Constitutional errors of bone development include dysostoses, disruptions, and skeletal dysplasias. The dysostoses are malformations of single bones, although multiple sites can be involved. These disorders usually are due to genetic defects that predominantly affect organogenesis. Disruptions are secondary malformations of bones, resulting from extrinsic interference with the normal developmental process by a toxic substance, infection, or transiently expressed gene (e.g., rubella embryopathy). The skeletal dysplasias (osteochondrodysplasias) are intrinsic developmental disorders of chondro-osseous tissue. There are over 400 recognized skeletal dysplasias. Unlike the dysostoses, the genetic defects of the dysplasias affect bone development in both fetal and postnatal life, and have little or no affect on organogenesis. The dysplasias consist of primary lesions in which a genetic mutation is expressed in chondro-osseous tissue (e.g., “classic” dysplasias such as achondroplasia) and secondary dysplasias that are caused by factors extrinsic to the skeletal system (e.g., metabolic disorders). There are also mixed disorders that have features of a dysostosis and a dysplasia, for example, cleidocranial dysostosis and nail-patella syndrome.^1–8

Patients with short stature can have truncal shortening, extremity shortening, or both. With some of the osteochondrodysplasias, extremity shortening is generalized or proportionate. In others, there is preferential shortening of segments of the extremities. Rhizomelia refers to disproportionate shortening of the humeri and femurs. Mesomelia is shortening of the forearms and lower legs. Acromelia refers to short hands and feet.

Radiographic classification schemes of the osteochondrodysplasias are often based on features such as spinal involvement, the patterns of long bone involvement, joint deformities, and bone density. The epiphyseal dysplasias have small or irregular epiphyses as the predominant deformity. Metaphyseal dysplasias have widened, flared, and/or irregular metaphyses. A diaphyseal dysplasia has widening or other deformity of the diaphyses. Spondylodysplasias have vertebral deformities, often platyspondyly. The predominant features of some dysplasias are abnormally increased or decreased bone density. Classification based on genetic factors is also useful. However, there is considerable phenotypic variation between patients with similar mutations, similar phenotypes can occur with different genetic defects, and the defective genes are as yet unknown for some of these disorders.

Achondroplasia

Achondroplasia is the most common chondrodystrophic dysplasia, occurring in approximately 1 in 25,000 livebirths and accounting for approximately 80% of short-limb bone dysplasias. There are approximately 10,000 people in the United States with achondroplasia. Achondroplasia is transmitted as an autosomal dominant trait; approximately 80% of cases are due to spontaneous mutations. The responsible gene is fibroblast growth factor receptor 3 (FGFR3). The manifestations of achondroplasia are due to a subnormal rate of formation of qualitatively normal enchondral bone. This leads to shortening of the long bones and ribs and underdevelopment of the flat bones, facial bones, and base of the skull (i.e., the cartilaginous portion of the skull).^9–12

A number of clinical features are helpful for the diagnosis of achondroplasia and the differentiation from other short-limb skeletal dysplasias. Rhizomelic shortening of the limbs is present at birth. Additional common findings in neonates with this dysplasia include a large head with frontal bossing, depression of the nasal bridge, and a foreshortened body length. There is separation of the middle and ring fingers, producing a trident appearance of the hands. The trident appearance usually disappears by late childhood or adolescence, but the hands remain short and broad. The abdomen is protuberant and the buttocks are uplifted. A gibbous deformity is common in the lumbar region in infancy; this regresses after the first year of life, and is replaced by a straight upper back and prominent lumbar lordosis.

Infants with achondroplasia are hypotonic and have delayed motor development; however, normal neuromuscular tone is usually attained by 2 to 3 years of age. Although mental development is age-appropriate, neurological complications can develop due to osseous compression of the brainstem or spinal cord. Resultant clinical manifestations can include paresthesias, tendon reflex changes, progressive paraparesis, quadriparesis, and apnea. Other potential complications of achondroplasia include conductive hearing loss, chronic serous otitis media, hydrocephalus, choanal atresia, respiratory compromise, and reduced zinc and increased copper concentrations in the hair. In some patients, there are signs of chronic increase in intracranial pressure due to bilateral jugular foramen hypoplasia and impaired venous drainage.^13–15

Radiographs of children with achondroplasia show shortening and thickening of the long bones, with flaring and cupping of the metaphyses (Figure 57-1). The proximal segments of the appendicular skeleton are more severely involved than the distal portions, producing a rhizomelic pattern of shortening. In older children, the widened metaphyses may partially surround the epiphyses, producing a ball-and-socket appearance. There is bowing of the lower extremities.

Hand radiographs of children with achondroplasia demonstrate short digits; infants may have a trident hand configuration, as described above. The phalanges are short, broad, and cupped (Figure 57-2). The radial heads are enlarged, irregular, and subluxed. The ulna is usually shorter than the radius. Shortening of the fibula is usually less than that of the tibia; the fibular head is high relative to the knee (Figure 57-3). The clavicles are less severely involved than other portions of the skeleton. The thorax is small, due to foreshortened ribs. The ribs have flared anterior ends. The sternum is thick and short. The inferior margin of the scapula is squared. The glenoid fossa is small.

Abnormal development of the pelvis is a constant feature in achondroplasia; however, the appearance is similar to that of chondroectodermal dysplasia, asphyxiating thoracic dystrophy, and thanatophoric dwarfism. Radiographs of the pelvis show short and rectangular-shaped iliac bones, with narrow sacrosciatic notches and short, wide pubic and ischial bones (Figure 57-4). The acetabular roofs are horizontal. The appearance of the inner margins of the pelvis in achondroplasia has been likened to that of a champagne glass.

