Skeletal Dysplasias and Selected Chromosomal Disorders

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Chapter 133

Skeletal Dysplasias and Selected Chromosomal Disorders

As opposed to just a decade ago, the study of congenital syndromes is no longer an exercise in the rote memorization of seemingly disconnected syndromes. Instead, the unveiling of the intricacies of the genetic code has made apparent relationships among many inborn syndromes that had been previously unsuspected. What has emerged is that a relatively few genes are the cause of a multitude of syndromes, and by grouping syndromes and dysplasias into families based on the gene at fault, a taxonomy has emerged and has allowed a framework within which we can understand the relationships among a number of dysplasias and syndromes.

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.

Box 133-1   Nosology and Classification of Genetic Skeletal Disorders

In this chapter, the terms syndrome and dysplasia are used somewhat loosely. A syndrome is a set of characteristic findings that occur together and suggest a particular diagnosis, although the cause may not be known. A dysplasia is a set of characteristic findings in which the cause and effect are known. The distinction now has lost its value, as the cause of many “syndromes” are now known, and the term dysplasia is used to indicate not just purely a grouping of symptoms but the actual disease entity.

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 I: Assessment of Disproportion

Micromelia is overall shortening of the extremities. Rhizomelia is relative shortening of the femurs and humeri. Mesomelia is relative shortening of the radii, ulnae, tibiae, and fibulae. Acromelia is relative shortening of the bones of hands and feet.

Classification of the shortened appendicular segment is helpful for diagnosis. Rhizomelia may be very helpful to confirm the specific diagnosis of the rhizomelic form of chondrodysplasia punctata. Very significant mesomelia suggests a group of specific disorders loosely classified as the mesomelic dysplasias. Acromelia is found in many disorders; when it occurs by itself, several specific dysplasias are suggested, including acrodysostosis, acromicric dysplasia, or pseudohypoparathyroidism.

The pattern of brachydactyly may facilitate diagnosis. For instance, brachydactyly type E manifests with variable shortening of the metacarpals and distal phalanges, and brachydactyly type A4 manifests with shortening restricted to the second and fifth middle phalanges. Even the absence of acromelia may be helpful. The lack of significant hand and foot shortening is a significant feature of spondyloepiphyseal dysplasia congenita (SEDC), a type 2 collagenopathy.

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).

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.

Step V: Analysis of the Vertebral Bodies

Decreased height of the vertebral bodies is termed platyspondyly. The lumbar vertebral bodies are the best level to analyze compared with the cervical level, especially in infancy. The cervical vertebral bodies tend to appear relatively hypoplastic compared with other levels in the normal infant. This is because ossification occurs later in cervical vertebral bodies compared with vertebral bodies elsewhere. In addition to platyspondyly, other vertebral body changes are important. In the lumbar spine in normal children, the interpediculate distance usually widens on a frontal film moving inferiorly. Narrowing of the interpediculate distance is a feature of fibroblast growth factor receptor 3 (FGFR3) abnormalities such achondroplasia and thanatophoria.

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.

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

Several common radiologic threads run through this group. FGFR3 slows endochondral bone growth, so long bones are short. However, it does not affect overall bone thickness because of membranous ossification. Therefore, long bones are relatively thick. The fibula is usually longer than the tibia. Femoral necks are short and broadened and have a peculiar scooped-out appearance. It is seen as an ovoid lucency of femoral necks, as if an ice cream scoop was radiographed en face. The finding can be seen in all forms of thanatophoria. It is well seen in achondroplasia but not in most forms of hypochondroplasia.

In the normal individual, on a frontal radiograph, the horizontal distance between the pedicles of the vertebral bodies should widen moving inferiorly. FGFR3 group abnormalities exhibit narrowing in the interpediculate distance in the lumber spine. The decrease in the velocity of endochondral ossification also causes platyspondyly. Brachydactyly of all the bones of the hand is present. Since soft tissues are relatively unaffected, fingers are splayed into the “trident configuration.”

Thanatophoric Dwarfism

Given the lethality of this dysplasia, it is aptly named after Thanatos, the Greek god of death (Thantophoria, meaning “death loving”). Although it is nearly uniformly fatal, rare cases of survivors have been reported.

Type 1 includes “cloverleaf skull,” caused by in utero craniosynostosis, and curved long bones. The femurs have a “French telephone receiver” appearance. The type 2 variant has straight long bones and no craniosynostosis.

Platyspondyly is severe. They are described as U-shaped or H-shaped on an anteroposterior projection.

Radiographic Findings (Fig. 133-5):

Achondroplasia

Patients with achondroplasia have normal mentation and a normal or near normal lifespan. As in other members of the FGFR3 family, long bones are short and thick. Interpediculate narrowing is present. In infancy, femoral necks have a scooped out appearance. Since the sacrosciatic notches are narrowed, the pelvic inlet has an appearance of a wide-mouthed champagne glass.

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):

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

Achondrogenesis type 2

The most severely affected member of the group, achondrogenesis type 2 is invariably lethal. Patients with less severe hypochondrogenesis die in the first few months of life.

