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Current Concepts Review - Update on the Genetic Bases of Disorders with Orthopaedic Manifestations*

FREDERICK R. DIETZ, M.D. and KATHERINE D. MATHEWS, M.D., IOWA CITY, IOWA

Investigation performed at the University of Iowa Hospitals and Clinics, Iowa City

	Introduction

Top Introduction Skeletal Dysplasias Metabolic Bone Diseases Connective-Tissue Disorders Neuromuscular Disorders Miscellaneous Syndromes and... Disorders with Complex... The Orthopaedic Surgeon and... References

 
New technology in molecular biology and quantitative analysis has led to an explosion of the knowledge and understanding of inherited diseases. Efforts to map the entire human genome have progressed further than had been expected. Gene therapy is being investigated for possible use in the treatment of a host of diseases, ranging from cystic fibrosis to cancer. Diagnosis before the development of symptoms is possible for people at risk for some diseases with a delayed onset, such as Huntington disease, Alzheimer disease, and familial breast cancer.

Advances in analytical and molecular tools in the 1980's made it feasible, for the first time, to begin sequencing the three billion nucleotides of DNA that make up the human genome. The Human Genome Project, an international effort, was initiated under the auspices of the human gene-mapping conferences and was formalized through the Human Genome Organization (HUGO). In the United States, the efforts have been jointly funded and coordinated by the National Institutes of Health and the Department of Energy since 1990, although private organizations also have played a prominent role. In addition to supporting scientific inquiry, the National Institutes of Health and the Department of Energy have allocated approximately 5 per cent of their funding for the human genome project for the study of the ethical, legal, and social issues relating to that project.

In the first five years in which funding was provided, substantial progress was made toward an initial set of primary goals²⁸ that included the development of high-resolution genetic maps⁷³, improvements in analytical strategies⁵¹, and tremendous increases in the numbers of available polymorphic markers, physical mapping reagents, and mapped genes. At the present time, genetic maps composed of markers that are easy to use, inexpensive, and efficient (that is, those that are based on a polymerase chain reaction) make it practical for even groups of a few individuals to map genes in only a few years. This is in contrast to the hundreds of person-years that were required for earlier successful searches, such as those that resulted in the discovery of the causative gene for cystic fibrosis. Similarly, advances in analysis allow the practical study of even complex disorders such as clubfoot or scoliosis. Because of the tremendous strides in physical mapping, once a gene is localized by this means the gene itself may be more quickly identified. There is now an emphasis on finding and mapping of all of the approximately 80,000 human genes along with mouse homologs. An effort to complete the full human DNA sequence has recently been initiated and is likely to be completed in the next fifteen years. In the last five years alone, the number of polymorphisms has increased from 2000 to 15,000; the number of mapped genes, from 1500 to more than 8000; and the amount of DNA sequenced in humans, from five million to more than fifty million base pairs.

The causative genes for many conditions, including skeletal dysplasias (achondroplasia, multiple epiphyseal dysplasia, pseudoachondroplasia, spondyloepiphyseal dysplasia, diastrophic dysplasia, metaphyseal chondrodysplasia, and precocious osteoarthrosis), connective-tissue disorders (Marfan syndrome and Ehlers-Danlos syndrome), metabolic diseases (osteoporosis, osteopetrosis, and hypophosphatemic rickets,), muscular dystrophies (Duchenne and Becker dystrophy, limb-girdle dystrophy, facioscapulohumeral dystrophy, and myotonic dystrophy), peripheral neuropathies (Charcot-Marie-Tooth disease), and syndromes with orthopaedic manifestations (McCune-Albright polyostotic fibrous dysplasia, Apert syndrome, and distal arthrogryposis) have been identified or localized by investigators. The mechanisms by which mutations in the disease-causing genes result in the disease phenotype are being actively investigated. These investigations are producing new information concerning the biology of normal and abnormal growth and development and tissue function at the molecular level.

Gene-mapping and identification is only the initial step toward understanding the complex biological interactions that must be defined if this information is to be used therapeutically. After a disease-causing gene is identified, cell biologists, embryologists, biochemists, clinicians, anatomists, physiologists, and others must work together to make sense of the preliminary data in ways that will benefit patients and their families.

Little of this information appears in the literature directed at orthopaedic surgeons for two main reasons. First, orthopaedics is a treatment-oriented field of medicine and none of the new information, to date, affects orthopaedic treatment of patients. Second, geneticists and epidemiologists report their work with use of a vocabulary and mathematics that are unfamiliar to most orthopaedic surgeons who are not recent graduates from medical school. Excessive background information is required to present any new results in an intelligible fashion in an orthopaedic journal.

Nonetheless, abnormal genes are the basis of many orthopaedic disorders, ranging from skeletal dysplasias to osteoarthrosis. If orthopaedic surgeons wish to remain orthopaedic physicians, and not be mere operative technicians, they must be aware of this new information. There are more concrete reasons to be familiar with this information. One is that patients' confidence will decrease if they find orthopaedists unaware that the genetic cause is known for the disease for which they are being treated. Another is that orthopaedists must be familiar with new information in order to refer patients appropriately for genetic counseling. A third reason is that specific diagnoses based on genotype as well as phenotype will refine orthopaedists' ability to determine the prognosis for many disorders. Fourth, patients constitute a resource from which new knowledge is gained. Awareness of investigations in progress will allow orthopaedists to collaborate with those performing research. A single patient who has a rare translocation or deletion can provide the key for identifying a disease-causing gene; this occurred in the search for the gene that causes Duchenne muscular dystrophy⁵⁰. Finally, orthopaedists' knowledge regarding primarily orthopaedic disorders can aid in the search for their causes. Accuracy in diagnosis for the patients who are being studied is vital in the common approaches that are used for isolating disease-causing genes. Assigning the correct diagnosis is not always straightforward. An idiopathic clubfoot is more readily identified by an orthopaedist than by a pediatrician or a geneticist. Including the wrong diseases in a genetic analysis (misascertainment) can delay or misdirect the investigation. Furthermore, orthopaedists' knowledge of the pathological characteristics of orthopaedic disorders can help researchers to select appropriate candidate genes for investigation.