The vertebral column of the newborn with achondroplasia usually appears normal; there may be minimal platyspondyly. The vertebral bodies are often bullet-shaped in infants. Prominent thoracolumbar kyphosis is common in infants, but this usually resolves as the child begins to walk. An important characterizing feature of achondroplasia is narrowing of the caudal (lumbar) spinal canal, which becomes more obvious with increasing age during childhood. Frontal radiographs show progressive narrowing of the interpedicular distances from the thoracolumbar junction inferiorly through the lumbar spine. The lateral projection shows shortening of the pedicles. Posterior scalloping of the lumbar vertebrae and anterior wedging of the vertebrae in the lower thoracic and upper lumbar regions are frequently present in older children and adults. The intervertebral discs are widened. There is exaggerated lumbar lordosis.

The skull of the achondroplastic child is brachycephalic, with frontal bossing and nasal bone flattening. The cranium is large with respect to the face. The foramen magnum is small; this occasionally leads to symptoms of cord/brainstem compression. The mandible is normal; because of hypoplastic maxillae, the patients appear to be prognathic.

Achondroplasia can be confused clinically and radiographically with various other osteochondrodysplasias. Dysplasias that share at least some imaging or clinical features with achondroplasia include diastrophic dysplasia, pseudoachondroplastic dysplasia, metatropic dysplasia, Kniest dysplasia, chondroectodermal dysplasia, asphyxiating thoracic dystrophy, chondrodysplasia punctata, metaphyseal dysplasia, thanatophoric dysplasia, and achondrogenesis.

Thanatophoric Dysplasia

Thanatophoric dysplasia is an autosomal dominant lethal micromelic osteochondrodysplasia that is caused by mutations of the gene that encodes the FGFR3. There are 2 clinical and genetic subtypes of thanatophoric dysplasia. Most cases of thanatophoric dysplasia are sporadic. These infants have markedly foreshortened extremities. Trunk length is relatively preserved, but the thorax is narrow. The head is disproportionately large, with a prominent forehead, depressed nasal bridge, and bulging eyes. These infants are stillborn or die shortly after birth due to respiratory insufficiency. Other reported abnormalities with thanatophoric dysplasia include increased subcutaneous fat, hydrocephalus, and microgyria.

The radiological manifestations of thanatophoric dysplasia include small facial bones, a short skull base, and relatively large calvaria with frontal bossing. There is an association of thanatophoric dysplasia with craniosynostosis and cloverleaf skull deformity, particularly with type II. The trunk is long and narrow with widely cupped costochondral junctions and small scapulae. The vertebrae have a characteristic appearance: the vertebral bodies are markedly flattened and the midportions are narrow, resulting in an inverted U- or egg-shaped appearance on frontal radiographs (Figure 57-5). Notch-like defects may be present in the central portions of the end plates. Vertebral body flattening is more pronounced with type I thanatophoric dysplasia than with type II. The vertebral flattening is an important finding in the differentiation of thanatophoric dwarfism from severe instances of achondroplasia.

The pelvis of an infant with thanatophoric dysplasia resembles that of achondroplasia. The iliac bones are short and the acetabula are flat. The sacrosciatic notches are small and have protrusions from both the acetabula and the ischia. The sacroiliac joints are small. Shortening of the extremities is rhizomelic; there is extreme disproportion between the length of the trunk and the length of the extremities. With the type I form, the femurs are bowed. The tubular bones also have metaphyseal flaring and cupping. The tubular bones of the hands and feet are extremely short and broad. Radioulnar synostosis may occur.

Hypochondroplasia

Hypochondroplasia is a relatively common autosomal dominant bone dysplasia of mild to moderate severity. This disorder is due to mutations of the FGFR3 gene. Hypochondroplasia has considerable genetic and clinical heterogeneity. These patients have short stature, with short limbs and a relatively long trunk. The head is normal in appearance or minimally enlarged. Bowleg deformity may develop in early childhood. Intellectual impairment is common.

The radiographic features of hypochondroplasia are similar to, but less severe than, those of achondroplasia. The relatively normal appearance of the skull in hypochondroplasia is an important distinguishing feature; occasionally, the skull is somewhat enlarged and has protuberant frontal bones. In addition, there is proportionate shortening of the bones of the extremities, as opposed to the rhizomelic pattern of achondroplasia. The tubular bones may be somewhat squared. The femoral neck is short and broad; however, this finding is lacking in some patients. The distal end of the fibula is elongated in comparison to the tibia (Figure 57-6). Radiographs of the spine in hypochondroplasia show slight narrowing of the interpedicular distances in the lumbar region, as well as shortening of the pedicles. The sacrum has a lordotic configuration. The pelvis is often somewhat small, but the overt pelvic dysplasia of achondroplasia is lacking.

Metaphyseal Chondrodysplasia

The metaphyseal chondrodysplasias (metaphyseal dysostoses) are a heterogeneous group of disorders that predominantly involve the metaphyses. The epiphyses and spine are relatively normal. These diseases are more often confused with rickets than with achondroplasia and should always be considered in the differential diagnosis when radiographs suggest rickets. There are 3 main varieties of metaphyseal chondrodysplasia: the Jansen type (autosomal dominant), Schmid type (autosomal dominant), and McKusick type (autosomal recessive). The McKusick type is also referred to as cartilage-hair hypoplasia.^16,17

Jansen Type

The Jansen type of metaphyseal chondrodysplasia is due to mutations of the PTHR1 gene on chromosome 3, which leads to activation of the G-protein-coupled receptor for the parathyroid hormone-related protein in prehypertrophic chondrocytes of the growth plate. Delayed differentiation of chondrocytes interferes with bone formation in the metaphyses. Of the major types of metaphyseal chondrodysplasia, the Jansen type causes the most severe skeletal deformity. This variety is usually detected in the newborn period with rhizomelic short stature, severe bowing of the legs, prominent eyes, choanal stenosis, prominent cranial sutures, and mandibular hypoplasia. The joints are large; the enlarged ends of the bones limit joint mobility. Usually, there is evidence of ligamentous laxity. Because the legs are more severely affected than the arms, the arms appear to hang down to the knees, causing an ape-like appearance. Laboratory findings include hypercalcemia and elevation of serum alkaline phosphatase.^18–20

