Skeletal Dysplasias and Selected Chromosomal Disorders
The abridged form of the International Skeletal Dysplasia Society skeletal dysplasia classification serves as the organization of this chapter (Box 133-1).1 The full nosology text can be found at http://isds.ch/uploads/pdf_files/Nosology2010.pdf (accessed August 12, 2012). The major genetic families are presented with a short description of the salient unifying characteristics of the diseases within each group. When known, the gene and protein involved are considered and the impact of the mechanism of action discussed. The major members of each group are then expanded on to provide a clear picture for the reader.
Radiologic Assessment
In the history of the delineation of many of the specific skeletal dysplasias, radiologic assessment plays a major role. By using an orderly approach to the radiographic analysis, the general type of the dysplasia may be elucidated. Many of the skeletal dysplasias and syndromes have distinctive radiographic features that will allow an exact diagnosis when even one of those distinctive features is identified and used as a search criterion in textbooks on skeletal dysplasia. Two such texts are Taybi and Lachman’s Radiology of Syndromes, Metabolic Disorders and Skeletal Dysplasias, which includes an excellent gamuts section, and Bone Dysplasias, An Atlas of Genetic Disorders of Skeletal Development by Spranger and colleagues, in which the images are particularly helpful.2,3 In the online version of Taybi and Lachman’s book, the gamut search may be built iteratively, with the diagnoses becoming more selective as findings are added to the search criteria. Internet searches can also be performed on the Online Mendelian Inheritance in Man database, which is accessed through the U.S. Library of Medicine portal at http://www.ncbi.nlm.nih.gov/pubmed/.
Step II: Assessment of Epiphyseal Ossification
If epiphyseal ossification is delayed or if the ossified epiphyses are very small, irregular for age, or both, then an epiphyseal dysplasia of some sort is present. Carpal and tarsal bones are often affected. In diseases that can be considered pure epiphyseal dysplasias such as multiple epiphyseal dysplasia and pseudoachondroplasia, carpal and the tarsal bones are markedly crenellated and small (Fig. 133-1). Another excellent location for epiphyseal analysis is the ring apophyses of the vertebral bodies, which exhibit delayed and irregular epiphyseal ossification in epiphyseal dysplasia. Central anterior vertebral body protrusions (central tongues or beaking) noted in Morquio syndrome and pseudoachondroplasia are also disorders related to abnormalities of the ring apophyses.
Step III: Assessment of Metaphyses and Physes
Fraying and irregularity of the physes and abnormal flaring of the metaphyses indicate disturbed endochondral ossification. Marked irregularity of the physes is characteristic of the pure metaphyseal dysplasias such as metaphyseal dysplasia, Jansen or Schmid type. When the metaphyses are merely flared and the physes are fairly normal, endochondral ossification may be slowed but the actual process of endochondral ossification progresses normally. This occurs in achondroplasia. The metaphyses are flared, whereas the physis and the zone of provisional calcification (ZPC) are sharply defined (Fig. 133-2).
Figure 133-2 A 14-year-old boy with achondroplasia.
The long bones are short and thick. Note the normal, sharp-appearing physes.
It must be kept in mind that rickets also disturbs the physis. In rickets, the physis is frayed and cupped. Except in healing rickets, the ZPC is inapparent. In metaphyseal chondrodysplasias, the ZPC is present, although it is markedly irregular (Fig. 133-3). Analysis of the sclerotic line of the ZPC is frequently an excellent differentiating feature. Other factors include prominent osteopenia in rickets with blurring of the trabeculae; clinical data are also very helpful.
Figure 133-3 An 8-old boy with Schmid metaphyseal chondrodysplasia.
A, Note the presence of zone of provisional calcification (arrowheads). Normal laboratory values help confirm the diagnosis. B, A 15-month-old girl with rickets. The physes are frayed with mild metaphyseal cupping. The bright white line of the zone of provisional calcification is not evident.