The approach that is most commonly used to find a new gene is positional cloning (previously called reverse genetics). This is performed by finding an allele of a polymorphic marker of known location that is inherited with the disease more commonly in a family than would occur by chance. This significant association suggests that the disease-causing gene is near the polymorphic marker. The marker and the disease are said to be linked.

After the approximate chromosomal location is found by linkage, genes in this region are isolated. When a biologically plausible gene is shown to be mutated in patients who have the disease, it is probable that this is the causative gene. If that is confirmed, it is possible that diagnostic testing can be carried out on the basis of analysis of an individual's DNA or the protein product of the gene.

Another approach to identifying disease-causing genes is the candidate-gene approach, and this may prove more valuable than positional cloning for the investigation of orthopaedic disorders with complex patterns of inheritance. Positional cloning requires the study of families with many affected members, but families in which many members have a disorder with a complex pattern of inheritance are rare. With the candidate-gene approach, an understanding of the biology of the disorder is used to suggest genes that may be involved in the pathogenesis. Polymorphisms in the candidate genes are directly investigated with a variety of statistical techniques (association studies, sib-pair analysis, analysis of affected pedigree members, and others) to determine if a specific allele of the candidate gene is inherited by people affected by the disorder more commonly than would occur by chance.

This review will summarize current genetic information about disorders with orthopaedic manifestations. A few disorders that are commonly seen by orthopaedists or that illustrate new information on the pathophysiology of genetic disorders with orthopaedic manifestations will be presented in more detail. Most of the information has been tabulated and organized into categories of disorders, such as metabolic disorders, skeletal dysplasias, and so on, for easy reference (Table I).

	Skeletal Dysplasias

Top Introduction Skeletal Dysplasias Metabolic Bone Diseases Connective-Tissue Disorders Neuromuscular Disorders Miscellaneous Syndromes and... Disorders with Complex... The Orthopaedic Surgeon and... References

 

Achondroplasia, Hypochondroplasia, and Thanatophoric Dysplasia
Achondroplasia, the most common form of dwarfism, is an autosomal dominant disorder. In most affected individuals, the disorder represents a new mutation. In a study that attempted to include all individuals affected by dwarfism in Victoria, Australia, Oberklaid et al. found that only two of sixty individuals with achondroplasia had a positive family history⁷⁵. Murdoch et al. reported that, of 148 individuals with achondroplasia who attended regional and national meetings of the Little People of America, thirty-one had a familial disorder⁷². People with achondroplasia often have varus deformity of the lower extremities and are at risk for atlanto-axial instability and spinal stenosis. The cause of achondroplasia has been reported^67,88 to be a point mutation in the gene coding for fibroblast growth factor receptor-3. This mutation is always at the same nucleotide (nucleotide number 1138) and causes a single amino acid change (arginine to glycine) in the transmembrane portion of this cell surface receptor. This receptor is expressed in all pre-bone cartilage as well as diffusely in the central nervous system. The remarkable homogeneity of the phenotype in achondroplasia results from the remarkable homogeneity of the mutation in this disorder. No other autosomal dominant disorder for which the gene defect is known has such a homogeneous mutation. In fact, this is the most mutable single nucleotide known in the entire human genome.

The function of fibroblast growth factor receptor-3 has been studied in mice by disrupting the normal gene¹⁷. Fibroblast growth factor receptor-3-deficient mice have an elongated vertebral column and elongated bone as a result of accelerated and prolonged growth compared with that in normal mice. The normal function of fibroblast growth factor receptor-3 causes inhibition of chondrocyte proliferation in the proliferative zone of the physis. Thus, fibroblast growth factor receptor-3 seems to regulate bone growth by limiting endochondral ossification. A possible explanation for the dwarfing phenotype in humans who have an abnormal gene for fibroblast growth factor receptor-3 is that the human mutation results in a receptor that is active even without the binding of a fibroblast growth factor ligand to the receptor. There is an overactivity of the function of the receptor and thus an inhibition of endochondral ossification. This is an example of a gain-of-function mutation.

Hypochondroplasia is similar to achondroplasia, but the dwarfing is milder and affected people have normal skulls and facies. Associated problems, such as spinal stenosis and severe genu varum, are less common in hypochondroplasia. Most people with this disorder who have been studied have a mutation of the fibroblast growth factor receptor-3 gene, as do people with achondroplasia^4,88. The mutation in hypochondroplasia affects the tyrosine kinase domain instead of the transmembrane domain of fibroblast growth factor receptor-3, which is affected in achondroplasia.

Thanatophoric dysplasia, the most common neonatal lethal skeletal dysplasia, is also caused by a mutation of the fibroblast growth factor receptor-3 gene. This association was suggested by a phenotypic similarity between thanatophoric dysplasia and homozygous achondroplasia^88,91.

Pseudoachondroplasia
Pseudoachondroplasia is one of the more common skeletal dysplasias and is characterized by disproportionate short-limbed dwarfism and ligamentous laxity. Pseudoachondroplasia is not clinically apparent at birth, although platyspondylisis is evident on radiographs. Growth retardation becomes apparent between the ages of one and three years. The disproportionate shortness of the limbs increases with growth. The hands and feet are short and broad. The facies are normal but tend to resemble those of other individuals who have pseudoachondroplasia.

Electron microscopy demonstrates dilated rough endoplasmic reticulum containing material that has a laminar structure in epiphyseal and physeal chondrocytes. Immunostaining suggests that this material is proteoglycan link protein or aggrecan. The cause of this disorder, however, is a mutation in the calmodulin-like calcium-binding region of the gene coding for cartilage oligomeric matrix protein^6,35. A high level of this protein is present in the territorial matrix of cartilage. The mechanism by which this defective gene causes pseudoachondroplasia is speculative. It may be that a disruption of calcium-dependent proteoglycan-binding by cartilage oligomeric protein results in accumulation of proteoglycan in chondrocytes, leading to the typical findings with regard to the endoplasmic reticulum.

