Skeletal Dysplasias

The following section will be a discussion of the basic science and molecular genetics of several diseases with orthopedic issues. It is not meant to be a full description of each disease; rather, it will briefly discuss how the advances in molecular biology and gene discovery are advancing our understanding of diseases that are commonly encountered in orthopedics.


Achondroplasia is and autosomal dominant disorder that has been linked to a point mutation in the FGFR3 receptor. In this disease a single point mutation causes an amino acid change that effects the transmembrane portion of the FGFR3 receptor, which is found throughout cartilage. This mutation produces a dysfunction in a protein that normally limits the endochondral ossification and produces failure of proliferative zone chondrocytes to proliferate. The result is a dwarfing phenotype that is characterized by…


Pseudoachondroplasia is another common form of dwarfism that causes “short-limbed” dwarfism and ligamentous laxity. The phenotype does not become apparent until ages 1 through 3 when the growth of the limbs fails to keep pace with the axial skeleton, which becomes more pronounced with maturity. The face maintains unaffected though will resemble other pseudoachondroplasts. The defect in this disorder is linked to a mutation in the gene encoding the calmodulin-like calcium binding region of the gene encoding for COMP. The exact details of how this mutation produces pseudoachondroplasia are not known, but it does appear to interfere with the territorial matrix of protein.

Multiple Epiphyseal Dysplasia (MED)

Multiple epiphyseal dysplasia encompasses several disorders that effect the epiphyses of tubular long bones (i.e. the femur, tibia, humerus, radius & ulna) while preserving the axial skeleton. Dwarfing is usually mild and can present throughout life. Children will present with a waddling gait and difficulty with running or climbing stairs. Adults with mild disease will develop premature osteoarthritis. MED-1 is a subtype known to be caused by a mutation in the gene encoding COMP. Like pseudoachondroplasia, the mutation strikes the calmodulin-like domain but causes less structural change in the protein. This is turn produces a less dramatic phenotype. MED-2 is a subtype with a completely different mutation. It strikes the gene encoding for a component of collagen type IX. Collagen type IX is found on the surface of collagen type II (which predominates in articular cartilage) and is theorized to have a role in maintaining the integrity of articular cartilage. MED-2 is most known for its premature, non-inflammatory osteoarthritis. Other families with the MED phenotype have been found but specific causes have not been identified.

Spondyloepiphyseal Dysplasia (SED) Family

Mutations of the genes encoding type II collagen produce several known genetic diseases of varying severity. The severity often depends on the effect of the mutation on the subunit structure of type II collagen. Three amino acids with the basic structure X-Y-Gly compose the basic understructure of type II collagen (X and Y are any amino acid and Gly is glycine). The glycine is configured such that collagen monofibrils can fold into a triple helix superstructure. Substitution of the glycine can cause perinatally lethal disorders such a achondrogenesis type II and hypochondrogenesis. SEDs all have varying mutations in type II collagen that include duplications, deletions, and premature stop codons. The subtypes include Spondyloepiphyseal dysplasia congenita, Kniest type spondyloepiphyseal dysplasia, Stickler syndrome (hereditary arthro-ophthalmopathy), and precocious osteoarthropathy.

Diastrophic Dysplasia

Diastrophic dysplasia is caused by a mutation in the gene encoding a sulfate transporter protein located on chromosome 5. This gene is present on virtually every cell in the body, but its effects are most pronounced in areas such as proteoglycan synthesis in cartilage where sulfation is required in large quantities. The phenotype is well characterized by short limbs, kyphoscoliosis, limited finger flexion, hitchhiker thumbs, valgus hindfeet and adducted forefeet. OA will often present at an early age and can be crippling. Life span and intelligence are often normal.

Hypophosphatemic Ricketts

Ricketts is most commonly caused by a diet deficient in vitamin D. There is a class of rickets called vitamin D-resistant rickets, that mimics the signs and symptoms of rickets but will not respond to dietary replacement with Vitamin D. Instead, the disease produces a malfunction in phosphate resorption in the proximal renal tubule. The result is wasting of phosphate by the kidneys and inability to form calcium phosphate moieties needed to calcify bone. In most cases the disease has been linked to the X Chromosome to a gene called PEX (phosphate regulating gene with
homologies to endopeptidases, on the X chromosome). Treatment instead requires phosphate supplementation (1-3 grams daily) with high dose vitamin D3.

Osteogenesis Imperfecta (OI)

There are four known types of osteogenesis imperfecta. With rare exception, these four types are variable expressions of an autosomal dominant condition that involves either of the two chains required to make Type I collagen. Normal collagen is consists of a three stranded superhelix. Two of the strands are composed of the alpha-1 chain and one strand is composed of the alpha-2 chain. The chains are about 1,000 amino acids long with the repeating structure X-Y-glycine. The mutations have been linked to the COLIA2 gene in most cases. In type I OI, the mutation causes abnormal messenger RNA (mRNA) that is rapidly degraded. This results in the translation of very little abnormal mRNA and while deficient, the protein is mostly normal. Type II OI involves a highly malformed collagen and is almost universally lethal in the perinatal period. Type III OI is a progressively deforming subtype that is clinically the most severe of the survivable phenotypes. Type IV is moderately severe. With fractures, the initial healing is normal, but bones will not remodel and progressive fractures will ultimately lead to severe deformities if untreated.