Step V: Analysis of the Vertebral Bodies
Anisospondyly is when the vertebral body shape varies wildly (e-Fig. 133-4). Multiple ossification centers may also be present. Although rare, this is a specific finding in dyssegmental dysplasia.
Step VIII: Summation
After all radiologic findings have been established, a gamut search of some or all of these abnormalities, in conjunction with the clinical findings, may lead to the specific diagnosis. If the “group” of dysplasias has been established, then the specific diagnosis can often be made by referring to a differential diagnosis table such as that developed by Taybi and Lachman.2
Selected Skeletal Dysplasias and Syndromes
Fibroblast Growth Factor Receptor Type 3 Group
Overview: This group includes thanatophoric dwarfism and achondroplasia. The former is probably the most common lethal skeletal dysplasia and the latter the most common skeletal dysplasia. The group includes the milder variant called hypochondroplasia, and homozygous achondroplasia, which is similar to thanatophoria.4
A common genetic locus (4p16.3) is involved. Differing allelic mutations are the cause of the variable severity of expression. The protein encoded is FGFR3, which governs the velocity of endochondral growth. Although long believed that achondroplasia and thanatophoria were caused by loss of function mutations, the mutation in this group actually results in an upmodulation of FGFR3 activity, which is inversely related to the velocity of endochondral growth. FGFR3 mutations have been linked to advanced paternal age, with mutations theoretically accumulating during spermatogenesis.5
Thanatophoric Dwarfism
Radiographic Findings (Fig. 133-5):
Figure 133-5 Thanatophoric dysplasia.
A and B, Radiographic findings in thanatophoric dysplasia type I. In an affected fetus of 30 weeks’ gestation (A), a long, narrow trunk; very short ribs; severe platyspondyly are seen. Note the H and U shapes of bodies are caused by angle of incidence of the x-ray beam; small, flared iliac wings; narrowed sacrosciatic notches; dysplastic (trident) acetabular roofs; and French telephone receiver–shaped femurs. At 22 weeks’ gestation in another affected fetus (B), a proportionally large skull, micromelia, and other findings similar to those in A are seen. C and D, Radiologic findings in thanatophoric dysplasia type II. An affected preterm fetus (C) exhibits findings similar to those in type I except for taller vertebral bodies and straighter femurs. Another affected fetus (D) also shows the same findings as in type I but with straighter femurs. E, Radiograph of affected infant with severe platyspondyly, anteriorly rounded vertebrae, straight femurs, and severely constricted skull base. F, Cloverleaf skull and almost straight femurs; otherwise, radiographic findings are similar to those in C. Note the ovoid lucency at the femoral necks in all cases.
1. Skull: proportionately large skull in relation to the body, narrow skull base, cloverleaf skull (type 1 only)
2. Thorax: long, narrow trunk; very short ribs; handlebar clavicles
3. Spine: severely flattened, small vertebral bodies with round anterior ends
4. Pelvis: small, flared iliac bones; very narrow sacrosciatic notches; flat, dysplastic acetabula
5. Extremities: generalized micromelia; ovoid lucency of femoral necks, round proximal femoral metaphyses with medial spike, curved long bones (type 1 only)
Achondroplasia
Except for the portions of the occipital bone that form the margin of the foramen magnum, all the bones of the skull are formed by membranous ossification.6 This results in an enlarged forehead and is termed frontal bossing. In contrast, the foramen magnum is narrowed and can cause cervicomedullary compression. Symptoms may include occipitocervical pain, ataxia, incontinence, apnea, paralysis, and respiratory arrest.7
Radiologic Findings (Fig. 133-6 and e-Fig. 133-7):
Figure 133-6 Achondroplasia.
