Skeletal Dysplasias

Skeletal Dysplasias

Patricia G. Wheeler

David D. Weaver

Skeletal dysplasias are conditions presenting primary problems in growth resulting from defective formation of bone or cartilage. This category of diseases includes a heterogenous group of disorders with a wide variety of clinical and radiographic manifestations. Much of the variation stems from the different combinations of involved bones and the ways in which these bones are affected in their shape, length, and density. Most skeletal dysplasias are genetically determined, can be inherited, and result in disproportionately short stature. Because of the last problem, the term dwarfism frequently is applied to these disorders. Other names include chondrodysplasias, osteochondrodysplasias, and bone dysplasias.

More than 200 recognized types of skeletal dysplasias exist. The incidence of any single dysplasia is relatively low. Collectively, however, they are relatively frequent (1 in 3,000 to 5,000 births). Because of this frequency and the diversity of these conditions, it is essential that the practitioner be able to recognize a fetus, newborn, or child with a skeletal dysplasia so that the diagnosis can be established, the prognosis determined, and a treatment plan developed. Genetic counseling should be
available to the individual, parents and family in regards to recurrence risks.

This chapter provides the primary-care physician with a basic understanding of skeletal dysplasias and presents the major clinical and radiographic features and complications of the more commonly encountered disorders. When encountering one of these disorders, the responsibilities of the primary-care physician are to treat any immediate medical problems, become familiar with the particular skeletal dysplasia present in the patient, and obtain appropriate and timely consultation. In all cases in which the patient survives the neonatal period, a long-term treatment program should be established.


Most skeletal dysplasias are uncommon, and often their exact incidence is unknown. Osteogenesis imperfecta (OI or brittle bone disease), type I, which is one of the milder forms of the disorder, has an estimated frequency of 1 in 20,000 births. OI type II, the more severe and normally lethal form, is less common and affects approximately 1 in 50,000. Thanatophoric dysplasia, the most frequently encountered lethal skeletal dysplasia, is seen in approximately 1 in 30,000 births. Classic or heterozygous achondroplasia, the most common nonlethal skeletal dysplasia, occurs with a frequency of 1 in 25,000.

On the other hand, the incidence of some skeletal dysplasias in certain ethnic groups may be much higher. For instance, the McKusick type of metaphyseal chondrodysplasia (cartilage-hair hypoplasia) is rare in the general population, but is found in approximately 1 in 500 live births among the Amish population of North America. The higher incidence of certain bone dysplasias in some ethnic groups normally is the result of inbreeding or other factors that have increased the gene frequency in that group.


Development and Anatomy of Bone

Bone is formed from either mesodermal or neural crest cells. These cells form mesenchyme, which in turn forms embryonic connective tissue. For cartilaginous bone, cartilage is formed within the embryonic connective tissue, which then changes to bone. For membranous bone, the bone is formed directly within the connective tissue. The cartilage in cartilaginous bone is formed by chondroblasts, whereas the mineral portion of the bone is derived from osteoblasts in both bone types. The skull (except for its base), maxilla, mandible, squamous portion of the temporalis, nasal bones, and clavicles are membranous bone; all the rest of the skeleton is cartilaginous bone.

The anatomy of long bones is depicted in Figure 433.1. When long bones are growing, the growing end is known as the epiphysis. Below the epiphyseal center is the metaphysis. Longitudinal growth actually occurs at the junction between the epiphysis and the metaphysis, an area called the physis or growth plate. During puberty, the growth plate is obliterated, the epiphysis and metaphysis fuse, and lengthening of the bone ceases. The shaft of the bone is called the diaphysis. Molding of the diaphysis takes place as the bone becomes longer. The diaphysis also thickens with age and in response to increased stress exerted on the bone.

FIGURE 433.1. Anatomy of normal prepubertal tubular bone. Note that the bone is divided into four segments, each of which may be involved in skeletal dysplasias either separately or in combination.

Nomenclature and Classification of Skeletal Dysplasias

Skeletal dysplasias in general are named after the anatomic parts of the bones that are affected, after the appearance of the bone, or after the individual(s) who originally described the condition (Fig. 433.2). In some cases, a combination of these methods is used.

An example of the anatomic naming of bone dysplasias is multiple epiphyseal dysplasia (Fig. 433.3). In this condition,
numerous epiphyses (see Fig. 433.2B) are involved, whereas the spine is affected only minimally. As a result of the involvement of multiple epiphyses, the individual usually has short stature and, with age, may develop significant arthritis in the involved joints. Another example of anatomic nomenclature is spondyloepiphyseal dysplasia congenita, in which many of the epiphyses, including those of the spine (spondylo-), are abnormal. The clinical picture is one of small, irregular epiphyses, flattened vertebral bodies (platyspondyly; see Fig. 433.2E, F) and, in some cases, kyphoscoliosis.

FIGURE 433.2. Diagrammatic representation of various types of bone dysplasias. A: Normal shape of growing long bones. B: Epiphyseal involvement such as in multiple epiphyseal dysplasia; note flattened and irregular epiphysis. C: Metaphyseal involvement that might be seen in achondroplasia; note widening and irregular surface of metaphysis. D: Diaphyseal involvement as seen in craniodiaphysial dysplasia. E: Normal lateral view of vertebra. F: Vertebral involvement that can be found in spondyloepiphyseal dysplasia congenita; note vertebral body flattening and surface irregularities. (Modified with permission from Rimoin DL, Lachman RS. The chondrodysplasias. In: Emery AEH, Rimoin DL, eds. Principles and practice of medical genetics. New York: Churchill Livingstone, 1990:895.)