The radiographic manifestations of the Jansen variety of metaphyseal chondrodysplasia predominantly involve the metaphyses. All metaphyses, including those of the small bones of the hands and feet, are severely involved. The metaphyseal changes include markedly irregular mineralization, expansion and cupping, and areas of nonossified cartilage mixed with densely calcified bone. The epiphyses are slightly enlarged but have a normal shape. There is widening of the distance between the ossified portions of the metaphyses and the epiphyses, producing the appearance of widened growth plates (similar to rickets). Other radiographic findings include generalized osteopenia, cortical erosions (in infants), brachycephaly, platybasia, paranasal sinus hypoplasia, micrognathia, tubular bone shortening and bowing, and irregular mineralization of the anterior rib ends and pubic symphysis. In infants, there may be a reticular pattern of calvarial ossification; the sutures are wide. Older children may have calvarial hyperostosis. The spine is normal.²¹

Schmid Type

The Schmid variety of metaphyseal chondrodysplasia is due to mutations in the COL10A1 gene, resulting in deficient assembly of type 10 collagen in the growth plates. The clinical features include mild to moderate short stature, moderate bowing of the legs, and a waddling gait. The initial clinical presentation usually occurs during the toddler years. The severity of short stature becomes more prominent with age. Bowleg deformity persists into adulthood.²²

The metaphyseal changes associated with the Schmid form of metaphyseal chondrodysplasia are less pronounced than in the Jansen variety. The metaphyses are flared, cupped, irregular, and fragmented, with radiolucent streaks extending into the diaphyses (Figure 57-7). The growth plates are widened. The changes are most marked in the hips, shoulders, and knees. The femurs may be bowed. Involvement of the femoral necks may be quite severe, with marked coxa vara and shortened femoral necks. Genu varus deformities are common. There is variable, usually mild, involvement of the hands: shortening of the tubular bones and metaphyseal cupping of the proximal phalanges and metacarpals. The radiographic features of this disorder mimic those of rickets. Differentiation is predominantly based on laboratory studies and the radiographic recognition of preserved skeletal mineralization.^23–25

McKusick Type

The McKusick type of metaphyseal chondrodysplasia (cartilage-hair hypoplasia) is due to mutations of the RMRP gene on chromosome 9p13, which encodes the RNA component of a ribonucleoprotein endoribonuclease. This disorder most often occurs in individuals of Amish and Finnish ancestry. Among the Amish, approximately 80% of affected individuals can trace their ancestry to Jacob or Catherine Hochstetler, who immigrated to the United States in the middle part of the 18th century. These patients have severe growth deficiency, bowing deformities of the limbs, and short, broad (pudgy) hands with hypermobile joints. The cranium is large with respect to the face. The manifestations of ectodermal dysplasia are also present, including fine, light, sparse hair and a fair complexion. Young children have a propensity for recurrent infections. Patients with the McKusick type of metaphyseal chondrodysplasia have an increased incidence of malignancies, especially Hodgkin disease.²⁶

In the McKusick variety of metaphyseal chondrodysplasia, metaphyseal deformities occur in the long and short tubular bones. The metaphyses are wide and irregular with mixed sclerotic and lucent areas. The knees are prominently involved, sometimes leading to severe bowleg deformities. Femoral bowing is common during infancy. The fibulas are disproportionately long distally in comparison to the tibias. The skull, spine, and epiphyses are normal. Involvement of the femoral necks is usually less marked than in the Schmid variety. The bones of the hands and feet are uniformly shortened. The ribs are usually short and flared anteriorly. This disorder is distinguished from achondroplasia by the pattern of metaphyseal irregularity and by the presence of hypoplastic cartilage and hair.

Metaphyseal Chondrodysplasia with Immune Deficiency

A combination of metaphyseal abnormalities and im mune deficiencies can occur in some autosomal recessive forms of metaphyseal chondrodysplasia. These include Shwachman-Diamond syndrome (Shwachman syndrome), in which metaphyseal lesions are associated with deficiency of pancreatic exocrine secretion and chronic neutropenia; metaphyseal chondrodysplasia-thymolymphopenia syndrome; and combined immunodeficiency due to adenosine deaminase deficiency, in which growth failure occurs with marked metaphyseal irregularities and flaring of the anterior ends of the ribs.

Common clinical features of Shwachman-Diamond syndrome include recurrent infections, failure to thrive, hepatomegaly, and steatorrhea (exocrine pancreatic insufficiency). The metaphyses of the tubular bones are irregular, although the findings are much less pronounced than in most of the other metaphyseal chondrodysplasias. There are small lucent areas in the metaphyses, and most patients have sclerotic serrations in the region of the zone of provisional calcification in the metaphyses. The hips and knees are the areas of greatest involvement. There is irregular ossification of the anterior rib margins. Coxa vara is often present. There is a propensity for slipped capital femoral epiphysis. Cross-sectional imaging studies show fatty infiltration of the pancreas.

The radiographic features of adenosine deaminase deficiency include splaying and irregularity of the metaphyseal ends of the long bones. Metaphyseal spurs may be present. The ribs are short and widened. There is usually marked flaring at the anterior margins of the ribs. Spine radiographs may show central beaking of the lower thoracic vertebrae, mild platyspondyly, and a bone within a bone appearance of the vertebral bodies. There are square iliac wings and flat acetabular roofs. Chest radiographs show absence of a normal thymic shadow (Figure 57-8).

Metaphyseal chondrodysplasia-thymolymphopenia syndrome (Omenn syndrome with metaphyseal chondrodysplasia) is a rare autosomal recessive disorder caused by mutations of the RAG1 or RAG2 genes. These patients may have hair at birth, but alopecia soon develops. Small stature is evident at birth. Infants with this disorder develop a scaling erythroderma. Other findings include persistent diarrhea, bacterial infections (sometimes life threatening), hepatosplenomegaly, and lymphadenopathy. Radiographs show metaphyseal widening, mild metaphyseal cupping, foreshortened tubular bones, cupping of the anterior rib margins, flat acetabular angles, and hypoplasia of the inferior aspects of the iliac bones.