A to D, Radiographs of an affected newborn. A, Severe midface hypoplasia. B, Thorax: small thorax and short ribs. C, Thorax: short ribs with anterior scalloping and bullet-shaped vertebrae. D, Pelvis: rounded ilia (elephant ear–shaped) iliac bones, narrow sacrosciatic notches, flat acetabular roof, and proximal femoral ovoid lucency. Achondroplasia. E, Extremities: rhizomelia and mesomelia. F, Radiograph in an affected 1½-year-old with classic vertebrae with short pedicles, posterior scalloping, and somewhat short vertebral bodies. G, Radiograph in an affected woman with flat acetabular roofs, elephant ear–shaped iliac wings, and short femoral necks (compare with D). (G, From Silverman FN: Achondroplasia. Prog Pediatr Radiol. 1973;4:94-124.)
1. Skull: enlarged, with significant midface hypoplasia; hydrocephalus rarely present; small skull base with tight foramen magnum
2. Thorax: small; shortened and anteriorly splayed ribs
3. Spine: short pedicles with decreased interpediculate distance most marked in the lumbar spine moving downward; posterior vertebral body scalloping, gibbus deformity.
4. Pelvis: round iliac wings with lack of flaring (elephant ear–shaped), flattened acetabular roofs, narrow sacrosciatic notches with champagne glass shaped pelvic inlet
5. Extremities: rhizomelic micromelia
6. Hands: brachydactyly with trident hands
7. Knees: Central deep notch in growth plates (Chevron deformity)
8. Hips: proximal femoral ovoid lucency (infancy); hemispheric capital femoral epiphyses, short femoral necks
9. Legs: prominent tibial tubercle apophyseal region, fibula overgrowth
10. Arms: Cortical hyperostosis at deltoid insertion on anterolateral humerus
Hypochondroplasia
In hypochondroplasia radiographic and clinical findings are less severe compared with achondroplasia, and the diagnosis can be challenging. Stature is slightly shortened but is highly variable and may be normal given the range of normal stature in society. Radiographically, aside from shortening of the long bones, interpediculate narrowing is a very sensitive finding (Fig. 133-8).8
Type 2 Collagen Group
Overview: Defects in chromosome 12q13.1-13.3 result in abnormalities of type 2 collagen. Type 2 collagen is present in cartilaginous epiphyses and in the vitreous humor. Therefore, abnormalities of collagen 2 manifest with platyspondyly due to lack of normal growth at the ring epiphysis, a general delay in epiphyseal ossification, and myopia. Cleft palate completes the phenotypic picture.
Achondrogenesis type 2
Radiologic Findings (Fig. 133-9):
1. Skull: proportionately large
2. Thorax: very small and short ribs
3. Spine: almost complete lack of mineralization; cervical and sacral posterior elements also often unossified
4. Pelvis: small iliac wings with concave inferior and medial margins; absence of ischia, pubic bones, and sacral elements
5. Extremities: micromelia, mostly rhizomelia and mesomelia, with relative sparing of hands and feet; metaphyseal flaring; absence of talus and calcaneal ossification (epiphyseal equivalents)
Spondyloepiphyseal Dysplasia Congenita
Radiologic Findings (Fig. 133-10):
Figure 133-10 Spondyloepiphyseal dysplasia congenita.
A, Radiograph in an affected newborn with a small thorax, rounded iliac wings, vertical ischia, absence of pubic ossification, short femurs, and metaphyseal rounding of long bones. B, Radiograph in an affected newborn with bell-shaped chest, short ribs, and elongated clavicles. C, Radiograph in an affected newborn with moderately short ribs with mild anterior splaying and anteriorly rounded vertebral bodies with minimal flattening and no coronal clefts.
