linkage study by Hunter et al. found the highest heritabilities at CMC1 and DIP joints as well as the highest LOD scores (51). These investigators also concluded that a joint-specific approach to hand OA genetics may provide greater linkage, as evaluating hand OA as a general entity may decrease the strength of association (51).
CHAPTER 163 Hereditary Noninflammatory Arthropathies
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The type II collagen gene is a good candidate for the basic defect in primary OA, and linkage was reported more than a decade ago (52,53). This observation would have been of immense importance, in view of the very high frequency of OA in the population as a whole. On further study, however, it emerged that the condition in question was a mild chondrodysplasia with involvement of the vertebrae and epiphyses, and it could thus be categorized in the SED group of disorders (54,55). The pathogenesis of primary OA is still the subject of intensive investigation. A candidate gene approach to autosomal dominant nonsyndromic OA in a large Dutch family involved 14 collagen or collagen-related candidate genes, of which 10 were excluded (56). Following a radiographic survey in middle-aged persons in Holland, these authors undertook haplotype analysis and identified associations between generalized OA and three polymorphisms in the COL2A1 gene (57). Loughlin et al. (50) carried out a genomic screen and identified possible OA-related loci on chromosomes 4, 6, and 16. In a subsequent investigation that was focused on chromosome 6, they demonstrated linkage in females but not in males between primary OA of the hip and a locus at 6p12.3–q13, close to the COL9A1 gene. Further studies of this region using single nucleotide polymorphisms (SNPs) did not support the contention that COL9A1 was associated with primary OA (58). Possible linkage of OA to a locus on chromosome 2q has been reported (45,59,60). In an investigation in 69 persons in 22 Tasmanian families with digital OA and Heberden’s nodes, no linkage with the putative locus on 2q could be demonstrated (61). It is apparent that there is considerable nonallelic heterogeneity in generalized OA and that the genes that are involved differ in the degree to which they confer susceptibility. In view of the rapid progress in molecular genetics and the importance of OA, however, it seems very likely that determinant genes will be identified in the foreseeable future.
twins, concordance of OA hip was greater in the monzygous twins. The severity of OA was also greater in the monozygous pairs. The authors concluded that genetic factors made a significant contribution to OA of the hip in females (65). Populations of different genetic stock living in the same environment may provide clues; for instance, in Hawaii, total hip replacement rates are higher in whites than in Asians (66). Similarly, there is a very low prevalence of primary OA of the hip in Asian, black, and East Indian populations (67). In a large investigation in Iceland, using a database of total hip joint replacements undertaken between 1972 and 1996, family clustering was identified (68). Thereafter, a susceptibility locus on chromosome 16p was identified in a large family (LOD 2.58) (69). At the clinical, radiologic, histologic, and phenotypic levels, this familial OA of the hip was indistinguishable from the idiopathic, nonfamilial OA of the hip (70). The determinant genes for the α1 chain of type II collagen and the vitamin D receptor are adjacent loci on 12q. Granchi et al. (71) investigated polymorphic sites in these genes in 143 persons in whom hip joint replacement had been undertaken for primary or secondary OA. The findings were interpreted as providing evidence for a genetic component for the risk of OA in persons with severe hip dysplasia. Part of the heritability of hip OA may be explained by the hip morphology produced by many of the identified susceptibility genes, which are active during skeletal development (72). On the other hand, as with generalized OA, it is possible that collagen polymorphisms might be involved in the pathogenesis of OA of the hip. The Genetics, Osteoarthritis and Progression (GARP) study identified the deiodinase, iodothyronine, type II (D2) gene (DIO2) as a susceptibility gene for hip OA, and found that a mutation in this gene is more likely to increase the vulnerability of cartilage to non-optimal hip morphology instead of causing these shapes (73).