Pseudoachondroplastic Dysplasia

Pseudoachondroplastic dysplasia (pseudoachondroplasia) encompasses a group of disorders that are characterized by short-limbed short stature, moderately severe reduction in truncal height, and a normal-appearing face. An autosomal dominant inheritance pattern occurs in most patients. The cause of this dysplasia is mutation of the COMP gene on chromosome 19p13.1-p12, which encodes cartilage oligomeric matrix protein. The degree of growth retardation is variable and is usually not clinically apparent until 2 to 3 years of age. The character of limb shortening is also variable, with primarily rhizomelic shortening in some patients and a mesomelic pattern in others. Marked shortening of the hands and feet is typical.²⁷

Radiographic skeletal surveys of patients with pseudoachondroplastic dysplasia typically show foreshortened tubular bones, with widening and irregularity of the metaphyses (Figure 57-9). In children, the subphyseal portions of the metaphyses are sclerotic. There is delayed ossification of the epiphyses. The epiphyseal ossification centers sometimes are fragmented. The femoral heads are dysplastic in adults. The proximal ends of the metacarpals are rounded, and the carpal bones are hypoplastic. Images of the spine in young children often show platyspondyly and irregularity of the vertebral end plates. Central tongue-like projections of the vertebral bodies are common. In older children, the vertebral bodies are biconcave. The triradiate cartilage is wide in young children with pseudoachondroplastic dysplasia. The inferior-medial aspects of the iliac bones are tapered and there are small spurs at the lateral acetabular margins. There are no craniofacial abnormalities in patients with pseudoachondroplastic dysplasia.^28,29

The body proportions of patients with pseudoachondroplasia are similar to those of achondroplasia. Craniofacial development is normal in the former. There is no substantial interpedicular distance narrowing. In adults and teenagers, the pelvis deformities are less pronounced than in achondroplasia. Differentiation of pseudoachondroplastic dysplasia from multiple epiphyseal dysplasia (MED) is by a lesser severity of long bone shortening in the latter. Vertebral deformities in children with MED tend to be less severe, and metaphyseal involvement is less pronounced.

Achondrogenesis

Achondrogenesis type 1A is associated with a large head, small mouth, short trunk, prominent abdomen, and flipper-like extremities. The skull of the affected infant appears soft on palpation. Radiographs show absent or markedly compromised ossification of the vertebral bodies. The ribs are short and have splayed anterior ends and multiple fractures in various stages of healing. The iliac bones are small. The tubular bones are markedly foreshortened and irregular. Longitudinal spurs may arise from the metaphyses.³⁰

Achondrogenesis type 1B also leads to severe micromelia. The trunk is short and the abdomen is protuberant. The radiographic features are similar to those of type 1A. There is markedly deficient ossification of the vertebral bodies, sacrum, pubic bones, and ischial bones. Only very short irregular tubular bones are present in the extremities; these may have round or triangular configurations. The cause of achondrogenesis type 1B is a mutation in SLC26A2.³¹

Achondrogenesis type 2 (mutation of COL2A1) results in severe micromelia and a short trunk as with the other forms; however, the size of the head is relatively proportionate to that of the body. Micrognathia and cleft palate are common. Radiographs show small iliac bones, deficient ossification of the pubic and ischial bones, marked foreshortening of the ribs, poor ossification of the vertebral bodies and sacrum, and short tubular bones with metaphyseal flaring.³²

Multiple Epiphyseal Dysplasia

MED (epiphyseal dysplasia multiplex) is an inherited skeletal disorder that predominantly involves the epiphyses. This dysplasia is usually inherited as an autosomal dominant disorder, although there are occasional instances of recessive inheritance. Mutations in 5 genes have been detected with this disorder: COMP, MATN3, COL9A1, COL9A2, and COL9A3. Encoded proteins include type IX collagen, cartilage oligomeric matrix protein, and matrilin-3 (an extracellular matrix protein). The primary defect appears to be defective cartilage formation. There is considerable variation in severity of this dysplasia. Some patients have symptomatic involvement of only a few joints, usually symmetrically; others have extensive disease. Affected patients have short stature of variable severity (usually mild). The hands and feet are somewhat short. Joint pain and stiffness are common, particularly in the hips, knees, and ankles. Flexion deformities and osteoarthritis may develop.^33–36

The radiographic manifestations of MED include: (1) small, irregular, and fragmented epiphyses, (2) growth plate irregularity, (3) delayed ossification of epiphyses, and (4) premature osteoarthritis in adults (Figure 57-10). In older children and adults, the abnormal epiphyses are flat (Ribbing type) or small (Fairbank type) (Figure 57-11). The epiphyseal abnormalities are most prominent in the lower extremities, the wrists, and the hands. The osseous abnormalities are bilaterally symmetric. The metaphyseal deformities are mild. Coxa vara, genu valgum, and tibiotalar slant are common in older children. These children are susceptible to slipped capital epiphysis. There is delay in the appearance of the ossification centers of the carpal and tarsal bones. The tubular bones of the hands and feet are short and broad. The fibula may be relatively long in comparison to the tibia. Spinal involvement occurs in about two-thirds of individuals with MED (there is additional discussion of associated spinal abnormalities in the section “Spondyloepiphyseal Dysplasia”). When present, the appearance is similar to that of Scheuermann disease, with mild platyspondyly and slight irregularity of the vertebral end plates.

The Fairbank type of MED shares some of the features of pseudoachondroplastic dysplasia. Findings in pseudoachondroplastic dysplasia that are useful for the differentiation include more severe tubular bone shortening, greater metaphyseal deformity, widening of the triradiate cartilage in young children, and central vertebral body protrusions in young children.

There is a localized type of epiphyseal dysplasia in which there is involvement of the epiphyseal ossification centers in the hands, feet, elbows, hips, and knees. Associated osteochondromas develop in some of these patients. This disorder is a form of peripheral dysostosis.