Duchenne & Becker Muscular Dystrophy

In 1987, the gene dystrophin was cloned and shortly thereafter was linked to both Duchenne and Becker muscular dystrophy. What had been considered two different entities came to be understood as different phenotypes caused by different mutations in the same gene. Dystrophin has the largest gene sequenced to date; this fact makes it an inherently vulnerable target for new mutation. Dystrophin is a protein that is associated with dystroglycan complex and sarcoglycan complex. Both of these complexes have large transmembrane regions and the loss of dystrophin leads to loss of all components of these complexes. Duchenne is considered the most severe form of this X-linked disease and represents the complete loss of dystrophin. These phenotypes will often present in young male children with a failure to progress through motor milestones. The disease is progressive from with age. Becker, on the hand, is a milder phenotype that results from a relative deficiency or abnormality in the dystrophin protein. This milder form has a highly variable clinical presentation. Women are not entirely protected as variable inactivation of a single X chromosome carrier can cause mild expressions of this disease to occur. In most cases the mutation can be detected by genetic analysis and muscle biopsies are not required.

Hereditary Motor Sensory Neuropathies (Charcot-Marie-Tooth Disease)

There are two varieties of Charcot-Marie-Tooth disease. The first is Type I (also known as Hereditary Motor Sensory Neuropathy (HSMN) Type I) and most profoundly demonstrates distal muscle wasting and weakness. The peroneal and ulnar nerves are most commonly affected. Most patients with this disease will initially present to an orthopedic surgeon with foot abnormalities (cavovarus feet). At least seven different loci have been identified as causative mutations in different patients with the CMT phenotype but a duplication of 17p11 appears to be the most common and produces an abnormal gene product called PMP22. This disease is inherited in an autosomal dominant fashion and is the most heritable neuromuscular disorder. Nerve conduction velocities are severely slowed in this disease and histopathologic evaluation shows simultaneous abnormal myelination and demyelination of peripheral nerves. Type II represents a distinct disease that has been mapped to chromosomes 1, 3, & 7 though no specific gene product has been identified. It does appear to a propensity to strike the axon of a peripheral nerve.

Friedrich’s Ataxia

Friedrich’s ataxia often strikes victims with a progressive ataxia in their early 20’s. It is an autosomal recessive disorder that is accompanied by muscle weakness, cardiomyopathy and diabetes. Orthopedic manifestations include severe scoliosis and pes cavus. The gene X25 has been identified as the root cause with a gene product call frataxin that has an unknown function.

Hereditary Multiple Exostosis (HME)

HME is a disease that forms sporadic exostoses throughout the skeleton. While a single phenotype has been described there are three chromosomal abnormalities linked with the disease (EXT1, EXT2, EXT3). The disease is autosomal dominant but thought to represent a new class of tumor suppressor genes that fall victim to the “2-hit” hypothesis. In an unaffected genotype, a mutation of each gene would be required to cause the formation of an exostosis. In affected individuals, one gene is dysfunctional and any mutation in the other gene causes a cartilage cell to go awry and form an exostosis. From this point the tumor suppression cascade is further vulnerable to mutation and the formation of chondrosarcoma.


Neurofibromatosis is the most heritable single gene disorder with an incidence of 1 in 3,000. There are two forms, which are both autosomal dominant and show nearly complete penetrance. The majority of cases result from new mutations. From an orthopedic standpoint, type I is more pertinent. Clinical features include café-au-lait spots, neurofibromas, congenital pseudarthrosis of the tibia, and scoliosis. The tumor suppressor gene neurofibromin has been implicated. The “2-hit” hypothesis has also been implicated as the method of disease formation. In this theory, the abnormal tumor suppressor is inherited and dysfunctional. The functioning allele is vulnerable to mutation, which leaves the cell with inability to suppress genetically mutated cells from replicating. Thus the abnormal cells are propagated and the disease is manifested. Type II neurofibromatosis has been linked to an abnormality in chromosome 22 and more commonly presents with acoustic neuromas. It is far less frequent and rarely has orthopedic complications.

McCune-Albright Syndrome

McCune-Albright Syndrome presents with fibrous dysplasia, sexual precocity, hyperplastic endocrine disorders and café-au-lait spots. The mutation has been linked to the alpha subunit of the Gs protein in the cyclic-AMP activation cascade. The affected tissues inappropriately stimulate adenyl cyclase and have increased expression of the c-fos proto-oncogene.

Paget Disease

Paget’s disease is extremely common and affects almost 3% of adults older than 40 years of age. Forty percent of affected people have a first degree relative with the disease. Paramyxovirus-like inclusion bodies are often found in osteoclasts. However, several large families have been found to show an autosomal dominant pattern linked to chromosome 18. Most theorize that a certain genetic composition confers a susceptibility to formation of paget’s disease upon infection with a virus.