FIGURE 433.3. Radiographs of a patient with multiple epiphyseal dysplasia. A: Pelvis and hips at age 8 years; note small irregular proximal femoral epiphyses and poorly developed acetabular roof. B: Knees of patient at age 10 years; note irregular and mottled epiphyses of the long bones.

Other bone dysplasias are named after the appearance of the bone. An example is campomelic (or camptomelic) dysplasia. In this disorder, a characteristic bowing of the long bones of the lower extremities occurs. The term camptomelic is coined from the Greek campo, which means bent or curved. In OI, the term imperfecta refers to poorly mineralized bone. In a newly described disorder, schneckenbecken dysplasia, the pelvis is shaped like a snail shell; schneckenbecken is German for “snail-shaped.”

The third mechanism for naming bone dysplasias involves the use of eponyms. For example, Kniest dysplasia is a rare, autosomal dominant disorder characterized by short stature and dumbbell-shaped femurs with extremely broad and shortened femoral necks. Kniest first reported the condition in 1952.

Frequently, eponyms are used in combination with one of the first two methods of naming skeletal dysplasias, most often to delineate the particular subtype of dysplasia. For instance, two types of achondrogenesis exist, one known as Parenti-Fraccaro achondrogenesis (type I) and the other as Langer-Saldino achondrogenesis (type II; Fig. 433.4). These two subtypes are not based on differences in the clinical appearance of the affected children (both types have nearly identical clinical phenotypes), but on radiographic variations. Type I has been subdivided further into type IA, with rib fractures and spike-shaped femurs; and type IB, without the rib fractures but with a pelvis that appears to be turned upside down. Type IA also has been denoted as the Houston-Harris type and type IB as the Fraccaro type.

Various systems for classifying the skeletal dysplasias have been devised. One of the earliest of these was based on the relative shortening of the limb or spine: For example, was the short stature of the child caused by primary shortening of the extremities, with relatively normal spinal length, or was the spine relatively short compared with the length of the arms and legs?

Achondroplasia is one example of a short-limbed skeletal dysplasia. In this condition, the sitting height—that is—the length of the trunk and head of an individual when she is sitting, is nearly normal, but the standing height is far less than normal. This reflects the very short legs in this condition. On the other hand, patients with Morquio syndrome (mucopolysaccharidosis, type IV) have the opposite characteristics. They have short trunk and, in relationship to the spinal length, long extremities. The shortening of the spine in Morquio syndrome is primarily a result of platyspondyly.

Another classification system is based on the age at which the first manifestation of the skeletal dysplasia appears. Some disorders can be detected prenatally or at birth (congenita), whereas others do not have clinical or radiographic manifestations until months or years after birth (tarda). Yet another system is based on the pattern of bone involvement and the types of skeletal changes seen in a particular disorder. The International Nosology and Classification of Constitutional Disorders of the Bone (Table 433.1) use this approach.

Yet another approach has been put forth by Kornak and Mundlos. Utilizing recent advances in molecular genetics, these authors have presented a classification based on a combination of molecular pathology and embryology. Bones develop first by the formation of a pattern: the determination of the location, size and shape of individual bones. Next, mesenchymal cells differentiate and condense into cartilage. Third, growth occurs in the cartilaginous growth plates at the ends of long bones. Finally, remodeling and homeostasis occurs. These authors have classified bone disorders according to how these disorders affect these four phases of bone development and maintenance. Bone disorders also may be classified as lethal and nonlethal.


Dysostoses are conditions predominately affecting individual bones, either singly or a few in combination. A specific bone may be absent, hypoplastic, or malformed. Further dysostoses are distinguished from more generalized skeletal dysplasias
by being formed during embryogenesis (the third through the eighth week post conception), whereas skeletal dysplasias generally develop throughout intrauterine development and childhood.

FIGURE 433.4. Achondrogenesis, type II in a term newborn. A: Note severe growth deficiency (standard ballpoint pen alongside for comparison), small chest and extremities, and protruding abdomen. This was a postmortem picture. B: Radiograph of the same patient; note the very short, irregularly shaped bones of the extremities, short and horizontal ribs, and poorly calcified vertebral bodies.

Delineation of Skeletal Dysplasias

The discovery of new skeletal dysplasias has been an ongoing process since the 1940s. As noted already, a bewildering number of different disorders are recognized, making diagnosis problematic for the average clinician. The recognition of a specific disorder further is complicated by the similar appearances of many of these conditions. Furthermore, a spectrum of severity may exist within a single entity, or two conditions may have overlapping features, making arrival at a correct diagnosis exasperating even for the experts. A further characteristic of many skeletal dysplasias is that these conditions often become more severe with time. The condition may manifest prenatally, and may be severe, if not lethal, at birth. If the disorder is not lethal or not expressed at birth, it invariably worsens with age. If a child is seen early in the course of the condition, when the features often are not expressed fully, one may find it difficult or impossible to make the diagnosis.