In some patients with MED, the clinical and radiographic manifestations predominantly involve the hips, sometimes resulting in radiographic features that are similar to those of Legg-Calvé-Perthes disease. Several findings help distinguish epiphyseal dysplasia from Legg-Calvé-Perthes disease: (1) there is typically bilateral and relatively symmetric involvement of the hips with MED (bilateral Perthes disease is usually not concurrent); (2) at least minor involvement of other ossification centers, such as in the knees, elbows, hands, and feet, is present in MED; (3) patients with MED often have short stature; (4) in most patients, the age of onset of Legg-Calvé-Perthes disease is later than that of MED; (5) in those cases in which the clinical and radiographic findings are inconclusive, skeletal scintigraphy is definitive. Radiopharmaceutical uptake in the ossification centers in cases of MED is normal, whereas Legg-Calvé-Perthes disease results in absent or diminished uptake early in the process and prominent uptake during the revascularization phase.

Meyer Dysplasia

Meyer dysplasia (dysplasia epiphysealis capitis femoris) is a developmental disorder of the hips that is characterized by delayed, irregular ossification of the capital femoral epiphyses. The radiographic findings mimic those of Legg-Calvé-Perthes disease. Meyer hypothesized that the pathogenesis involves circulatory disturbances that cause delayed, irregular ossification.³⁷ Others have attributed the dysplasia to congenital focal hypoplasia of the femoral epiphysis.³⁸ Many cases may actually represent a physiological variant of ossification, and not a true dysplasia. Appropriate diagnosis is essential, to prevent unnecessary diagnostic procedures and treatments.

Meyer dysplasia is usually diagnosed during the second or third years of life and the findings spontaneously disappear by the end of the sixth year. About half of affected patients have bilateral abnormalities. Boys are affected more often than girls. The lesion is usually asymptomatic, and the diagnosis is made on radiographs obtained for unrelated pain or other purposes. With bilateral involvement, some patients have a mild inconsistent waddling gait. Other rare reported clinical findings include pain, limping, or limitation of movement.^39,40

Radiographs show delay in ossification of the capital femoral epiphysis. Ossification in these patients is first visible at approximately 2 years of age. Signs of delayed maturation of other parts of the skeleton may also be present. The ossification center of the femoral head in patients with Meyer dysplasia appears as a small epiphyseal nucleus composed of multiple independent bony foci (Figure 57-12), or (rarely) a single, small ossification center with a cortical defect along the articular surface. These foci gradually increase in size, coalesce, and finally fuse into a single center over a period of approximately 3 years. Ultimately, the femoral head has a normal appearance, although some authors have reported a tendency for diminished height.

The differential diagnosis for patients with radiographic sings of Meyer dysplasia includes Perthes disease, MED, and hypothyroidism. In patients with MED, growth plate irregularity and widening of the metaphysis usually accompany the small fragmented pattern of epiphyseal ossification. Children with MED are short and have radiographic abnormalities of epiphyses throughout the skeleton. Delayed epiphyseal ossification in children with hypothyroidism occurs throughout the skeleton. The epiphyseal ossification fragments in Meyer dysplasia lack the increased density that is typical of Perthes disease. If the findings are inconclusive, further evaluation with bone scintigraphy or MR can be performed. Bone scintigraphy is normal with Meyer dysplasia. MR shows multiple centers of ossification of the femoral head, with normal signal intensity on all sequences; there may be reduced height of the cartilaginous epiphysis.⁴⁰

Chondrodysplasia Punctata

Chondrodysplasia punctata (punctate epiphyseal dysplasia; stippled epiphyses) refers to several dysplasias that share the common radiographic findings of stippled epiphyses and calcification in the periarticular tissues and physes. At least 4 genetic skeletal dysplasias are included in this designation: an autosomal recessive form with severe rhizomelic limb shortening (mutation of PEX7 gene), an X-linked dominant form due to abnormality of 3β-hydroxysteroid-Δ⁸, Δ⁷-isomerase (Conradi-Hünermann disease), a milder X-linked recessive form (mutation or deletion of the gene for aryl sulfatase E), and chondrodysplasia punctata, tibial-metacarpal type (autosomal dominant). Puncta also occur in Zellweger syndrome.

The rhizomelic type of chondrodysplasia punctata is clinically evident at birth. Common clinical features include a flat face with a small “saddle” nose, short stature (predominantly rhizomelic), contractures, cataracts, failure to thrive, and mental retardation. Radiographs of infants with this disorder show punctate epiphyses; this finding disappears by 2 to 3 years of age. Tubular bone shortening most severely involves the humeri; the femora are also foreshortened. In infants, cartilaginous coronal clefts separate the anterior and posterior ossification centers of the vertebral bodies.

The Conradi-Hünermann form of chondrodysplasia punctata (Happle syndrome) is associated with a markedly depressed nasal bridge, extremity shortening, scoliosis, joint contractures, cataracts, and alopecia. Laryngomalacia due to calcification of the laryngeal cartilages may cause respiratory distress. Radiographs of affected infants show stippled calcifications, most prominently involving the long bone epiphyses, carpal bones, tarsal bones, vertebrae, ischium, and pubis (Figure 57-13). Irregular calcification may also occur in articular cartilage and costal cartilage. Punctata usually disappears by the age of 3 to 4 years; there is often some degree of residual epiphyseal flattening or irregularity. Long bone shortening is frequently asymmetric.

The brachytelephalangic type of chondrodysplasia punctata is an X-linked recessive disorder. The face is dysmorphic, with a very small nose and anteverted nares. The epiphyseal punctate calcifications that occur with this form tend to be subtler than in most other instances of chondrodysplasia punctata; spontaneous resolution occurs by age 3. An important characterizing feature of this disorder is foreshortening of the distal phalanges of the hands and feet. In infants, the proximal aspects of the distal phalanges are tapered. Phalangeal involvement is frequently nonuniform. Calcaneal ossification is often delayed and irregular. Older patients may have irregular ossification of the femoral heads.