2. Spine: dorsally wedged or oval vertebral bodies (at birth); anteriorly rounded platyspondyly (later)
3. Pelvis: absent pubic ossification (at birth and during infancy), vertical ischia with short ilia
4. Extremities: normal tubulization with mild micromelia, significant generalized ossification delay (early) and hypoplastic-appearing or dysplastic epiphyses (later), unossified talus or calcaneus in the newborn, normal hands and feet with ossification delay (epiphyses or carpal, tarsal)
Kniest Dysplasia
The same delay in epiphyseal ossification is seen along with platyspondyly. Cloudlike dystrophic calcification is present in abnormally enlarged epiphyses as the child gets older. On magnetic resonance imaging (MRI), the areas of calcification have prolonged T2 values that are likely related to the degeneration of abnormal collagen matrix.9
Radiologic Findings (e-Fig. 133-11):
2. Spine: coronal clefts (at birth and during infancy), platyspondyly with endplate irregularity (later)
3. Extremities: dumbbell femurs; generalized ossification delay, epiphyses becoming hypoplastic or dysplastic and then later even mega-epiphyses, cloudlike irregular calcification in physeal plate regions (in late childhood and early adulthood); hands with bulbous joints (metaphyseal flaring or epiphyseal fragmentation) mimicking rheumatoid arthritis
Common Features in Type 11 Collagenopathy Group
• Similar to type 2 collagenopathy
• Myopia (except for Stickler type 3)
Abnormal Sulfation Group
The abnormal sulfation group is a molecularly defined group of disorders with a defect in the sulfate transporter gene on chromosome 5 coding for the diastrophic dysplasia sulfate transporter (DTDST) protein. This group comprises not only diastrophic dysplasia but also multiple epiphyseal dysplasia MED–multilayered patellae/brachydactyly/clubfeet, as well as achondrogenesis type IB and atelosteogenesis type II.10 These conditions are all autosomal recessive, and the severity of the phenotype is inversely related to the level of sulfation.11,12
Common Features in Abnormal Sulfation Group
Achondrogenesis Type I
Achondrogenesis type I is actually two separate disorders that appear almost identical radiographically. Achondrogenesis type IB belongs to this diastrophic dysplasia (molecular) group.11 In achondrogenesis type IA, a molecular or gene abnormality has not yet been identified. Clinically, the two types appear identical: proportionately large skull; micromelic, hydropic, pear-shaped trunk; polyhydramnios; and lethality.
Radiologic Findings (Fig. 133-12):
Figure 133-12 Achondrogenesis.
A, Radiograph from a stillborn infant with type IA achondrogenesis demonstrates a tiny thorax; short, anteriorly cupped ribs with beading; micromelia; wedged femurs; and poor to absent vertebral body ossification. B, Radiograph from a stillborn infant with type IB achondrogenesis. Findings are similar to those in type IA but with arched iliac wings, no rib beading, and trapezoidal femurs
1. Skull: decreased ossification
2. Thorax: tiny; very short ribs with anterior splaying
3. Spine: absent or minimal vertebral body ossification
4. Pelvis: short iliac bones with concave acetabular roofs, absent pubic (ischial) ossification
5. Extremities: severe micromelia with broadened ends of limbs, trapezoidal or wedge-shaped femurs
Diastrophic Dysplasia
Radiologic Findings (Fig. 133-13):
Figure 133-13 Diastrophic dysplasia.
A and B, Radiographs from an affected newborn. A, Lower extremities: rhizomelia and mesomelia and severe clubfeet deformities. B, Upper extremity: elbow dislocation and short, ovoid first metacarpal. C and D, Radiographs from an affected 21-year-old. C, Upper extremity: hitchhiker thumb, ovoid first metacarpal, brachydactyly, and irregular and extra carpal bones. D, Lower extremities: unusual clubfoot and twisted metatarsals
1. Head: ear pinna calcification, cleft or high arched palate
3. Spine: progressive scoliosis, kyphosis, upper cervical subluxation (odontoid hypoplasia), cervical kyphosis, posterior process clefting (cervical and sacral)
4. Extremities: often micromelia; short, thick tubular bones; generalized brachydactyly; short ovoid first metacarpal delta phalanx causing proximal placement of thumb (hitchhiker thumb), twisted metatarsals, accessory and irregular carpal bones; epiphyseal dysplasia with multiple joint contractures
5. Other sites: precocious costochondral and laryngeal area cartilage calcification; multiple sternal and patella centers
Multiple Epiphyseal Dysplasia: Multilayered Patellae/Brachydactyly/Clubfeet
Radiologic Findings: Extremities show the following: epiphyseal dysplasia, especially at hips (half- or quarter-moon–shaped); double-layered or multilayered patella (visible on lateral knee radiograph); mild brachydactyly; clubfeet or twisted metatarsals; mildly shortened long bones, some with mild undertubulation.
