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 IV: Assessment of the Diaphyses

Diaphyseal abnormalities primarily include bent bones and thickened sclerotic bones. The classic bent bone dysplasia is campomelic dysplasia. Others include hypophosphatasia and kyphomelic dysplasia. Thickened and sclerotic diaphyseal cortices may indicate one of the craniotubular dysplasias.

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.

Step VI: Assessment of Bone Mineralization

Bone mineral density should be assessed by not only examining the actual “whiteness” of bones but also by determining the relative thickness of the cortices relative to the medullary cavity and the coarseness of the trabecula. Osteopenia, especially when severe, indicates defective bone mineralization, as seen in rickets, hypophosphatasia, and osteogenesis imperfecta. Abnormally dense bones may indicate one of the craniotubular disorders such as pyknodysostosis and osteopetrosis. In the neonate, bones are normally sclerotic and the medullary cavity narrowed. Distinguishing abnormally dense bones from normal neonatal sclerosis can be difficult.

Step VII: Assessment of Joints

Multiple joint dislocations are a salient and persistent feature of some dysplasias. A standard skeletal survey frequently includes only frontal views of the skeleton, which may make it difficult to identify joint dislocations, especially in the infant. The elbow is frequently involved in the setting of dislocations secondary to a dysplasia. Dedicated lateral views are recommended when dislocation is clinically suspected.

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

Fibroblast Growth Factor Receptor Type 3 Group

Common Features in FGFR3 Group

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.

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

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

Common Features in Type 2 Collagenopathy Group

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.

Hypochondrogenesis

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.

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

Type 11 Collagenopathy Group

• Similar to type 2 collagenopathy

• Cleft palate

• Sensorineural hearing loss

• Myopia (except for Stickler type 3)

• Epiphyseal dysplasia (may be large or mildly flattened)

• Early arthritis

• platyspondyly

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

• Platyspondyly

• Scoliosis

• Proximally placed and short first metacarpal (“hitchhiker thumb”)

• Clubfoot

• Short thick long bones

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.

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.

Multiple Epiphyseal Dysplasia: Multilayered Patellae/Brachydactyly/Clubfeet

In some cases of MED, DTDST gene abnormalities exist. Radiographs reveal MED changes, but patients also exhibit mildly short or normal stature, clubfeet, and additional deformities due to the DTDST gene abnormality.

Common Features in the Filamin Group

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.

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

Common Features in the TRPV4 Group

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.

Spondylometaphyseal Dysplasia Koslowski Type

Characteristic radiographic findings (e-Fig. 133-18) include severe platyspondyly with overfaced pedicles. The extremities show sclerosis, flaring, and irregularity at the metaphyses. Carpal bone ossification is delayed and may not be apparent until age 5 to 6 years.

Short Rib–Polydactyly Dysplasia

SRP dysplasia is a subgroup of disorders that are typed largely on radiographic grounds. Types I and III are quite similar, as are types II and IV. The role of the pediatric radiologist is to make the diagnosis of this subgroup as separate from ATD and chondroectodermal dysplasia. To that end, it is important to note the SRP dysplasias have the shortest ribs of any of the skeletal dysplasias.

Asphyxiating Thoracic Dysplasia (Jeune Syndrome)

ATD is a genetically heterogeneous disorder with a mixed prognosis. Many affected patients die in the perinatal period from respiratory complications related to a small chest. Survivors may die from renal complications (progressive nephropathy) later in life. Other internal organs may also be involved. Sometimes, postaxial polydactyly is present. Definite radiographic (but not clinical) similarities to chondroectodermal dysplasia are evident. An allelic relationship has been considered but remains unproven.²¹ Some cases are so alike radiologically that they are best termed ATD/Ellis–van Creveld syndrome complex.

Chondroectodermal Dysplasia (Ellis–van Creveld Syndrome)

Chondroectodermal dysplasia is a nonlethal skeletal dysplasia. The nonskeletal involvement in this disorder is extremely important in defining this condition and distinguishing this lesion from ATD. Signs include hair, nail, and teeth abnormalities, as well as congenital heart disease. Polydactyly is almost invariably present. The radiologic findings are very similar to those of ATD. The genes involved in this autosomal recessive condition have been identified (EvC genes 1, 2), located at chromosome 4p16.