During the 1940s, most individuals with disproportionately short stature were classified as having achondroplasia if the extremities were relatively short, or as having Morquio disease if the trunk was shortened disproportionately. Since then, numerous different skeletal dysplasias with similar appearances have been delineated from each of these disorders. This demarcation has been accomplished by the careful study of clinical, radiographic, and pathologic features, and noting the inheritance patterns of each. A newer trend in the grouping of skeletal dysplasias involves categorizing each skeletal dysplasia based on the specific protein, enzyme, or gene defect involved, if known.

The biochemical and/or genetic delineation of numerous skeletal dysplasias has made it clear that many previously described and well-characterized conditions are, in actuality, the result of mutations at different locations within the same gene. The opposite also is true; individuals with the same apparent clinical condition may be biochemically and molecularly distinct. This heterogeneity in part accounts for the difference in severity of the “same” clinical condition.

Molecular Genetics and Biochemistry of Skeletal Dysplasias

During the last two decades, much has been learned about the molecular genetics and biochemistry of many skeletal dysplasias. Biochemical errors have been found in the structural proteins of cartilage (specifically different types of collagen), enzymes of cartilage metabolism (lysosomal enzymes), and regulators of cartilage growth (fibroblast growth factor receptors). As other genes and biochemical pathways in bone formation and function are found, one would expect to find additional errors in the bone matrix, osteoid (the mineral portion of the bone), and other components of cartilage. In addition, problems may be found in the function of the osteoblasts (those cells that form bone) or the osteoclasts (those cells that degrade and reshape bone).

One of the first skeletal dysplasias to be understood on the molecular and biochemical levels was OI. This disorder is characterized by bone fragility resulting in fractures. OI is divided into four main types based on clinical and radiographic findings. Type II is normally a perinatal or neonatal lethal, with multiple fractures occurring in utero, and the affected newborn typically having marked respiratory distress because of a small and excessively flexible chest and short and curved long bones. OI type III also presents at birth with multiple fractures, but respiratory complications are not as severe as in type II. Individuals with OI type III typically have multiple broken bones occurring throughout their life, progressive bone deformation, and marked short stature. OI types I and IV are less severe, with fewer fractures and most fractures occurring postnatally;

short stature and teeth abnormalities also may be present. All four types of OI are produced by a defect in either the procollagen pro-alpha1 gene (COL1A1) or the procollagen pro-alpha2 gene (COL1A2). These genes normally produce the polypeptides pro-alpha1 and pro-alpha2, respectively. Under normal circumstances, two pro-alpha1 chains combine with one pro-alpha2 procollagen in a helical structure to form type I procollagen (Fig. 433.5). The end portions of the type I procollagen molecules then are cleaved to form mature procollagen molecules that are then secreted into the extracellular matrix and incorporated into the definitive type I collagen fibril. Deletions of one or more amino acids, or the substitutions of amino acids in the pro-alpha1 or pro-alpha2 chains, have been found in most patients with OI.