The tibial-metacarpal type of chondrodysplasia punctata predominantly involves the metacarpals. Limb shortening in these children typically follows a mesomelic pattern. The nasal bridge is depressed and the midface is hypoplastic. Radiographs of affected infants show shortening and stippled calcifications in the metacarpals, typically with nonuniform involvement. Other potential sites of puncta in these children include the carpal bones, tarsal bones, long bone epiphyses, and sacrum. Long bone shortening most frequently involves the tibia; other potential sites include ulna, humerus, and femur.

Diastrophic Dysplasia

Diastrophic dysplasia is a severe autosomal recessive rhizomelic skeletal system disorder. The cause of this condition is a mutation in the SLC26A2 gene, which encodes diastrophic dysplasia sulfate transporter. Affected patients have dysplastic abnormalities of chondro-osseous tissues, cartilage, and ligaments. Restricted joint motion or joint contractures may occur. The presence of severe clubfoot deformities and scoliosis aids in differentiating this entity from other dysplasias such as achondroplasia.⁴¹

Common external ear abnormalities in children with diastrophic dysplasia include cystic masses of the lobes and antihelix, sometimes leading to prominent scars. Radiographs may show ossification of the pinna. Premature costochondral and laryngeal cartilage calcification also occurs. Other potential extraskeletal manifestations include inguinal hernia, thick pectinate strands at the root of the iris, micrognathia, hyperelasticity of the skin, cryptorchidism, and abnormal glucose metabolism. Most patients have a characteristic abduction deformity of the thumbs, termed the “hitchhiker thumb”; a similar deformity occurs in the great toes. About half of patients with diastrophic dysplasia have cleft palate.

The tubular bones of patients with diastrophic dysplasia are short, thick, and clubbed; there is flaring at the bone ends. There is a delay in appearance of the epiphyseal ossification centers (Figure 57-14). Stippled epiphyses may be present at birth. The first metacarpals are often small and oval; the other metacarpals are broad distally and tapered proximally (Figure 57-15). Joint involvement is typical in diastrophic dysplasia, including subluxations and contractures. The joints that are most often symptomatic include the shoulders, elbows, hips, and interphalangeal joints. The pelvis is broad and short. The femoral necks are short and broad. The trochanters are prominent. Progressive thoracolumbar kyphoscoliosis is nearly universal in patients with diastrophic dysplasia. Narrowing of the lumbar interpedicular distances, which is a feature of achondroplasia, does not occur with diastrophic dysplasia. Severe kyphosis of the cervical spine in older children can lead to spinal cord compression (Figure 57-16).^42–47

Campomelic Dysplasia

Campomelic dysplasia is a rare inherited dysplasia that is often fatal. Bowing of the long bones is a characteristic feature of this disorder. Bowing deformities tend to be more pronounced in the lower extremities. The extremities are also foreshortened. Additional potential clinical findings include clubfoot, dolichocephaly, cleft palate, and micrognathia. The major cause of death in these infants is respiratory insufficiency related to defective tracheobronchial cartilage formation and a small thoracic cavity. The responsible gene is SOX9, located at 17q24.3-q25.1.⁴⁸

Radiographs of the lower extremities of infants with campomelic dysplasia show anterolateral bowing. Bowing deformities also occur in the upper extremities, but are less pronounced. The long bones are foreshortened. Hip dislocation is common. Other potential skeletal manifestations of this disease include poor pubic bone ossification, short first metacarpals and middle phalanges, mandibular hypoplasia, hypoplastic scapulae, narrow iliac bones, absent sacral alae, a bell-shaped thorax, thin ribs and clavicles, foot deformities, and vertebral anomalies (Figures 57-17 and 57-18).

Spondyloepiphyseal Dysplasia

Spondyloepiphyseal dysplasia encompasses a group of chondrodystrophic disorders in which there are abnormalities of the vertebrae and the tubular bone epiphyses and metaphyses. Some of the spondyloepiphyseal dysplasias have characteristic radiographic and clinical features, whereas others are less well defined. Growth during the first few months of infancy is normal in most patients with spondyloepiphyseal dysplasia. Skeletal development becomes increasingly compromised, often leading to severe short stature. The peak age at diagnosis is near the second year of life. There are 3 major groups of spondyloepiphyseal dysplasia and several subtypes.

The form of spondyloepiphyseal dysplasia in which there is minimal vertebral involvement is termed multiple epiphyseal dysplasia (MED) (see additional discussion in the section “Multiple Epiphyseal Dysplasia“). The abnormalities are limited to the epiphyses of the long bones and the vertebral end plates. The vertebral body heights are normal or only slightly decreased. In older children, the vertebral abnormalities can resemble those of Scheuermann disease: mild platyspondyly and slight irregularity of the vertebral end plates. The involved epiphyseal ossification centers of the extremities appear late and are irregular and small. A variable degree of epiphyseal flattening is present in some patients. The metaphyses are normal or have subphyseal irregularity. The epiphyseal abnormalities contribute to short stature. This type of epiphyseal dysplasia has joint deformities of moderate severity, especially in the hips.

In the proximal limb type of MED, the proximal epiphyseal ossification centers of the humeri and femurs are the most severely involved. Other epiphyseal ossification centers are normal or have only minimal involvement. The vertebral end plates are irregular, particularly in the lower thoracic and upper lumbar regions. Degenerative arthritis eventually develops in these patients, with the hips being the most commonly affected joints.

Spondyloepiphyseal dysplasia congenita is clinically evident at birth. These patients have shortening of the spine, barrel chest, pectus carinatum deformity, and genu valgum. Short stature in these patients is due to spinal and long bone involvement. This disorder is transmitted as an autosomal dominant trait with variable expression. The responsible gene is COL2A1.

Radiographs of children with spondyloepiphyseal dysplasia congenita show delayed skeletal ossification. At birth, ossification is lacking in the pubic bones and the epiphyses of the knees. The vertebral bodies are flattened, and sometimes are wedged dorsally (Figure 57-19). Hypoplasia and delayed ossification of the odontoid process is associated with a predisposition to atlantoaxial dislocation or subluxation. The acetabular roofs have horizontal orientations. There is retarded ossification of the femoral head and neck, resulting in severe coxa vara. There is a variable degree of involvement of the epiphyses and metaphyses of the long tubular bones (deformities and delayed ossification), resulting in shortening of the extremities. The hands and feet are relatively normal, aside from delayed appearance of the carpal and tarsal ossification centers.