Radiologic Findings (Fig. 133-9):

Spondyloepiphyseal Dysplasia Congenita

The combination of platyspondyly and short long bones make spondyloepiphyseal dysplasia congenita (SEDC) a good example of short-limbed, short-trunk dwarfism. It is also a good model for an epiphyseal dysplasia. Ossification in the vertebral bodies begins in the fetus at the lower thoracic spine and progresses superiorly and inferiorly. The cervical spine ossifies last. The normal cervical spine vertebrae at birth are slightly dorsally wedged and are small. In infants with SEDC, the cervical vertebral bodies show little or no ossification. Thoracic and lumbar bodies are, however, small, dorsally wedged, and anteriorly rounded (pear or oval shaped), similar in appearance to the cervical spine in the normal infant. In childhood, characteristic central beaks, typical of epiphyseal delay, may be seen. In the adult, vertebral bodies are flattened with irregular end plates.

At birth, no ossification of the talus, calcaneus, or the epiphyses at the knee is present. Normally, the talus and the calcaneus ossify at 20 to 24 weeks’ gestation and the epiphyses at about 36 weeks’ gestation.

One salient feature is that the hands and feet in patients with SEDC are normal, apart from carpal, midfoot, and hindfoot ossification delay.

Radiologic Findings (Fig. 133-10):

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):

Note: In the newborn, Kniest syndrome is radiographically identical to SEDC except for coronal clefts and dumbbell femurs.

Type 11 Collagenopathy Group

Overview: Members of this group include Stickler syndrome type 2, Marshall syndrome, oto-spondylo-mega-epiphyseal dysplasia (OSMED) autosomal-dominant type (Weisenbach-Zweymuller phenotype, and Stickler type 3).

The multiple synonyms and names applied to the different members of the group cause some confusion. Stickler syndrome type 2 is a type 11 collagenopathy and has a similar appearance to Stickler syndrome type 1 (see type 2 collagenopathy above) with milder ocular changes and more severe auditory changes. It is autosomal recessive. Marshall syndrome is very similar to Stickler syndrome type 2 and may be considered, for all practical purposes, the same entity.

OSMED autosomal-dominant type is a type 11 collagenopathy as well. It is also called nonocular Stickler syndrome or Stickler syndrome type 3. Osseous changes in OSMED are usually worse with greater shortening of the long bones and platyspondyly. OSMED may be also called Weisenbach-Zweymuller syndrome.

Adding to the confusion is a very similar form of Stickler syndrome, which is a type 9 collagenopathy. The similarity is not coincidental. Type 11 and type 2 collagens along with type 9 collagen form collagen fibrils so that the phenotypic expression of a type 2, type 11, or type 9 collagenopathy may be similar. This is an important point in the phenotypic expression of genetic abnormalities. Since the tissues of the body are constructed of multiple elements, differing genetic and biochemical abnormalities may have similar outcomes when considering the end results of the tissues produced.

In practice, when faced with a case with a resemblance to a mild or intermediate severity type 2 or type 11 collagenopathy, both paths should be investigated.

Common Features in Type 11 Collagenopathy Group

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):

Note: Radiographic findings in achondrogenesis type IA include multiple fractured, beaded ribs, and wedged femurs. Achondrogenesis type IB shows no rib fractures or beading and has trapezoidal femurs.

Diastrophic Dysplasia

Diastrophic dysplasia is, like all the other disorders of this group, is an autosomal-recessive condition. It is commonly identifiable at birth and usually nonlethal.

Radiologic Findings (Fig. 133-13):

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

OPD syndrome causes hearing loss, cleft palate, and deformity of the digits, especially the first digit. Hearing loss is caused by malformation of the auditory ossicles. Multiple carpal bone abnormalities, including accessory carpal bones and fusion of carpal bones, are present. The capitate may be malformed, with its long axis in the transverse plane. The trapezoid is commonly fused to the base of the second metacarpal, although the finding may not manifest until skeletal ossification nears maturity in late adolescence. The distal phalanx of the thumb is short and wide. The same deformity is present in the foot, where the hallux is short. Prominence of the frontal and occipital bones is present, with a prominent supraorbital ridge. In the more severe type 2 variety, rib shortening is marked. The radial head is usually dislocated.

Radiographic Findings in OPD (e-Fig. 133-14):

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

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

The key to this group is the appearance of the vertebral bodies on a frontal view. Because of a relatively wide but flat vertebral body, the pedicles appear “overfaced.” This means that the pedicle outline projects completely within the contour of the vertebral body instead of at the margin of the body overlying the superior end plate. The appearance has been also described as an” open staircase.” Additionally, the major members of the group—metatropic dysplasia, brachyolmia (autosomal-dominant type), and spondylometaphyseal dysplasia (SMD) Koslowski type—also manifest delay in carpal bone ossification. Although brachyolmia primarily affects the vertebral bodies, subtle metaphyseal changes are seen as they are in metatropic dysplasia and SMD Koslowski type. It may be very difficult to differentiate between metatropic dysplasia and SMD Koslowski type.

Metatropic Dysplasia

Metatropic dysplasia, or metatropic dwarfism, is evident in the newborn with a relatively long trunk and markedly shortened limbs. This “changing” dysplasia over time produces a short-trunk or short-limb form of dwarfism with a “tail.” Although heterogeneous, most cases are nonlethal and are autosomal dominant.

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