  1. Osteochondrodysplasias (Defects of tubular [and flat] bones and/or axial skeleton)

    1. Achondroplasia group
      SADDAN (severe achondroplasia, developmental delay, acanthosis nigricans)
      Thanatophoric dysplasia, type I
      Thanatophoric dysplasia, type II (cloverleaf skull, straight femur)
    2. Severe spondylodysplastic dysplasias
      Achondrogenesis, type IA
      Lethal platyspondylic skeletal dysplasias (Torrance and Luton types)
      Spondylometaphyseal dysplasia, Sedaghatian type
    3. Metatropic dysplasia group
      Metatropic dysplasia (various forms)
      Schneckenbecken dysplasia
    4. Short-rib dysplasia with or without polydactyly
      Asphyxiating thoracic dysplasia (Jeune syndrome)
      Chondroectodermal dysplasia (Ellis-van Creveld dysplasia)
      Short-rib dysplasia, type 1/III (Saldino-Noonan/Verma-Naumoff types)
      Short-rib dysplasia, type II (Majewski type)
      Short-rib dysplasia, type IV (Beemer type)
      Thoracolaryngopelvic dysplasia (Barnes syndrome)
    5. Atelosteogenesis-omodysplasia group
      Atelosteogenesis type I (includes “boomerang dysplasia”)
      Atelosteogenesis, type III de la Chapelle dysplasia
      Omodysplasia I, Maroteaux type
      Omodysplasia II, Borochowitz type
    6. Diastrophic dysplasia group
      Achondrogenesis, type 1B
      Diastrophic dysplasia
      Multiple epiphyseal dysplasia, autosomal recessive type
    7. Dyssegmental dysplasia group
      Dyssegmental dysplasia, Rolland-Desbuquois type
      Dyssegmental dysplasia, Silverman-Handmaker type
    8. Type II collagenopathies
      Achondrogenesis, type II (Langer-Saldino type)
      Kniest dysplasia
      Mild spondyloepidysplasia with premature onset arthrosis
      Spondyloepimetaphyseal dysplasia
      Spondyloepiphyseal dysplasia congenita
      Spondyloepiphyseal dysplasia, Namaqualand type
      Spondyloperipheral dysplasia
      Stickler syndrome, type I
      Strudwick type
    9. Type XI collagenopathies Stickler syndrome, type II (with or without ocular involvement)
      Marshall syndrome
      Otospondylomegaepiphyseal dysplasia
      Stickler syndrome, type III (without ocular involvement)
    10. Other spondyloepi (meta) physeal dysplasias
      Anauxetic dysplasia
      Dyggve-Melchior-Clausen dysplasia
      Immunoosseous dysplasia (Schimke immunoosseous dysplasia)
      Progressive pseudorheumatoid dysplasia
      Schwartz-Jampel syndrome
      SPONASTRIME dysplasia
      Spondyloepimetaphyseal dysplasia short limb-abnormal calcification type
      Spondyloepimetaphyseal dysplasia with joint laxity
      Spondyloepimetaphyseal dysplasia with multiple dislocations, Hall type
      Spondyloepimetaphyseal dysplasia, Handigodu type
      Spondyloepimetaphyseal dysplasia, Pakistani type
      Wolcott-Rallison dysplasia
      X-linked spondyloepiphyseal dysplasia tarda
    11. Multiple epiphyseal dysplasias and pseudoachondroplasia
      Familial hip dysplasia, Beukes type
      Multiple epiphyseal dysplasia, Fairbanks and Ribbing types
    12. Chondrodysplasia punctata (stippled epiphyses group)
      CHILD (limb-reduction ichthyosis)
      Chondrodysplasia punctata, X-linked dominant, Conradi-Hünermann type
      Chondrodysplasia punctata, X-linked dominant, rhizomelic type 1
      Chondrodysplasia punctata, X-linked dominant, rhizomelic type 2
      Chondrodysplasia punctata, X-linked dominant, rhizomelic type 3
      Chondrodysplasia punctata, X-linked dominant, tibia-metacarpal type
      Chondrodysplasia punctata, X-linked recessive type (brachytelephalangic)
      Dappled diaphyseal dysplasia
      Hydrops-ectopic calcification-moth-eaten appearance (Greenberg dysplasia)
    13. Metaphyseal dysplasias
      Acroscyphodysplasia (various types)
      Adenosine deaminase deficiency
      Cartilage hair hypoplasia (metaphyseal chondrodysplasia, McKusick type)
      Metaphyseal anadysplasia (various types)
      Metaphyseal chondrodysplasia, Jansen type
      Metaphyseal chondrodysplasia, Schmid type
      Metaphyseal chondrodysplasia, Spahr type
      Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Shwachmann-Diamond syndrome)
    14. Spondylometaphyseal dysplasias
      Spondylometaphyseal dysplasia (Sutcliffe corner fracture type)
      Spondylometaphyseal dysplasia with severe genu valgum (including Schmidt and Algerian types)
      Spondylometaphyseal dysplasia, Kozlowski type
    15. Brachyolmia spondylodysplasias
      Brachyolmia spondylodysplasias, autosomal dominant type
      Brachyolmia spondylodysplasias, Hobaek and Toledo types
      Brachyolmia spondylodysplasias, Maroteaux type
    16. Mesomelic dysplasias
      Leri-Weill dyschondrosteosis
      Mesomelic dysplasia with synostoses
      Mesomelic dysplasia, Kantaputra type
      Mesomelic dysplasia, Kozlowski-Reardon type
      Mesomelic dysplasia, Langer type (homozygous Leri-Weill dyschondrosteosis)
      Mesomelic dysplasia, Nievergelt type
      Mesomelic dysplasia, Reinhardt-Pfeiffer type
      Mesomelic dysplasia, Robinow type, dominant
      Mesomelic dysplasia, Robinow type, recessive
    17. Acromelic dysplasias
      Acromicric dysplasia
      Angel-shaped phalangoepiphysea dysplasia
      Brachydactyly, type A1
      Brachydactyly, type A2
      Brachydactyly, type A3
      Brachydactyly, type B
      Brachydactyly, type C
      Brachydactyly, type D
      Brachydactyly, type E
      Brachydactyly-hypertension dysplasia (Bilginturan syndrome)
      Camptodactyly arthropathy coxa vara pericarditis
      Christian brachydactyly
      Craniofacial conodysplasia
      Geleophysic dysplasia
      Myhre dysplasia
      Pseudohypoparathyroidism (Albright hereditary osteodystrophy)
      Saldino-Mainzer dysplasia
      Trichorhinophalangeal dysplasia type II (Langer-Giedion syndrome)
      Trichorhinophalangeal dysplasia types I/III
      Weill-Marchesani dysplasia
    18. Acromesomelic dysplasias
      Acromesomelic dysplasia, Campailla-Martinelli type
      Acromesomelic dysplasia, Ferraz/Ohba type
      Acromesomelic dysplasia, Maroteaux type
      Acromesomelic dysplasia, type Osebold-Remondini
      Cranioectodermal dysplasia
      Grebe dysplasia
    19. Dysplasias with predominant membranous bone involvement
      Cleidocranial dysplasia
      Parietal foramina (isolated)
      Yunis-Varon dysplasia
    20. Bent-bone dysplasia group
      Camptomelic dysplasia
      Cummins syndrome
      Stuve-Wiedemann dysplasia (neonatal Schwartz-Jampel)
    21. Multiple dislocations with dysplasias
      Desbuquois syndrome
      Larsen syndrome
      Larsen-like syndromes (including La Reunion Island)
      Pseudodiastrophic dysplasia
    22. Dysplasias with decreased bone density
      Bruck dysplasia, types I–II
      Cole-Carpenter dysplasia
      Geroderma osteodysplasticum
      Idiopathic juvenile osteoporosis
      Osteogenesis imperfecta, types I–IV
      Osteopenia with radiolucent lesions of the mandible
      Osteoporosis with pseudoglioma
      Singleton-Merten syndrome
    23. Dysplasias with defective mineralization
      Hypophosphatasia, adult form
      Hypophosphatasia, autosomal recessive perinatal lethal and infantile forms
      Hypophosphatemic rickets
      Neonatal hyperparathyroidism
      Transient neonatal hyperparathyroidism with hypocalciuric hypercalcemia
    24. Increased bone density without modification of bone shape
      Cranial osteosclerosis with bamboo hair (Netherton syndrome)
      Mixed sclerosing bone dysplasia
      Osteopathia striata with cranial sclerosis
      Osteopathia striata, isolated
         Delayed form, type I
         Delayed form, type II
         Infantile form
         Intermediate form
         With ectodermal dysplasia and immune defect
         With infantile neuroaxonal dysplasia
      Osteosclerosis, Stanescu type
    25. Increased bone density with diaphyseal involvement
      Craniodiaphysial dysplasia
      Diaphyseal dysplasia (Camurati-Engelmann syndrome)
      Diaphyseal dysplasia with anemia (Ghosal hematodiaphseal dysplasia)
      Diaphyseal medullary stenosis with bone malignancy
      Kenny-Caffey dysplasia, type I
      Kenny-Caffey dysplasia, type II
      Lenz-Majewski dysplasia
         Endosteal hyperostosis
         Scleroosteocerebellar dysplasia
         van Buchem type
         Worth type
      Oculodentoosseous dysplasia
      Osteoectasia with hyperphosphatasia (juvenile Paget disease)
      Trichodento-osseous dysplasia
    26. Increased bone density with metaphyseal involvement
      Pyle dysplasia
         Craniometaphyseal dysplasia
         Mild type
            Severe type