Spondyloepiphyseal Dysplasia Family
Most skeletal dysplasias are descriptively named on the basis of phenotypic or radiographic features. Some are commonly referred to by eponym. An increased understanding of the cause of these disorders will lead to improved classification in the near future. Families of chondrodysplasias are being defined because the members all have the same known or presumed abnormal gene⁴⁰. The spondyloepiphyseal dysplasia family denotes a group of allelic chondrodysplasias that are caused by different mutations in the gene coding for type-II collagen. The most severe disorder in this family is the perinatally lethal type-II achondrogenesis. Hypochondrogenesis, spondyloepiphyseal dysplasia congenita and tarda, Kniest-type spondyloepiphyseal dysplasia, Stickler syndrome (hereditary arthro-ophthalmopathy), and precocious osteoarthropathy are progressively milder disorders that share a defect in type-II collagen^{1,5,74,77,78,86,92,93}. Stickler syndrome without involvement of the eyes is caused by a gene coding for type-XI collagen. This collagen is a minor fibrillar collagen that is important in determining the diameter and orientation of type-II collagen fibers.

Osteoarthrosis
It has been long recognized that osteoarthrosis runs in some families. It is also clear that, barring trauma or infection, some people will never have osteoarthrosis. The age of the individual at the onset of non-traumatic osteoarthrosis varies greatly. Osteoarthrosis has been considered a multifactorial disorder—that is, a combination of genetic predisposition and unknown environmental factors has been thought to be the cause. One reason that disorders with non-Mendelian patterns of inheritance may be categorized as multifactorial is the mixing of several different disorders, with different causes and different patterns of inheritance. It is important to be as specific as possible about the phenotype that causes inclusion in a group. Although all end-stage osteoarthrotic joints look alike, it appears that osteoarthrosis that develops in the second to fifth decades of life has a different cause than does osteoarthrosis that develops in the seventh or eighth decade.

A form of familial, precocious osteoarthrosis has been localized to chromosome 12 (12q13.11-q13.2)⁴⁸. A distinct polymorphism in the gene coding for type-II collagen (Col2A1) is associated with this mild chondrodysplasia. Premature osteoarthrosis accompanied by chondrocalcinosis has been found³ to be localized to chromosome 8. A small percentage of cases of primary osteoarthrosis have been demonstrated to be the result of a rare allele coding for type-II collagen that causes reduced gene expression⁵⁷. Much of what is now considered primary osteoarthrosis may have a detectable genetic cause or predisposition.

Multiple Epiphyseal Dysplasia
Multiple epiphyseal dysplasia denotes a group of disorders characterized by dysplasia of the epiphyses of the tubular bones and normal or nearly normal vertebrae. Dwarfing is mild, and the presentation in childhood (a waddling gait and difficulties with running or with climbing stairs) differs from that in adulthood (premature osteoarthrosis). Pain, a limp, or a decreased range of motion of the weight-bearing joints prompts evaluation.

Several disorders with different causes are included under the label of multiple epiphyseal dysplasia. The cause of type I, in which there is dilated rough endoplasmic reticulum with lamellar inclusions (similar to those seen in pseudoachondroplasia), is known. It is a mutation in the gene coding for cartilage oligomeric matrix protein⁶. This gene is the same as that mutated in pseudoachondroplasia. Presumably, different sorts of mutations in the cartilage oligomeric protein gene result in the different phenotypes of these two disorders.

Type-II multiple epiphyseal dysplasia is caused by a mutation in the gene coding for the alpha 2 polypeptide chain of type-IX collagen^7,71. Type-IX collagen is located on the surface of type-II collagen fibrils. Since defects in type-IX collagen cause early, non-inflammatory degeneration of articular cartilage in both humans and mice, it has been hypothesized that type-IX collagen is essential for the long-term integrity of articular cartilage⁷¹.

Diastrophic Dysplasia
Diastrophic dysplasia is a well characterized skeletal dysplasia featuring short limbs, short stature, kyphoscoliosis, generalized dysplasia of the joints with limitation of flexion of the fingers, hitchhiker thumbs, and deformities of the feet ranging from the more common valgus angulation of the hindfoot and adductus of the forefoot to clubfoot. The abnormalities of the joints in this disorder result in painful osteoarthrosis at an early age. Affected individuals, who are of normal intelligence, are severely handicapped by the abnormalities of the joints. Although there is increased mortality in infancy, the life span after that time is not markedly decreased. Diastrophic dysplasia is caused by a mutation in a gene coding for a sulfate transporter protein located on chromosome 5. The sulfate transporter function of the gene product was suggested by protein sequence analysis showing a similarity in amino acid sequence to known sulfate transporter proteins and was supported by greatly diminished sulfate uptake in skin fibroblasts from a patient who had diastrophic dysplasia. This gene has been named diastrophic dysplasia sulfate transporter³³.

In normal cartilage, proper sulfation of proteoglycans is necessary for them to be sufficiently negatively charged to function properly. There is evidence that the sulfation of proteoglycans is sensitive to both extra-articular and intra-cellular sulfate concentrations. A defect in the sulfate transporter protein could easily explain the defective cartilage in this disorder. The gene responsible for the synthesis of this protein is expressed in virtually all cell types. The reason that its effects are most pronounced in cartilage-producing cells may simply be the greater requirement for sulfate for proteoglycan synthesis in cartilage compared with that in other tissues. Specifically, a defect in sulfate transport might result in the undersulfation of type-IX collagen, which, in one of its forms, is a chondroitin sulfate. Type-IX collagen is important for holding together the lattice of type-II collagen and it helps to determine the diameter of type-II collagen fibrils. This might explain the histological abnormalities of collagen that have been reported in diastrophic dysplasia³³.