Multiple Epiphyseal Dysplasia

Historically MED was divided into the milder Ribbing form and the more severe Fairbanks form. Although the classification does not agree with molecular genetics data, the distinction is helpful from a clinical point of view. Ribbing MED may entail only hip involvement and can be confused with bilateral Legg-Calvé-Perthes disease and Meyer dysplasia. Differentiation from these entities is possible because almost all patients with MED have clinically significant short stature. Many patients with MED later go through an asymptomatic phase of avascular necrosis of the capital femoral epiphyses. This makes differentiation of MED from Legg-Calvé-Perthes disease very difficult if old radiographs are not available. The Fairbanks form has involvement of all the long bone epiphyses to some degree. MED manifests after about 2 years of age but is most commonly diagnosed in an adolescent or young adult. Involvement is always bilateral and symmetric. The shortening is quite mild.

It is possible to suggest the molecular defect from the radiologic changes. The COMP group has a greater resemblance to pseudoachondroplasia. Those affected by the COMP gene locus have tiny capital femoral epiphyses, irregular and poorly formed acetabula, mushroomlike flaring at the knees, brachydactyly with proximally rounded metacarpals and central protrusions in the vertebral bodies caused by delayed ossification of the ring apophyses. As noted elsewhere in this chapter, the presence of central vertebral body protrusions is a good radiologic marker for epiphyseal dysplasia.

The MED multilayered patella form includes a multilayered ossific center of the patella, clubfoot and brachydactyly.

Pseudoachondroplasia

This short-limb, short-trunk form of skeletal dysplasia was referred to at first as “achondroplasia with a normal face.” In actuality, the affected individual usually has the most beautiful or the most handsome face in the family.

Jansen-Type Metaphyseal Chondrodysplasia

This is the severest form of MCD. The presentation is in the neonatal period or during late infancy, with marked short stature and a waddling gait. This is a distinct autosomal-dominant disorder with an abnormality in a parathyroid receptor gene (PTHR), leading to hypercalcemia and its complications.²² However, the radiographic findings in the skeleton are not those of typical hyperparathyroidism or hypoparathyroidism.²³

Schmid-Type Metaphyseal Chondrodysplasia

This form of MCD is an autosomal-dominant condition caused by a specific defect in collagen type X, the gene for which is located on chromosome 6. This disorder is the mildest of the MCDs. Presentation is usually at about 2 years of age or later with a waddling gait or bowed legs, or both. Mild short stature is present.

McKusick-Type Metaphyseal Chondrodysplasia

Cartilage-hair hypoplasia, as this entity is also known, is an autosomal recessive disorder. The genetic defect is at the 9p region (RMRP gene), with a high frequency among the Amish and Finnish populations.24–26 The presentation is of variable short-limbed dwarfism in early childhood. Significant clinical features indicate the diagnosis and are important for medical management: sparse, thin, light-colored hair; Hirschsprung disease; immunological problems; and increased incidence of malignancy.

Shwachman-Diamond Dysplasia

This rare autosomal-recessive disorder is also known as MCD. Major clinical findings include pancreatic insufficiency and cyclic neutropenia. It manifests in infancy with recurrent infections and failure to thrive. The skeletal radiographic features are quite mild. The defect, involving the Shwachman-Bodian-Diamond syndrome (SBDS) gene, is located on chromosome 7q11.

Spondyloenchondromatosis

This autosomal-recessive disorder is also known as spondyloenchondrodysplasia, characterized by low-normal or mild short stature, with kyphosis, lordosis, or both. Prominent joints may be apparent.

Trichorhinophalangeal Syndrome Types I and II

Both of these disorders have been located on the long arm of chromosome 8. The gene implicated in TRPS type I (also known as Giedion syndrome) is TRPS1. TRPS type II (also known as Langer-Giedion syndrome) is slightly more complicated. TRPS type II is the result of a contiguous gene abnormality resulting from the loss of not only TRPS1 but also EXT1, a major cause of multiple hereditary exostoses located distal to TRPS1. TRPS type I is autosomal dominant, whereas most cases of TRPS type II are sporadic. The clinical manifestations of both disorders include mild short stature; sparse, slow-growing hair; pear-shaped nose (“hose nose”); and short, crooked fingers. The contiguous gene abnormality explains the added features in TRPS type II, which include multiple exostoses and mental retardation.²⁷

Acromesomelic Dysplasia of Maroteaux

This skeletal dysplasia is actually a misnomer in that the changes in this disorder are hardly just acromelic and mesomelic. Significant spinal abnormalities are also present. The disorder is autosomal recessive with a defect in NPR2, which maps to chromosome 9p and is involved in regulation of skeletal growth. Abnormalities are discoverable at birth but are quite significant by 1 year of age. Clinical findings include moderate short stature, short forearms, stubby hands and feet, and short lower legs.