  2. Disorganized development of cartilaginous and fibrous components of the skeleton
    Carpotarsal osteochondromatosis
    Cherubism with gingival fibromatosis
    Dysplasia epiphysealis hemimelica
    Enchondromatosis (Ollier disease)
    Enchondromatosis with hemangiomata (Maffucci syndrome)
    Fibrodysplasia ossificans progressiva
    Fibrous dysplasia (McCune-Albright and other types)
    Jaffe-Campanacci type
    Multiple cartilaginous exostoses
    Osteoglophonic dysplasia
    Spondyloenchondromatosis with basal ganglia calcification
Modified with permission from Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002;113:65.

FIGURE 433.5. Normal type I procollagen molecule on the left showing normal helical formation. The figure on the right depicts the lack of coiling of the polypeptides when a change in or deletion of one or more amino acids occurs in both pro-alpha1 chains, leading to degradation of the molecule. One pro-alpha1 chain in each figure has been thickened for clarity.

When these defects occur in the pro-alpha1 or pro-alpha2 chains, the formation of the normal helical structure of the type I procollagen molecule frequently is disrupted (see Fig. 433.5). If the disruption is significant enough, the abnormally formed procollagen is degraded within the cell, a process called protein suicide. The end result of protein suicide is a deficiency of type I collagen, but the type I collagen that is formed is normal. When the disruption of the helical formation is less severe, intracellular degradation of the procollagen fiber may not occur, and the abnormal procollagen is secreted from the cell and incorporated into the collagen fiber, thus making the collagen abnormal. Studies have shown that individuals who have more severe mutations (for example, premature stop codons or a substitution of a glycine) that prevent a pro-alpha1 or a pro-alpha2 chain from being formed typically have a milder form of OI (OI type I or IV), whereas those who have less disruptive mutations (single base-pair changes leading to substitution of a nonglycine amino acid) that allow the abnormal protein to be incorporated into the procollagen strand tend to have a more severe form of OI (type II or III). The clinical phenotype appears to be milder if only 50% of the normal collagen protein is present, as opposed to having a normal amount of abnormally formed collagen. In reality, OI is a continuous spectrum of severity with type II being at one end and normally an early lethal condition, and types I and IV being at the other, with some individuals having few problems and a normal lifespan. This spectrum in part is due to the fact that over 200 mutations have been reported in COL1A1 and COL1A2 genes. However, the severity in any one family is frequently often similar, because affected individuals normally possess the identical mutations (the exception being type IV, in which striking intrafamilial variability may be present).

Until recently, isolated cases of possible OI were evaluated by looking for the abnormal or reduced production of procollagen in tissue samples, usually through skin biopsy from affected individuals. This evaluation detected approximately 85% of individuals with OI. However, direct gene testing of COL1A1 or COL1A2 now is available. Testing for these genes can be done on a blood sample and involves sequencing of both the COL1A1 and COL1A2 genes. This testing finds a mutation in 95% of individuals with clinical OI.