Spondyloepiphyseal dysplasia tarda is a milder skeletal dysplasia than the congenita form, with clinical manifestations usually not apparent until late childhood (second decade). This is an X-linked recessive disorder. The trunk is short with respect to the length of the extremities.

The major radiographic findings of spondyloepiphyseal dysplasia tarda are in the spine. There is generalized flattening of the vertebral bodies. Hump-shaped bony thickening is present in the central and dorsal portions of the upper and lower end plates of the lumbar vertebrae. The normal ossification of the ring epiphyses of the vertebral bodies is lacking. The iliac bones are relatively small and the pubic bones somewhat elongated. The femoral necks are foreshortened. The long bones are otherwise normal. The bones of the hands and feet are normal.

Spondyloepiphyseal dysplasia tarda with progressive arthropathy (progressive pseudorheumatoid chondrodysplasia) is a rare autosomal recessive disorder. There is an increased prevalence in individuals of Arab descent. Clinical manifestations of this dysplasia are usually first apparent in early childhood. Potential findings include joint stiffness, joint contractures, muscular weakness, and gait disturbance.

Spine radiographs of children with spondyloepiphyseal dysplasia tarda with progressive arthropathy show platyspondyly and erosive changes of the anterior aspects of the end plates. The interpedicular distances may be widened. The acetabula are irregular, and the hip joints are narrow. The femoral heads are somewhat enlarged. The hands have joint space narrowing, metaphyseal widening, and epiphyseal flattening. Findings in the knees and other large joints include enlargement of the epiphyses, joint space narrowing, and osteoporosis; these findings mimic, in some respects, those of juvenile idiopathic arthritis.

The pseudoachondroplastic form of spondyloepiphyseal dysplasia has many of the clinical findings of achondroplasia. There is rhizomelic limb shortening, with a normal trunk. Unlike achondroplasia, however, the skull is normal. Radiographs show small, irregular epiphyses and irregularities of the metaphyses. The vertebral bodies are misshapen and irregular. The anterior aspects are biconvex in affected neonates; in the adult, the vertebral bodies are slightly wedged.

Metatropic Dysplasia

Metatropic dysplasia is a relatively severe skeletal dysplasia that involves the axial and appendicular portions of the skeleton. The pattern of genetic transmission is variable. The clinical manifestations of this dysplasia often resemble those of achondroplasia during infancy. The affected infant is short-limbed but has a normal or slightly elongated trunk. There is often a prominent skin fold over the coccyx. The large joints are enlarged and have restricted mobility. The thorax is narrow in the neonate with metatropic dysplasia. With increasing age, there is transformation of patient morphology to an ape-like appearance because of disproportionate shortening of the trunk with respect to the limbs.^49,50

Spinal radiographs of neonates with metatrophic dysplasia demonstrate universal platyspondyly. The vertebral bodies are dense and wafer-like (Figure 57-20). The intervertebral disc spaces are widened. Kyphoscoliosis is common. In infants with metatrophic dysplasia, there is generalized shortening of all tubular bones, including those of the hands and feet. The femurs and humeri are dumbbell-shaped. The iliac crests often are crescent-shaped. The skull is normal.

During childhood, the metaphyses are greatly widened in patients with metatrophic dysplasia and the shafts are short, producing a trumpet-shaped appearance. Epiphyseal ossification center development is delayed. Although the shortening of the tubular bones resembles that of achondroplasia, the markedly flared ends of the bones (without notching) and constriction of the diaphyses (drumstick deformity) help to distinguish this dysplasia from achondroplasia. Wide proximal femoral metaphyses and prominent trochanters produce the so-called battle-axe appearance.

Pelvis radiographs of children with metatrophic dysplasia show nearly horizontal acetabular roofs and short square iliac wings. There are short, deep sciatic notches. Other pelvis abnormalities include indentation of the margins of the iliac wings and the presence of accessory ossification centers for the ischial tuberosities. Platyspondyly persists throughout life in these patients. The kyphoscoliosis tends to be rapidly progressive and can lead to neurological complications. The odontoid is often hypoplastic; flexion radiographs may show atlantoaxial subluxation or dislocation.

Kniest Dysplasia

Kniest dysplasia is an autosomal dominant osteochondrodystrophy. The pathophysiology involves abnormal type 2 cartilage caused by mutations of the COL2A1 gene. Patients with Kniest dysplasia have a round, flat face and prominent eyes. Cleft palate is common. Blindness may result from myopia, retinal detachment, and cataracts. Sensorineural hearing loss occurs in some patients. Enlargement and restricted motion of joints is an important musculoskeletal manifestation of Kniest dysplasia; the knees and the small joints of the hands are most markedly affected. Progressive kyphosis, a short neck, hip dislocation, delayed sitting and walking, and an abnormal gait are additional clinical features.⁵¹

Radiographs of the spine in patients with Kniest dysplasia show platyspondyly and anterior wedging of the vertebral bodies. In infants and young children, there are coronal clefts in the midportions of the vertebral bodies. There is only minimal narrowing of the interpedicular distances of the lumbar vertebrae. The iliac bones are broad and the basilar portions are hypoplastic. The femoral necks are broad and short, and there is delayed ossification of the proximal femoral epiphyses. The tubular bones are short and have broad, irregular metaphyses and large, deformed epiphyses. Abnormal areas of calcification occur in both the metaphyses and the epiphyses. There is prominent genu varum. Patients with Kniest dysplasia develop premature severe osteoarthritis.⁵²

Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable disorder of the connective tissue. In the skeleton, these patients have deficient osteoblastic activity. This is the most common of the inherited osteoporosis syndromes. The estimated worldwide prevalence in the general population is 6 to 7 per 100,000. Patients with OI are prone to fractures and resultant skeletal deformities. Bowing of the long bones results from softening caused by osteoporosis and multiple fractures. Severe long bone bowing in children with OI is treated surgically with osteotomies and pinning. Medical treatment with bisphosphonates (e.g., pamidronate) is also frequently utilized. Although bisphosphonates do usually produce some clinical improvement, treated patients still have a propensity for fractures. Bisphosphonate therapy results in sclerotic metaphyseal bands on radiographs.^53–55

There is a spectrum of severity of OI. Severely affected patients have extreme fragility of the bones and numerous fractures (OI congenita); these infants may be stillborn or die in the neonatal period. At the other end of the clinical spectrum are patients who have only a moderately increased propensity for fractures, and suffer no specifically related life-threatening sequelae (OI tarda). Based on the clinical features, at least 8 types of OI are recognized. Genetic classification is also possible for most patients.^56,57

More than 90% of patients with OI have mutations in the COL1A1 or COL1A2 genes. These genes are involved in controlling synthesis of type I collagen. This form of collagen is the most abundant structural protein in bone, skin, and other connective tissues. Most of the mutations that cause OI type I occur in the COL1A1 (collagen, type I, α1) gene, resulting in reduced production of pro-α1(I) chains. With fewer pro-α1(I) chains available, cells make only about half the normal amount of type I collagen, thereby resulting in bone fragility. The mutations responsible for most instances of OI types II, III, and IV occur in either the COL1A1 or COL1A2 genes. The mutations in these patients alter the structure rather than the number of type I collagen molecules. The presence of this abnormal collagen results in weakening of bone and other connective tissue. Mutations in the CRTAP and LEPRE1 genes are responsible for rare, often severe, instances of types VII and VIII OI. Mutations in these genes cause faulty folding, assembly, and secretion of collagen molecules. The genetic causes of types V and VI are unknown. COL1A1 mutations also are responsible for some instances of Ehlers-Danlos syndrome and infantile cortical hyperostosis. There are occasional patients who have clinical manifestations of both OI and Ehlers-Danlos syndrome.⁵⁸

Osteogenesis Imperfecta Type I

OI type I is the most common form of this group of osteoporosis syndromes. The prevalence is approximately 1 in 30,000 individuals. The inheritance pattern is autosomal dominant. The major clinical manifestations include osteoporosis, excessive bone fragility, blue sclerae, and childhood-onset conductive hearing loss. OI type I is further subdivided into types A and B according to the presence or absence of abnormal dentinogenesis.

The sclerae of patients with OI type I are generally deep bluish black. Approximately 10% of affected infants have fractures that are detectable in the neonatal period. As with other forms of osteogenesis imperfects, limb deformities in those patients with the type I variety are largely the result of fractures. However, bowing, particularly of the lower limbs, can also result from bone weakening, without overt fractures. Approximately 20% of adults with osteogenesis type I have progressive kyphoscoliosis. There is usually hyperlaxity of ligaments, particularly those of the knees and the small joints of the hands and feet. During adolescence, there is usually a marked spontaneous reduction in the frequency of fractures.

The major radiographic findings in OI type I are fractures in thinned defective cortical bone and resultant skeletal deformities. The fractures usually heal with normal or exuberant callus; occasionally, a pseudarthrosis develops. The principal radiographic patterns in OI type I are descriptively categorized into thick bone, slender fragile bone, and cystic bone types.

The thick bone appearance of osteogenesis type I is due to an increase in bone width or diameter, usually with bowing deformity. The cortex is extremely thin and of reduced radiodensity (Figure 57-21). The bone widening is usually most prominent in the proximal ends of the extremities, giving the arms and legs a short, stubby appearance.

With the slender, fragile bone pattern of OI type I, the bone shafts are thin (Figure 57-22). The cortex is thin and the bone trabecular pattern is ill defined. The ends of the bones are wide in comparison to the shafts, as physeal cartilage growth is relatively normal; failure occurs at the point of cartilaginous calcification (Figure 57-23). Fractures in these patients lead to progressive deformities. Dense transverse lines of bone are sometimes visible at the junction of the metaphyses and epiphyses; these result from microfractures of the brittle calcified cartilage. Differentiation from growth arrest lines is possible by observing the lack of symmetry.

The skull of patients with OI type I is extremely thin. A mosaic pattern of wormian bones persists throughout life (Figure 57-24). These bones are most common adjacent to the lambdoid sutures. Radiographic visualization of the wormian bones is sometimes difficult in the infant with a poorly mineralized skull. The vertebral bodies are poorly mineralized; biconcave configurations and generalized flattening are typical. There is widening of the intervertebral disc spaces. Multiple Schmorl nodes may be present. Progressive kyphoscoliosis is common (Figure 57-25).

The cystic type of skeletal abnormality in OI type I is rare. Affected patients have cystic lesions at birth, and there is rapid progression. Multiple intraosseous cyst-like areas are visible radiographically, particularly in the lower extremities. The cortex is thin. Fractures and deformity occur as the disease progresses.

Osteogenesis Imperfecta Type II

OI type II is a lethal syndrome that is inherited as an autosomal recessive trait. The prevalence is approximately 1 in 54,000 livebirths. Neonates with OI type II have low birth weight and decreased body length. About half of these infants are stillborn; the others die soon after birth because of respiratory insufficiency precipitated by the very small thoracic size. The skull is soft and contains multiple palpable islands of poorly ossified bone. The limbs are extremely short, bent, and deformed due to multiple fractures, including fractures occurring in utero. The skin is thin and fragile.

Radiographs of infants with OI type II show severe diffuse osteopenia and bone deformities (Figure 57-26). Multiple rib fractures are typical, often producing a beaded appearance of the ribs. The chest is small and narrow. The long bones have a crumpled character, which is particularly evident in the femurs (i.e., accordion femurs). The skull is osteoporotic, and sometimes contains multiple islands of more prominently ossified bone within the poorly mineralized cranial vault. Most patients have platyspondyly.