Mutations of the diastrophic dysplasia sulfate transporter have also been found to cause the neonatally lethal type-IB achondrogenesis and type-II atelosteogenesis⁹⁰. Although these disorders may seem unimportant from an orthopaedic perspective, they suggest the existence of a family of diastrophic dysplasia sufate transporter skeletal dysplasias.

Schmid Metaphyseal Chondrodysplasia
This autosomal dominant disorder is characterized by short stature, bowed lower extremities, coxa vara, and a waddling gait. The metaphyses of the long bones are flared, and the physes are wide and irregular. The defective gene codes for abnormal type-X collagen^18,45,59. Normal type-X collagen is a short-chain collagen that is present predominantly in the hypertrophic zone of the physis and is thought to be important in endochondral ossification. Type-X collagen exists as a homotrimer (three identical chains linked together) in the pericellular matrix of hypertrophic chondrocytes. The mutations in this disease occur in the carboxy-terminal, non-collagenous domain of the protein and may limit the ability of the collagen to form trimers.

Jansen Metaphyseal Chondrodysplasia
Jansen metaphyseal chondrodysplasia is a rare, autosomal dominant disorder characterized at birth by severe shortening of the limbs, a prominent forehead, and micrognathia. The tubular bones are short, and the metaphyses are markedly flared with irregular ossification.

A patient with Jansen metaphyseal chondrodysplasia was shown to have a mutation in the gene coding for parathyroid hormone-parathyroid hormone-related peptide receptor⁸³. This explains the hypercalcemia and hypophosphatemia often associated with Jansen syndrome. Furthermore, this receptor is expressed in the growth plate, and animal models have suggested that parathyroid-related protein is important in the elongation and ossification of bones⁸³.

Craniosynostoses
Several disorders with premature fusion of the cranial suture and variable anomalies of the hands and feet are caused by mutation of the gene for fibroblast growth factor receptor-2. Apert, Jackson-Weiss, Crouzon, and most Pfeiffer syndromes are autosomal dominant disorders caused by fibroblast growth factor receptor-2 mutations. Syndactyly of the fingers and toes is more extensive in Apert syndrome than in the other disorders^67,76.

	Metabolic Bone Diseases

Top Introduction Skeletal Dysplasias Metabolic Bone Diseases Connective-Tissue Disorders Neuromuscular Disorders Miscellaneous Syndromes and... Disorders with Complex... The Orthopaedic Surgeon and... References

 

Osteoporosis
Osteoporosis is a major individual and public-health problem. Fracture of the femoral neck due to senile osteoporosis continues to result in a high rate of mortality. Peak bone mass is a major determinant of the development of osteoporosis. Multiple non-genetic factors are important in determining peak bone mass; they include exercise, drug use, alcohol intake, nutrition (including calcium intake), and smoking. A study⁶⁹ of white individuals of Anglo-Irish background living in Australia showed that the genetic contribution to peak bone mass can be explained by differing alleles for the gene coding for the receptor for 1,25-dihydroxyvitamin D. These results must be considered preliminary. The finding must be confirmed in other racial groups in order for it to be of general importance. It must be established that the alleles associated with low bone mass are the proximate cause and not merely a chance association with some other process that actually results in low bone mass. If different alleles coding for this vitamin-D receptor result in clinically important differences in peak bone mass, identification of specific alleles could be used clinically to identify a population that is at particular risk early in life. This population could be targeted for intensive prophylactic treatment and education before bone mass decreases to less than the level necessary to avoid osteoporotic fractures.

Vitamin D-Resistant Rickets
The most common cause of vitamin D-resistant rickets is X-linked hypophosphatemic rickets. This disorder causes short stature, deformities of the lower extremities, and bone pain. A decrease in proximal tubular resorption of phosphate resulting in hypophosphatemia causes the disorder. Recent evidence indicates that an intrinsic renal defect is not responsible for this disorder; rather, a humoral factor is produced that actively induces phosphate-wasting²⁴. This has been shown in transplant experiments in mice with an analogous disorder²². Furthermore, the gene in humans that codes for the sodium phosphate transport protein is on chromosome 5, whereas X-linked hyphosphatemic rickets has been linked to an area of the X chromosome (the Xp22.1 region)^22,24.

Identification of the abnormal gene and its protein that results in phosphate-wasting holds promise for the development of specific therapies to counteract this humoral protein and to ameliorate the effects of this disorder. Current treatments with phosphate and active vitamin-D metabolites are only partially effective in preventing the short stature, deformity, and bone pain.

	Connective-Tissue Disorders

Top Introduction Skeletal Dysplasias Metabolic Bone Diseases Connective-Tissue Disorders Neuromuscular Disorders Miscellaneous Syndromes and... Disorders with Complex... The Orthopaedic Surgeon and... References

 

Marfan Syndrome
Marfan syndrome is an autosomal dominant disorder affecting one in 10,000 people. The expression of the disorder is variable within and among families. Typical features include dolichostenomelia, pectus excavatum or carinatum, scoliosis, a high narrow palate, ectopia lentis, myopia, dilatation of the ascending aorta, aortic dissection, and dural ectasia. Because of the wide distribution of affected tissues, a connective-tissue defect was suspected for decades.

In 1991, the defective gene causing Marfan syndrome, located on chromosome 15, was found^19,20,61 to encode for fibrillin-1. Fibrillin is a large glycoprotein that is a structural component of elastin-containing microfibrils and is present in many tissues. The gene defect usually results in decreased amounts of fibrillin and, presumably, a structurally weakened elastin^26,36. Gene-based diagnosis is now possible, although it is not yet commercially available. Isolated ectopia lentis has been linked⁹⁴ to the fibrillin gene on chromosome 15.