Another bone dysplasia that has been studied in detail is achondroplasia, the most common nonlethal skeletal dysplasia causing short stature. The genetic defect in achondroplasia has been isolated to a specific mutation in the fibroblast growth factor receptor 3 (FGFR3) gene (Figs. 433.6 and 433.7). In more than 99% of analyzed achondroplastic cases, a glycine-to-arginine substitution has been found at amino acid position 380 of the receptor. On the other hand, mutations in other areas of the FGFR3 gene result in a lethal bone dysplasia, thanatophoric dysplasia, and a milder skeletal dysplasia,
hypochondroplasia. The location of these and other mutations in the FGFR3 gene are depicted in Fig. 433.7.

FIGURE 433.6. Model of fibroblast growth factor receptor 3 (FGFR3). The ligand, fibroblast grown factor (FGF), first binds to heparan sulfate proteoglycan (HSPG) (hashed half ovoids attached to the cell membrane), or heparan sulfate (HS). The complex then forms a trimolecular complex with FGFR3, resulting in structural changes in the tyrosine kinase parts of the molecules (KA and KB) and sequences genetic regulation of the cell. The IgI, IgII, and IgIII regions represent immunoglobin-like loops involved in the attachment of the FGF-HS/FGF-HSPG complex. The 23 recognized FGFs are structurally related polypeptides that play various roles in bone embryogenesis, growth, and homeostasis by inducing differentiation and mitogenesis, and stimulating chemotaxes, cell survival, and angiogenesis. Tyrosine kinase domains are involved in intracellular signalling. (Modified with permission from Givol D, Yayon A. Complexity of FGF receptors: genetic basis for structured diversity and functional specificity. FASEB J 1992;6:3362.)

FIGURE 433.7. Location of mutations found in fibroblast growth factor receptor 3 (FGFR3) protein resulting in the indicated bone dysplasias. Achondroplasia is produced at only one location, the transmembrane TM domain, whereas thanatophoric dysplasia, type I results from mutations at five different sites. Abbreviations starting from the left: SP, signal peptide; SS, sulfide bonds keeping the IgI, IgII and IgIII immunoglobin-like loops in their looped form. KA and KB are tyrosine kinase domain involved in intracellular signaling. (Modified with permission from Givol D, Yayon A. Complexity of FGF receptors: genetic basis for structured diversity and functional specificity. FASEB J 1992;6:3362 and Cohen MM Jr. Fibroblast growth factor receptor mutations. In: Cohen MM Jr., MacLean RE, eds. Craniosynostosis: diagnosis, evaluation, and management, 2nd ed. New York: Oxford University Press, 2000:77.)

One current hypothesis to explain why different mutations in the FGFR3 gene cause different bone dysplasias is based on the mutations causing a range of tyrosine kinase activity (referred to as a gain of function mutation). Tyrosine kinase acts as a negative regulator for endochondral bone growth. The more “turned on” the tyrosine kinase, the greater the reduction in bone length, and thus the greater the severity of the bone dysplasia. Different mutations in the FGFR3 gene lead to a varying degree of up-regulation of the tyrosine kinase and result in the various dysplasias associated with this gene.

Another recent advance in the understanding of normal and abnormal bone growth and the cause of certain bone dysplasias has been the discovery of the SHOX gene. SHOX is the abbreviation for short stature homeobox-containing gene. This gene is located in the pseudoautosomal region of the p-arm of the X and Y chromosomes. The pseudoautosomal regions in these chromosomes contain homologous genes, one gene on the X and one on the Y chromosomes. In females, the genes on the pseudoautosomal regions are not inactivated on the inactivated X-chromosome and, as a result, in both males and females both homologous genes are active. In Turner syndrome, in which only an X chromosome is present or in which the p arm of one X chromosome is missing or partially missing, only half the normal SHOX gene is produced; this in turn leads to the short stature seen in this condition. Furthermore, deletions and point mutations of this gene can lead to idiopathic short stature (ISS) or certain bone dysplasias. Deletions leading to ISS seem to be relatively common, and recently it has been shown that 7% of ISS cases are associated with deletions in the SHOX gene. In individuals with these deletions, the radiographic appearance of the skeleton and growth hormone secretion are normal. Of further interest is that two related skeletal dysplasias also have been found to have mutations or deletions in this gene. The first condition is Leri-Weill dyschondrosteosis, an autosomal dominant disorder, characterized by Madelung deformity of the wrists (bowing of the radius and distal hypoplasia of the dorsally dislocated ulna) and short stature, with most of the shortening in the forearms (mesomelic shortening). In roughly 80% of Leri-Weill dyschondrosteosis cases, a deletion of the gene occurs; in about 20% of cases, a point mutation occurs. A second, rare disorder is mesomelic dysplasia, Langer type, which is the homozygous dominant state of the Leri-Weill dyschondrosteosis; it is caused by mutations in or deletion of both SHOX genes. Why this range in phenotypic expression is associated with the various mutations and deletions of this gene has not been unraveled.