Dyschondrosteosis

This skeletal dysplasia, also known as Leri-Weill syndrome, is an autosomal-dominant condition. It consists of a pseudoautosomal homeobox gene (SHOX gene) found on the short arm of the X chromosome. Dyschondrosteosis manifests with mild to moderate short stature, usually with both forearm and calf shortening. Madelung deformity is the major marker for this disease. Interestingly, Madelung deformity is also common in Turner syndrome because of the lack of two copies of SHOX since only one X chromosome is present (see discussion of Turner syndrome).

MRI is important here from a therapeutic point of view. A thickened ligament has been described by Vickers and Nielsen, which appears to tether the medial radial physis.²⁸ It can be found on the volar side of the joint and may be an abnormally thickened volar radiolunotriquetral ligament. Operative lysis of this structure if performed early can ameliorate the Madelung-type deformity. Radiographically, the ligament should be suspected when a triangular lucency is seen at the medial aspect of the distal radial metaphysis. On MRI, the ligament is clearly visible as a thick hypointense band of tissue originating at the medial radial physis.²⁹

Rhizomelic Chondrodysplasia Punctata

This is a distinct form of chondrodysplasia punctata and has an autosomal-recessive inheritance pattern. It is a symmetric rhizomelic skeletal dysplasia manifesting in the neonatal period. Affected infants usually die in the first year of life. Associated clinical findings include cataracts, skin lesions, alopecia, and joint contractures. Later manifestations are severe psychomotor retardation and spasticity. These infants appear to be in constant pain. Thus far, abnormalities in three genes (PEX7, DHPAT, AGPS) have been noted.

Campomelic Dysplasia

This unusual entity is an autosomal-dominant disorder diagnosable at birth, manifesting as bent thighs, clubfeet, respiratory distress, and unusual small facies. Sex reversal is often present. All the extremities are moderately short. Neonatal or perinatal death occurs in most cases. The molecular defect is a homeobox gene abnormality called SOX9, found on chromosome 17. Radiographically the combination of kinked femora with severe hypoplasia of the blade of the scapula makes for an easy diagnosis.

Osteopetrosis

Our understanding of osteopetrosis has evolved considerably and no less than 13 general mutation loci have been described. For clinical purposes, the disease can be distinguished by age at onset. The types with onset in infancy are the most severe.

The very severe precocious or malignant type is autosomal recessive. Patients with this type present in infancy with hepatosplenomegaly, pancytopenia, multiple infections (osteomyelitis), and leukemia. Early death is common. The delayed type (late-onset form) is autosomal dominant. Lifespan is normal, and the condition is frequently diagnosed when a radiograph is obtained after minor trauma causes a fracture. Individuals with this type sustain multiple fractures and are at increased risk of osteomyelitis, particularly in the mandible.

The condition known as osteopetrosis with renal tubular acidosis (carbonic anhydrase II deficiency) is a rare entity localized to chromosomal locus 8q and gene CA2 (carbonic anhydrase II). Diffuse dense cerebral calcifications suggest the correct diagnosis.

An intermediate form is also recognized with onset within the first decade, and although significant clinical abnormalities, including hematologic disease, are present, findings are milder than in the infantile form.

Although multiple genes are involved, the defect ultimately leads to osteoclast dysfunction because of unresponsiveness to parathyroid hormone. Without the remodeling activity of normal osteoclasts, bone becomes sclerotic and brittle. Long bone fractures are common.

Of importance is the seemingly contradictory presentation of osteopetrosis with rickets. This occurs in the severe malignant form. With this combination, dense osteopetrosis changes are seen in conjunction with rickets physeal changes. It can be understood when considering that 99% of the calcium store is bound in highly calcified dense bone. Without osteoclast function, that calcium is unavailable for correct physeal growth and mineralization, and a relative calcium deficiency is present.

Bone marrow transplantation is curative as it repopulates the marrow with normally functioning osteoclasts.

Pyknodysostosis

Pyknodysostosis is an autosomal-recessive disorder that often manifests in infancy. Clinical findings include short-limbed dwarfism, micrognathia, fractures, and short fingertips. The impressionist painter Toulouse-Lautrec likely had this condition.³⁰

Osteopoikilosis

This is an autosomal-dominant condition caused by mutations in LEMD3.³¹ The gene function and its relationship to this disease are not clear. It is often asymptomatic and identified on routine radiographs. These lesions often show increased uptake on bone scans. When skin lesions of dermatofibrosis are also present, the combination is called Buschke-Ollendorff syndrome.

Osteopathia Striata

This is an asymptomatic sporadic condition, but when associated with cranial sclerosis, it is an X-linked dominant disorder. It is often identified on routine radiographs as a “normal variant.” It can be seen, however, as a manifestation of other discrete disorders such as the dysplasia of spondylar changes, nasal anomaly, and striated metaphyses (SPONASTRIME).