A second, distinct, fibrillin protein—fibrillin-2—is coded for by a gene on chromosome 5. An autosomal dominant disorder, congenital contractural arachnodactyly, has the same skeletal features as Marfan syndrome; however, joints are contracted instead of loose. This disorder has been reported⁹⁴ to be caused by a mutation in the fibrillin gene on chromosome 5.

	Neuromuscular Disorders

Top Introduction Skeletal Dysplasias Metabolic Bone Diseases Connective-Tissue Disorders Neuromuscular Disorders Miscellaneous Syndromes and... Disorders with Complex... The Orthopaedic Surgeon and... References

 

Duchenne and Becker Muscular Dystrophy
The dystrophinopathies, Duchenne and Becker muscular dystrophy, have traditionally been considered two different diseases. However, when the gene dystrophin was cloned in 1987, it became clear that these diseases represent different phenotypes resulting from different mutations in a single gene^38,66.

The most severe form of the disease, Duchenne muscular dystrophy, presents in early childhood with proximal muscle weakness and hypertrophy of the calves. Affected boys are mildly delayed in attaining motor milestones. Toe-walking may be an early manifestation of the disease. The course is one of steadily increasing weakness.

The milder dystrophinopathies are varied in clinical phenotype. When the disease affects a male individual and presents in childhood with proximal weakness, hypertrophy of the calves, and very high levels of creatine kinase, but follows a more indolent course than Duchenne muscular dystrophy, the diagnosis is Becker muscular dystrophy. Dystrophinopathies may be indistinguishable from limb-girdle dystrophy. In one series², seven (17 per cent) of forty-one patients with the clinical diagnosis of limb-girdle dystrophy had dystrophin mutations. Female carriers may be symptomatic on the basis of skewed X-inactivation. They usually are first seen with limb-girdle weakness and an elevated level of creatine kinase¹². Cardiomyopathy can be clinically important and on rare occasions is the primary manifestation of dystrophinopathy^21,65.

Dystrophin is an intracellular protein that is associated with two transmembrane complexes—the dystroglycan complex and the sarcoglycan complex. Loss of dystrophin leads to loss of all components of these complexes. The dystrophin gene is the largest human gene yet identified. This makes it a very large target for new mutations, and in one-third of affected patients the dystrophinopathy is the result of a new mutation⁷⁹. A review of all series reported by 1993 revealed that in 55 to 70 per cent of patients who have dystrophinopathy a deletion or duplication can be identified by DNA testing³⁷. A muscle biopsy is not necessary to make the diagnosis for these patients, although sometimes one is done to allow a more accurate prediction about the clinical course. (Dystrophin is absent from muscle in Duchenne muscular dystrophy, and it is decreased or abnormal in the milder phenotypes.)

Because there is no effective treatment for the dystrophinopathies, there is great interest in the possibility of introducing a functional dystrophin gene into the muscle fibers (gene therapy) and thus curing the disease⁴⁷. There are many problems to be overcome before this is a viable option. Among these are the identification of an appropriate vector for the new gene, overcoming of the host immune response to the vector or the expressed new protein, targeting of muscle, and regulation of the expression of the gene. These problems are the focus of active research. Most of the hurdles to be overcome before gene therapy is clinically useful for the treatment of muscular dystrophy are not specific to one missing protein, such as dystrophin. Thus, if the problems are solved for one type of muscular dystrophy, it is likely that the protocol will be adapted relatively quickly for other types with a similar pathogenesis.

Myotonic Dystrophy
Myotonic dystrophy is an autosomal dominant, multisystem disease with marked clinical variability. The most severely affected patients are infants who have congenital myotonic dystrophy. They have severe hypotonia and weakness, frequently require ventilatory support and nasogastric feeding, and often have clubfeet and dislocated hips. They are almost always born to myotonic mothers rather than affected fathers. If they survive the neonatal period, these children show improvement in strength but have persistent motor disability. In addition, they are uniformly mentally retarded. At the other extreme, the only manifestation of myotonic dystrophy in the most mildly affected individuals may be cataracts.

After the neonatal period, the disease presents with mild muscular weakness as well as myotonia exacerbated by cold. Wasting of the temporalis muscles contributes to the typical phenotype of a long narrow face with bitemporal narrowing. Defects in cardiac conduction are common and may necessitate the insertion of a pacemaker. Diabetes mellitus, male-pattern baldness, infertility, and mental retardation are also manifestations of myotonic dystrophy.

The abnormal gene myotonin is a protein kinase^23,64. The substrate for the kinase and the pathophysiology of the disease remain unknown. The mutation is an expansion of a trinucleotide repeat in the 3' untranslated region of the gene^23,32,64. The normal gene has five to thirty copies of this CTG repeat. This is expanded in myotonic dystrophy, reaching thousands of copies. Congenitally affected infants have the largest expansions, on the average, and the mildest phenotypes are associated with the smallest expansions into the disease-associated range^31,32,49.

The trinucleotide repeat expansion provides a molecular basis for so-called anticipation, a phenomenon recognized by astute clinical geneticists but discounted by colleagues in part because it failed to conform to classic Mendelian genetics. Anticipation, in genetic parlance, is the worsening of the clinical phenotype (with an earlier onset and more severe disease) in succeeding generations. It is now clear that the trinucleotide repeats tend to lengthen in succeeding generations and the severity of the disease correlates, although not perfectly, with the length of the repeat segment.

Expanded trinucleotide repeats are seen in a steadily increasing number of human diseases. Among those of interest to orthopaedists are spinocerebellar ataxia^11,25,46 and Friedreich ataxia^9,30.