Other biochemical defects also are known to cause skeletal dysplasias. In some forms of hypophosphatasia, a complete or partial deficiency of bone alkaline phosphatase occurs, thus leading to undermineralized osteoid. Vitamin-, mineral-, and hormone-deficient states also can produce skeletal dysplasias. One of the most severe bone dysplasias known (cretinism) is produced by the total absence of thyroxine. The dysplasia occurs because thyroxine appears to be one of the more important hormones involved in normal bone growth, and its deficiency produces a severe delay in osseous maturation.

With the continued application of DNA technologies, the identification of more of the defective genes producing bone dysplasias has been possible. Table 433.2 lists selected genes causing bone dysplasias, their chromosomal locations, and the gene products. In the future, the identification of additional genes will lead to further elucidation of the various biochemical defects, more reliable and specific methods of diagnosing bone dysplasias prenatally and postnatally and, ultimately, methods of treating or preventing these disorders.


The diagnosis of a skeletal dysplasia should be considered in any patient who has disproportionately short stature or abnormal development of one or more bones. When one encounters such an individual, that individual should be evaluated fully to determine whether a skeletal dysplasia is present and, if so, which one. The history should include a pregnancy history, with particular reference to any fetal evaluation; birth length, weight, and head circumference; postnatal growth and development; and medical problems. With regard to the family history, one should inquire about short stature and orthopedic problems in other family members and determine if consanguinity exists between the parents. While performing the physical examination, one should take care to search for nonosseous abnormalities such as cataracts, cleft palate, and congenital heart disease that would be useful in establishing the diagnosis and be helpful in formulating a treatment plan. Basic measurements should be obtained, including height, weight, head circumference, arm span, and upper segment–to–lower segment ratio. The lower segment length is determined by measuring the distance from the anterior-superior edge of the pubic symphysis to the floor while the patient is standing, or to the bottom of the feet in infants. The upper segment length is obtained by subtracting the lower segment length from the total body length. The upper segment–to–lower segment ratio is obtained by dividing the upper segment length by the

lower segment length. The upper segment–to–lower segment ratio in normal children varies from 1.6 at birth to 0.93 in older teenagers and adults. Many children with bone dysplasias have ratios that are greater than normal for their age as a result of having short lower extremities, whereas children with values less than normal for their age usually have short trunks.