163.4 PRIMARY OSTEOARTHROPATHY OF THE HIP
163.5 MSELENI JOINT DISEASE
In the context of primary OA, the question arises as to whether or not OA of the hip joint, in the absence of significant involvement of other joints, is an independent genetic entity. This common disorder in middle age and advancing years is important, as prosthetic joint replacement is often required. Risk factors such as trauma, obesity, and possibly sporting activities apply but are by no means absolute; there is no obvious simple mode of inheritance, but genealogic studies are difficult because of the late onset. Family clustering has been documented (32,62,63), and twin studies have yielded positive results (64). In a comparative study of pelvic radiographs of 135 monozygous and 277 dizygous sets of healthy female
Mseleni joint disease (MJD) is a remarkable disorder that presents with widespread generalized degenerative OA in late childhood and causes severe crippling handicap in adulthood (74). The condition occurs in high frequency in an isolated area in northern KwaZuluNatal, South Africa, near the border with Mozambique, and was first described in 1970 (75). Many persons are affected, and the condition has a major socioeconomic impact; the only option for management is prosthetic hip joint replacement. A condition very similar to MJD, Kasin–Beck disease, occurs in the Urov valley of Siberia, parts of China, and North Korea (76). Selenium deficiency, aflatoxins in foodstuffs, and hypoxia (13) have been incriminated in the latter, but despite more than
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CHAPTER 163 Hereditary Noninflammatory Arthropathies
FIGURE 163-6 Mseleni joint disease. An affected woman in her
home environment. (From Agarwal, S. S.; Phadke, S. R.; Fredlund, V., et al. Mseleni and Handigodu Familial Osteoarthropathies: Syndromic Identity? Am. J. Med. Genet. 1997, 72, 435–439.)
two decades of intensive investigations, no environmental determinants have been identified for MJD. It is of interest that a disorder that resembles MJD, bearing the geographic designation “Handigodu joint disease,” has been documented in several villages in the Shimoga district of Southern India (77). To date, extensive research has yet to uncover the etiology of MJD. There is no evidence for mendelian inheritance patterns and epigenetic changes in response to the environment have been postulated (78). Type VI collagen has been shown to be overabundant in hip joint cartilage in affected adults undergoing joint replacement, but this finding may represent a secondary phenomenon (79). Among affected persons are dwarfed individuals (Figures 163-6 and 163-7) with the characteristic clinical and radiographic stigmata in severe degree (80). These small persons do not represent a continuum with their affected relatives, in whom stature is essentially normal. Equally, genealogic data do not indicate that they are homozygous for the faulty
FIGURE 163-7 Mseleni joint disease. Two affected adults with severe stunting of stature. (From Agarwal, S. S.; Phadke, S. R.; Fredlund, V., et al. Mseleni and Handigodu Familial Osteoarthropathies: Syndromic Identity? Am. J. Med. Genet. 1997, 72, 435–439.)
gene. The status of the brachydactylous dwarfs of Mseleni thus remains uncertain. By the end of 2004, there was anecdotal evidence that the incidence of MJD in the Mseleni region was diminishing rapidly. This observation, if substantiated, would be suggestive of the fluctuation of the influence of an unrecognized environmental agent.
ACKNOWLEDGMENTS I would like to thank Dr Beighton for writing the earlier editions of this chapter and for the use of his figures. I would like to express my appreciation for the mentorship and guidance of Professor Michael Weisman, Professor Jerome Rotter, and Professor Dan Cohn. I would also like to acknowledge the assistance of Alisa Wilson in the organization of the literature review. This work was supported in part by NIH grant 5K23AR056996 and NIH NCRR CTSI grant UL1RR033176.
CHAPTER 163 Hereditary Noninflammatory Arthropathies
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Biography Mariko L Ishimori, MD, is currently Assistant Professor of Medicine at Cedars-Sinai Medical Center in Los Angeles, CA, and Assistant Health Sciences Clinical Professor of Medicine at the David Geffen School of Medicine at UCLA. Dr Ishimori’s research interest involves the genetic study of osteoarthritis and lupus nephritis as well as clinical studies in hand osteoarthritis and systemic lupus erythematosus. She has received funding from the General Clinical Research Centers (now Clinical and Translational Science Institute (CTSI)), the American College of Rheumatology, the Arthritis Foundation, and the National Institutes of Health for her research.