Hereditary Motor and Sensory Neuropathies (Charcot-Marie-Tooth Disease)
Charcot-Marie-Tooth disease has been subdivided on clinical grounds into types I and II. More recently, these were subsumed in the classification of hereditary motor and sensory neuropathies, in which types I and II Charcot-Marie-Tooth disease became types-I and II hereditary and motor sensory neuropathy. Type-I hereditary motor sensory neuropathy is the most common inherited neuromuscular disorder. It is autosomal dominant and is characterized by progressive distal muscle-wasting and weakness, areflexia, and deformities of the feet (most commonly cavovarus feet). There is severe slowing of nerve-conduction velocities, and pathological analysis of the nerves reveals simultaneous remyelination and demyelination. This disorder has variable expression but usually begins in childhood. Patients with deformities of the feet are usually seen by an orthopaedic surgeon in late childhood or early adolescence.

At the molecular level, this clinically homogeneous disease becomes quite complex. Seven different loci have been identified for the hereditary motor and sensory neuropathy phenotype^{10,16,27,39,43,44,53,56}. Mutations in at least three loci (chromosomes 17, 1, and X) result in autosomal dominant type-I hereditary motor and sensory neuropathy. The most common cause of the disease is a duplication of 17p11.2-p12 (resulting in type-IA hereditary motor and sensory neuropathy)^29,42. This duplication leads to trisomy for the peripheral myelin protein-22 gene. Rare patients with point mutations in this gene have also had the type-I hereditary motor and sensory neuropathy phenotype, providing strong evidence for the primary role of the peripheral myelin protein-22 gene in the etiology of the disease. Interestingly, a chromosome-17 deletion reciprocal to the duplication in type-IA hereditary motor and sensory neuropathy causes hereditary neuropathy with a propensity for pressure palsies (tomaculous neuropathy), another autosomal dominant neuropathy.

A second locus, identified for type-IB hereditary motor and sensory neuropathy, is found on chromosome 1 and codes for myelin protein zero; it is the most rare locus identified thus far. A third locus (for type-IC hereditary motor and sensory neuropathy) has not yet been mapped. Another hereditary neuropathy with severe slowing of nerve-conduction velocities is autosomal recessive and has been mapped to chromosome 8. In addition to these autosomal loci, there are three X-linked loci. The mutated gene in one of these is connexin-32; the gene product has not been identified for the other two. The phenotype associated with connexin-32 mutations often appears to be dominantly inherited, and familes with these mutations cannot be reliably distinguished from the autosomal dominant forms on a clinical basis.

The gene for type-II hereditary motor and sensory neuropathy, the axonal form, has not been mapped to any of the mentioned locations, confirming that this is a distinct disease at both the clinical and the molecular level⁵⁶.

It is difficult to calculate accurate population-based frequencies for the various genetic loci associated with the phenotype for hereditary motor and sensory neuropathy. The University of Iowa is a referral center for the genetic analysis of patients who have hereditary neuropathy. Of ninety-five families studied there, seventy-seven had the type-I phenotype. Of these seventy-seven, fifty-four showed linkage to chromosome 17 and fifty had duplication of the peripheral myelin protein-22 gene. In one family, the gene was mapped to chromosome 1, and twenty families had an X-linked-dominant disorder. Fifteen of the twenty demonstrated mutations of connexin-32. Eighteen of the ninety-five families had a type-II hereditary motor and sensory neuropathy phenotype (axonal neuropathy). The remaining two families were found to have an X-linked-recessive disorder on pedigree analysis. This was not a population-based study, and the referral pattern might have altered the frequencies slightly. Mutations of the peripheral myelin protein-22 gene or of connexin-32 can be identified in peripheral blood by commercial laboratories. Thus, in the University of Iowa series, for sixty-five (84 per cent) of the seventy-seven families who had the type-I hereditary motor and sensory neuropathy phenotype a specific diagnosis could be made through DNA analysis, allowing accurate genetic counseling and diagnosis before the development of symptoms⁴¹.

Spinal Muscular Atrophy
Spinal muscular atrophy has been classified into three clinical forms: Werdnig-Hoffmann disease, which is characterized by generalized muscle weakness and hypotonia at birth and by early death; the intermediate type of spinal muscular atrophy, with which patients have normal motor milestones initially but are never able to walk; and Kugelberg-Welander disease, which is the mildest type and with which muscle weakness becomes evident after the age of two years. All three types are characterized by degeneration of the anterior horn cells, and all result in paralysis of the limbs and trunk with muscle atrophy. The major orthopaedic problems associated with spinal muscular atrophy are scoliosis and instability of the hip. It has long been recognized that there is a continuum from the most severe, early forms of disease through the milder, later-onset forms. This clinical impression has been borne out^{60,68,70,87,89} by the mapping of all forms of spinal muscular atrophy to one small region of chromosome 5. In 226 (99 per cent) of 229 patients who had this disorder, a mutation was found in a gene called the survival motor neuron^13,54. The exact function of this gene is not known, but its identification will revolutionize the ability to perform diagnostic testing, prenatal testing, and genetic counseling.

It was surprising that no relationship was found between the nature of the mutation of the survival motor neuron gene and the severity of the disorder. Another gene quite near to the survival motor neuron gene, the neuronal apoptosis inhibitory protein gene, may provide an explanation for this failure of the mutation to predict phenotype^13,82. The neuronal apoptosis inhibitory protein gene functions to inhibit motor-neuron-programmed cell death. Programmed cell death is a normal occurrence in the development of the nervous system. Failure to inhibit cell death at the appropriate time could be part of the explanation for the loss of anterior horn cells seen in spinal muscular atrophy. In a group of patients who had the most severe type of spinal muscular atrophy, a high percentage of deletions in this gene was found⁸². A combination of mutations (specifically, a large deletion) involving both of these genes may explain some of the clinical variability in this disorder.