  Gene Chromosomal Locus Peptide/Protein/Enzyme
Disorders of Collagen
Type I collagenopathies
   Osteogenesis imperfecta
      Types I-IV COL1A1 17q21.31q22.05 α (1) I procollagen
      Types I-IV COL1A2 7q22.1 α (2) I procollagen
Type II collagenopathies COL2A1 (multiple mutations) 12q13.1q13.2 α (II) collagen
   Achondrogenesis, type II
   Kniest dysplasia
   Osteoarthrosis, precocious
   Spondyloepiphyseal dysplasia congenita
   Spondyloepimetaphyseal dysplasia, Strudwick type
   Spondyloepiphyseal dysplasia with brachydactyly
   Mild spondyloepiphyseal dysplasia with premature onset arthrosis
   Stickler syndrome, type I
   Wagner syndrome, type II
Type IX collagenopathies
   Multiple epiphyseal dysplasia COL9A1 6q13 Type IX collagen
   Multiple epiphyseal dysplasia, type 2 COL9A2 1p32.2p33 Type IX collagen
   Multiple epiphyseal dysplasia, type 3 COL9A3 20ql3.3 Type IX collagen
Type X collagenopathies
   Metaphyseal dysplasia, Schmid type COL10A1 6q21q22.3 COL10 α chain
Type XI collagenopathies
   Marshall syndrome COL11A1 1p21 Collagen II α1, α2 chains
   Otospondylomegaepiphyseal dysplasia COL11A2 6p21.3 Collagen II α1, α2 chains
   Stickler syndrome, type II COL11A2 6p21.3 Collagen II α1, α2 chains
   Stickler syndrome, type III COL11A1 1p21 Collagen II α1, α2 chains
Dysplasias with Significant Membranous Bone Involvement
Cleidocranial dysplasia CBFA1 6p21 Core binding factor transcription factor α1 subunit
Disorders with Ectopic Bone Formation
Fibrodysplasia ossificans progressiva BMP4 14q22q23 Bone morphogenetic protein 4
   Multiple cartilaginous exostoses EXT1
   Trichorhinophalangeal syndrome, type 2 (Langer-Giedion syndrome) EXT1 & TRPS1 8q
Disorders of Fibroblast Growth Factor Receptor 3
Achondroplasia FGFR3 (G1138A & G1138C mutations) 4p16.3 Fibroblast growth factor receptor protein
Hypochondroplasia FGFR3 (C1620A) 4p16.3 Fibroblast growth factor receptor protein
Platyspondylic lethal skeletal dysplasia, San Diego type FGFR3 4p16.3 Fibroblast growth factor receptor protein
SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) FGFR3 (A1949T) 4p16.3 Fibroblast growth factor receptor protein
Thanatophoric dysplasia, type I FGFR3 (C742T, A1118G & others) 4p16.3 Fibroblast growth factor receptor protein
Thanatophoric dysplasia, type II FGFR3 (A1948G) 4p16.3 Fibroblast growth factor receptor protein
Chondrodysplasia Punctatas
Chondrodysplasia punctata, rhizomelic type 1 PEX7 6q22–q24 PTS2 receptor
Chondrodysplasia punctata, rhizomelic type 2 DHAPAT 1q42 Dihydroxy-acetonphosphate acyltransesterase
Chondrodysplasia punctata, rhizomelic type 3 AGPS 2q31 alkyl-diahydroxy-diacetonphosphate synthase
Chondrodysplasia punctata, X-linked dominant Conradi-Hünermann type EBP Xp11.22p11.23 3β-hydroxy-steriod-δ8, δ7-isomerase
Chondrodysplasia punctata, X-linked recessive type (brachytelephalangic) ARSE Xp22.3 arylsulfatase E
Defects in Cartilage Oligomeric Matrix Protein
   Multiple epiphyseal dysplasia MATN3   matrilin-3
   Multiple epiphyseal dysplasia, Fairbanks and Ribbing types COMP 19p cartilage oligomeric matrix protein
COL9A2 1p32.2p33 type IX collagen
COL9A3 20q13.3 type IX collagen
MATN3 2p23p24 matrilin 3
   Pseudoachondroplasia COMP 19p cartilage oligomeric matrix protein
Defects in Diastrophic Dysplasia Sulfate Transporter
Achondrogenesis, type 1B DTDST 5q32q23 defect in diastrophic dysplasia sulfate transporter
Atelosteogenesis, type II DTDST 5q32q23 defect in diastrophic dysplasia sulfate transporter
de la Chapelle dysplasia DTDST 5q32q23 defect in diastrophic dysplasia sulfate transporter
Diastrophic dysplasia DTDST 5q32q23 defect in diastrophic dysplasia sulfate transporter
Multiple epiphyseal dysplasia, autosomal recessive type DTDST 5q32q23 defect in diastrophic dysplasia sulfate transporter
Dysplasias with Abnormal Mineralization
Hypophosphatasia, adult form ALPL 1p36.1p34 tissue nonspecific alkaline phosphatase
Hypophosphatasia, autosomal recessive perinatal lethal and infantile forms ALPL 1p36.1p34 tissue nonspecific alkaline phosphatase
Hypophosphatemic rickets PHEX Xp22.2p22.1 phosphate regulating neutral endopeptidase
Hypophosphatemic rickets, autosomal dominant type FGF23
fibroblast growth factor 23
osteoblast proton pump subunit
Osteopetrosis, infantile form CLCN7 11q13.4q13.5
chloride channel 7 pump
carbonic anhydrase II
Osteopetrosis with renal tubular acidosis CTSK 1q21 cathespin K
Pyknodysostosis VDDR1 12q14 25-α-hydroxycholecalciferol- 1-hydroxylase
Vitamin D-dependent rickets, type 1 VDDR2 12q12q14
Vitamin D-resistant rickets with end-organ unresponsiveness to vitamin D3 1,25-α-dehydroxy-vitamin D3 receptor
Mesomelic Dysplasias
Leri-Weill dyschondrosteosis SHOX Xpterp22.32 SHOX protein
Mesomelic dysplasia, Langer type (homozygous Leri-Weill dyschondrosteosis) SHOX Xpterp22.32 SHOX protein
Metaphyseal Chondrodysplasias
Cartilage-hair hypoplasia (metaphyseal chondrodysplasia, McKusick type) RMRP 9p13 RNA component mitochondrial
RNA processing endoribonuclease
Metaphyseal chondrodysplasia, Jansen type PTHR 3p22p21.1 parathyroid hormone receptor
Miscellaneous Disorders
Camptomelic dysplasia SOX9 17q24.3q25.1 SRY-box 9
Cherubism SH3BP2 4p16.3 SH3 domain-binding protein 2
Chondroectodermal dysplasia (Ellis-van Creveld dysplasia) EVC 4p16
Craniometaphyseal dysplasia ANKH 5p15.2p14.1 pyrophosphate transporter
Dyggve-Melchior-Clausen dysplasia FLJ90130 18q12q21.1 SH3 domain-binding protein 2
Dyssegmental dysplasia, Silverman-Handmaker type PLC (HSPG2) 1q36q34 perlecan
Grebe dysplasia CDMP1 20q11.2 cartilage derived morphogenic protein 1
McCune-Albright fibrous dysplasia GNAS1 20q13 guanine nucleotide protein α subunit
Nail-patella dysplasia LMX1B 9q34.1 LIM homeodomain
Pseudohypoparathyroidism (Albright hereditary osteodystrophy) GNAS1 20q13 guanine nucleotide binding protein of edenylate cyclase α–subunit
Robinow syndrome, autosomal recessive ROR2 9q22 orphan receptor tyrosine kinase anhydrase II
Schwartz-Jampel syndrome PLC (HSPG2) 1q36q34 perlecan
Spondylocostal dysplasia DLL3 19q13 delta-like 3 signaling protein
Spondyloepiphyseal dysplasia tarda SEDL Xp22.2p22.1 SEDLIN
Modified with permission from Cohen MM Jr. Merging the old skeletal biology with the new. II Molecular aspects of bone formation and bone growth. J Craniofac Gene Dev Biol 2000;20:94. Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002;113:65. Superti-Furga A, et al. Am J Med Genet (Semin Med Genet) 2001;106:282.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Skeletal Dysplasias
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