Filamin Group
The filamin group combines a wide group of dysplasias that have in common an abnormality in the number and configuration of carpal, tarsal, and vertebral bones with joint dislocations. The identification of the group is another triumph in the study of molecular genetics, as it reclassifies correctly a group of disorders described as “syndromes” within a common framework of genetically determined diseases no different from other skeletal dysplasias.13,14 The group includes oto-palato-digital (OPD) syndrome types 1 and 2, Larsen syndrome, frontometaphyseal dysplasia, Melnick-Needles osteodysplasty, and spondylo-carpal-tarsal synostosis.
OPD Syndrome
Radiographic Findings in OPD (e-Fig. 133-14):
1. Head: prominent supraorbital ridge
2. Spine: small pedicles with wide interpediculate distance
3. Extremities: accessory carpal bones, double ossification center of lunate, fusion of carpal bones especially trapezoid and scaphoid, fusion of the second metacarpal to trapezoid in adolescence, similar findings in feet; short first metatarsal and phalanges of great toe, and short and wide distal phalanx of thumb; radial head dislocation
e-Figure 133-14 Oto-palato-digital syndrome.
The radiograph at right shows typical findings of fusion of the accessory ossification centers of the second metacarpal with the adjacent deformed carpal bones. Widening and abnormal tubulation of the metacarpals are seen. The distal phalanx of the thumb is short with a coned-shaped epiphysis. Clinodactyly is present.
Larsen Syndrome
In Larsen syndrome, multiple joint dislocations are present. In keeping with the common theme of filamin abnormalities, supernumerary carpal bones are common along with other digital changes. A doubled calcaneal ossification center is a helpful clue to accurate diagnosis. Scoliosis is common. This is a filamin type B abnormality. A similar filamin type B abnormality causes spondylo-carpal-tarsal synostosis syndrome, whose name describes the pattern of skeletal involvement.15
Radiographic Features (Fig. 133-15 and e-Fig. 133-16):
Figure 133-15 A 5-year-old girl with Larsen syndrome.
A, Anteroposterior elbow radiograph shows chronic dislocation with epiphyseal deformities. B, Lateral radiograph of an ankle in a 5-year-old boy shows a bifid calcaneus and deformity of the talus and distal tibial epiphysis.
1. Spine: cervical spine kyphosis
2. Extremities: multiple joint dislocations, double or triple calcaneal ossification center, accessory carpal bones, broad irregular metacarpals
TRPV4 Group
TRPV4 (transient receptor potential cation channel, subfamily 5, member 4) is a calcium permeable nonselective cation channel that appears to play an important role in chondrogenesis. This channelopathy is also the cause of several other nonskeletal syndromes such as Charcot Marie-Tooth disease, scapula-peroneal spinal muscular atrophy, and congenital distal spinal muscular atrophy.16,17
Metatropic Dysplasia
Radiologic Findings (Fig. 133-17):
Figure 133-17 A newborn with metatropic dysplasia.
A, Thorax: long trunk and small chest. B, Spine: dense wafer vertebral bodies and short ribs with anterior splaying. C, Pelvis: short iliac wings, narrow sciatic notches, irregular acetabular roofs, and rounded, enlarged proximal femoral metaphyses (halberd shaped) with markedly flared distal metaphyses (trumpet-shaped) D, Upper extremities: flared proximal humeral and distal radial and ulnar metaphyses; shortened long bones.