	Miscellaneous Syndromes and Disorders

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Hereditary Multiple Exostosis
This autosomal dominant disorder is viewed as a single clinical phenotype, but it has been localized to three different chromosomal locations: chromosome 8 (8q24.11-q24.13), chromosome 11 (pericentric), and chromosome 19 (19p)^15,55,96,97. The specific gene has not been identified in any of these locations. However, chondrosarcomatous tissue from a small number of patients in whom the lesion underwent malignant transformation has been found³⁴ to have a loss of one allele (presumably the normal allele) in the region of the gene on either chromosome 8 or chromosome 11. No loss of an allele has been found in the region of chromosome 19. The genes that cause hereditary multiple exostosis may, therefore, be tumor-suppressor genes. This pattern has been seen in other inherited forms of malignancy. One copy of the gene carries an inherited mutation. The normal copy acquires a mutation (for example, a deletion) in a somatic cell, leading to uncontrolled cell division. It is possible that hereditary multiple exostoses caused by different gene mutations may have different propensities for malignant degeneration. This could explain the differing prevalences of malignant degeneration reported for these lesions. A report of the experience at any medical center will probably include a group of families in which one or another chromosomal mutation is present with greater frequency than that in the general population with hereditary multiple exostosis. Gene-based diagnosis may ultimately allow more accurate counseling of patients concerning the risk of malignant degeneration.

Neurofibromatosis
Neurofibromatosis is the most common single gene disorder. It is autosomal dominant, with a nearly complete penetrance.

There are two forms of neurofibromatosis. Type I has a prevalence of one in 3500 live births¹⁴. Half of reported cases are new mutations. The clinical features include café-au-lait spots, neurofibromas, dysostosis, congenital pseudarthrosis of the tibia, and scoliosis. The abnormal gene responsible for this disease codes for neurofibromin, a signal transduction protein¹⁴. The molecular pathophysiology has not yet been elucidated.

Type-II neurofibromatosis, with a gene location on chromosome 22, is far less common, with a prevalence of one in 50,000 live births. This type is associated with a high prevalence of acoustic neuromas and rarely involves orthopaedic complications. The mutant gene codes for schwannomin, which is a protein that links the cytoskeleton to the plasma membrane.

McCune-Albright Syndrome
McCune-Albright syndrome is sporadic and is characterized by polyostotic fibrous dysplasia, sexual precocity, hyperplastic endocrine disorders, and café-au-lait spots. A mutation of the gene for the alpha subunit of stimulatory guanine-nucleotide-binding protein, a protein that stimulates cyclic AMP formation, has been found in patients affected with this disorder⁸⁴. The mutation seems to result in an inappropriate stimulation of adenyl cyclase. There is strong evidence that the mutation of this gene is a somatic rather than a germline mutation, meaning that the mutation occurred after fertilization, during some subsequent cell division. The variation in the distribution of the abnormality in individuals can be explained by the tissues that have the mutated gene as opposed to the normal gene. In all patients studied so far, the abnormal gene was found in fibrous dysplasia material⁸⁵.

Abnormal tissues in this disease have been found by in situ hybridization to have increased expression of the c-fos proto-oncogene⁸. Transgenic mice that overexpress the c-fos proto-oncogene have bone-marrow fibrosis, increased formation of woven bone, and disordered bone-remodeling. The abnormal stimulatory guanine-nucleotide-binding protein may create the abnormal cells by increasing the level of cyclic AMP in affected tissues and, thereby, increasing the expression of the c-fos proto-oncogene, which is responsive to increased levels of cyclic AMP.

Mutations in this gene were also found in two patients who had monostotic fibrous dysplasia⁸⁵. It seems likely that different mutations within this gene might result in lesser or greater involvement of bones and other tissues.

	Disorders with Complex Inheritance: the Value of Complex Segregation Analysis

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Most orthopaedic disorders are not strictly Mendelian in their inheritance. Disorders with complex inheritance are more interesting to most orthopaedists, as they constitute many of the idiopathic disorders that they treat. These disorders are usually more common than Mendelian disorders—for example, Wynne-Davies found that idiopathic clubfoot occurred in 163 of 131,452 live births (1.24 per 1000 live births) in Devonshire, England⁹⁸; Rogala et al. found idiopathic scoliosis with a Cobb angle of more than 10 degrees in 2 per cent of 26,947 screened children in the at-risk age-group⁸¹; and Lawrence et al. reported a 0.9 per cent prevalence of rheumatoid arthritis in 6672 non-institutionalized civilians in the United States who were evaluated clinically, with radiographs of the hands and feet, with serum assays for rheumatoid factor, and with the bentonite flocculation test⁵². The risk of near-relatives being affected by a disorder with complex inheritance is much lower than that with Mendelian disorders.

There are three explanations for such data: (1) there is a non-genetic cause, such as an environmental factor, for these disorders; (2) there is a polygenic cause with the genes not acting in a strictly additive fashion (otherwise, the inheritance would appear dominant); or (3) there is a major gene effect responsible for a weak predisposition in most people or a strong predisposition in a subset of people with a disease phenotype. Various combinations of these possibilities can blur their borders. A sophisticated way of distinguishing between the possible causes of disorders with mild-to-moderate familial aggregation is by complex segregation analysis. Segregation analysis per se generally refers to the assessment of whether a trait segregates in a Mendelian fashion. Complex segregation analysis refers to sophisticated mathematical analysis of pedigrees with which the investigator can simultaneously look for apparently genetic and non-genetic components of the segregation of a trait or disease within families. Non-genetic components include environmental effects such as diet, geographic location, socioeconomic status, birth order, maternal age at pregnancy, and exposure to a common virus. Complex segregation analysis was developed in the 1970's by Elston and Howard. Computers are required to assess the likelihood of various models accurately representing the cause of familial clustering of traits or disorders because the pedigree data usually include hundreds of families with several generations in each family.

This technique provides an advanced understanding of how traits for specific disorders cluster in families. In general, four types of models of inheritance are tested by genetic epidemiologists. The first is the oligogenic, or major, gene model, which posits a single locus or a few loci that account for inheritance completely. Mendelian inheritance is in this category. The second is the polygenic model, which presupposes many contributing factors that are separately indistinguishable. However, cumulatively, their effects are transmissible. This model is used for multifactorial inheritance. Major gene effects are not detectable. The third type of model is the non-transmitted model, which describes disorders that cluster in families but are not transmitted between generations in a way that suggests genetic inheritance. This model suggests environmental causation. Finally, there is the mixed model, which combines the oligogenic and polygenic models. Major gene effects are detectable, but other factors appear to be influencing disease expression. These other factors are assumed to be polygenes or environmental effects. Basically, disorders with a major gene effect can now be identified without the requirement that a major gene alone account for all occurrences of the disorder. This is important for the purpose of planning research strategies. If a single gene is found to account for a large proportion of clustering of a disorder in families, molecular genetic techniques are appropriate for the search for the gene. If non-hereditary explanations fit the data best, then epidemiological studies are more likely to identify the cause of the disorder-clustering. This sort of analysis has been applied to diseases in all branches of medicine. Rheumatoid arthritis and idiopathic clubfoot are examples of diseases studied with complex segregation analysis that are of special interest to orthopaedists.

Lynn et al. evaluated the families of 247 consecutive patients who were seen for treatment of rheumatoid arthritis⁵⁸. After excluding families in which relatives had been misdiagnosed as being affected or in which it was not possible to determine whether a member was affected, the authors analyzed first-degree relatives from thirty families with more than one affected member and 135 families with only one affected member. They compared the fit of the data to a major gene model with those of multifactorial transmission and environmental transmission.

The best explanation of the pedigree data was a highly penetrant recessive gene with a prevalence in the population of 0.005. Not all pedigrees supported this result. The pedigrees that did so most strongly were those of families with an excess of affected male relatives and a young age at the onset of the disease. This information makes a molecular genetic search for a causative gene reasonable. The families with many affected male relatives and an early age of onset are the best families to study in the search for a causative gene.

Rebbeck et al. used the regressive logistic model of complex segregation analysis in a study of families with idiopathic clubfoot⁸⁰. This technique can be used to evaluate disorders with a large number of genes and environmental factors contributing to statistical dependence among relatives without presupposing any genetic model. The technique allows all variables to vary in order to fit the pedigree data in the best possible way. Models of major gene effect, multifactorial effect, and environmental effect are then compared with the best fit of the data.

Rebbeck et al. used pedigrees of 143 consecutive probands who had idiopathic clubfoot⁸⁰. The multifactorial and environmental models were strongly rejected. A single major gene effect with an additional effect (polygenes or environmental factors) shared among siblings gave the best fit of the data. The authors of two other studies, in which different models were used for complex segregation analysis of clubfoot, came to the same conclusion^95,99.

Complex segregation analysis is a useful first step in the investigation of the etiology of disorders with non-Mendelian clustering within families. The results can help the investigator to allocate resources effectively when seeking causative factors.

	The Orthopaedic Surgeon and the Geneticist at the End of the Twentieth Century

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The orthopaedic community must stay informed about and involved in the revolution in the understanding of the genetic and molecular bases of diseases. In the interest of achieving this goal, we offer several recommendations.

First, it is probably prudent for the orthopaedic surgeon who treats heritable disorders to be updated by a medical geneticist annually or biennially. New information is accumulating too rapidly for most practicing orthopaedic surgeons to stay abreast of new developments. Patients, however, expect orthopaedists to be at least as informed as they are, and rightly so. Educational lecture series in teaching institutions should include medical geneticists to relate new information concerning orthopaedic disorders. National educational meetings should include guest speakers who have expertise in genetics to allow a broad dispersion of this new knowledge in the orthopaedic community.

Second, a large family with an inherited disorder of unknown etiology should prompt a call or referral to a medical geneticist. He or she will be able to find out if active research into that disorder is occurring. If so, participation by the family in ongoing research may result in identification of the disease-causing gene.

Third, if there is any question about the availability of gene-based diagnosis, a geneticist should be consulted before a diagnostic biopsy is performed. Most cases of Duchenne muscular dystrophy and Charcot-Marie-Tooth disease, for example, can be diagnosed with blood analysis rather than muscle or nerve biopsy.

Fourth, if an orthopaedic surgeon is unfamiliar with the empirical risk of a disorder recurring, he or she should defer to a medical geneticist. Idiopathic clubfoot is an example of a disorder that treating orthopaedic surgeons commonly underestimate with regard to the risk of recurrence.

Fifth, patients who have multisystem congenital anomalies should be referred to a geneticist, who can attempt to identify a unifying diagnosis.

Finally, families who have diseases with Mendelian inheritance should be offered referral for genetic counseling. The practicing orthopaedist does not have the time or teaching aids with which to explain genetics to most families adequately.

Genetic research will alter the understanding and treatment of many disorders in the future. Prenatal and presymptomatic diagnosis will become available for an increasing number of diseases. Gene therapy or gene-product replacement will become available, with the potential for ameliorating or eliminating the effects of abnormal genes. The orthopaedist must stay abreast of this knowledge to participate in advances in diagnosis and treatment and to counsel patients appropriately. Molecular genetics and biology will reveal inherited susceptibilities to diseases that are not Mendelian in inheritance. Identifying a subpopulation of patients within a single disease phenotype based on differing genetic backgrounds may allow improved treatment for individual patients.

NOTE: The authors thank Dr. Jeffrey C. Murray, who not only read the manuscript and made important suggestions but also aided in very rapid revisions after the initial review. Their thanks also to Dr. Reginald R. Cooper, who reviewed an early version of the manuscript and made helpful suggestions.

	Footnotes

 
*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

Departments of Orthopaedic Surgery (F. R. D.) and Pediatrics (K. D. M.), University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa 52242.

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Top Introduction Skeletal Dysplasias Metabolic Bone Diseases Connective-Tissue Disorders Neuromuscular Disorders Miscellaneous Syndromes and... Disorders with Complex... The Orthopaedic Surgeon and... References

 

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