Melorheostosis

This is often sporadic but can be seen as an autosomal dominant entity in families with an LEMD3 gene mutation, similar to osteopoikilosis. Patients can experience bone pain and joint stiffening, as well as limb asymmetry.

Craniodiaphyseal Dysplasia

This rare autosomal-recessive condition manifests in early infancy with progressive facial and calvarial thickening. Sudden death, as the result of cranial foraminal narrowing, is frequent.

Craniometaphyseal Dysplasia

Two forms of this disease are described on two different gene loci. Both are similar but the autosomal-recessive form is more severe and manifests as cranial and facial thickening, often with nasal obstruction. Improvement may occur with age. Cranial encroachment–induced neurologic abnormalities may develop.

Pyle Dysplasia

This autosomal-recessive entity, also known as familial metaphyseal dysplasia, is somewhat similar to craniometaphyseal dysplasia but differs in its minimal craniofacial involvement. Patients are often asymptomatic or develop genu valgum (knock knee).

Hypophosphatasia

The two distinct genetic forms of hypophosphatasia are (1) the autosomal-recessive perinatal lethal or infantile type and (2) a later-onset autosomal-dominant adult type. Both result from an abnormality of the enzyme alkaline phosphatase. The chromosome loci for both conditions are 1p36.1-34 and involve TNSALP. The perinatal or lethal form appears to represent autosomal-recessive inheritance, whereas the adult form is probably autosomal dominant. As a consequence of defective alkaline phosphatase, bone formation is impaired because of local increase in phosphate, impaired hydroxyapatite formation, and hypercalcemia with resultant Rickets-like changes.

Hurler or Hurler Syndrome (Mucopolysaccharidosis Type IH & II)

The enzyme abnormality is alpha-L-l-iduronidase, located on chromosome 4p. As with all the other members of this group, the inheritance pattern is recessive. Most of the MPS entities manifest clinically in late infancy or early childhood.

Morquio Syndrome (Mucopolysaccharidosis Types IVA and IVB)

The enzyme abnormality is in galactose-6-sulfatase, resulting in the accumulation of excess MPS material in multiple organ systems, including the skeletal system. MPS IVB patients usually have more mild radiographic and clinical findings compared with MPS IVA.

Mucolipidosis Type II (I-Cell Disease)

Mucolipidosis type II is an enzyme abnormality, of N-acetylglucosamine phosphotransferase, the gene for which is found on chromosome 4q. It clinically and radiographically manifests in the newborn and can be seen prenatally. Most affected patients die in infancy. Certain radiographic features are quite unique.

1. Multicentric hands and feet

2. Acro-osteolysis

3. Diaphyseal and metaphyseal

Marfan Syndrome and Congenital Contractural Arachnodactyly

These two congenital syndromes are caused by errors in fibrilin. Fibrilin is a glycoprotein that functions as a structural scaffold for elastic microfibrils. It can be found in abundance in the connective tissues of the walls of large vessels, lungs, bones, and eyes. The marfanoid body habitus is a constant feature along with long spidery fingers (hence the term arachnodactyly) and tall stature. The loss of normal fibrillin may allow liberation of transforming growth factor-β from the connective tissues, thereby allowing greater expressivity as tall stature.36,37

Dislocation of the lens of the eye occurs since fibrillin is found in the supportive connective tissues of the lens. The lack of normal fibrillin damages the elastic walls of the large vessels. Aortic root dilatation and rupture are the leading cause of death.

Marfan syndrome is a fibrillin 1 abnormality, whereas CCA is a fibrillin 2 abnormality. The two are phenotypically similar, each manifesting the typical marfanoid body habitus. However, patients with CCA also have joint contractures at the proximal interphalangeal joints, elbows, and knees. Although joint contractures can occur in Marfan syndrome, it is not a hallmark.

Proteus Syndrome

Proteus syndrome is named for the Greek god Proteus, who was able to change his shape at will. Proteus syndrome is a congenital hamartomatous disorder, which may be autosomal dominant. Affected patients have overgrowth of the hands and feet, limb asymmetry, gross cranial hyperostosis, and facial asymmetry leading to a frequently grotesque appearance. Patients with Proteus syndrome may also have mixed vascular malformations. Some have suggested that Joseph Merrick, also known as “the elephant man,” may have had Proteus syndrome rather than neurofibromatosis as was originally thought.

The radiographic findings of Proteus syndrome reflect what is seen clinically, namely, overgrowth of limbs and digits from both bone and soft tissues. Several types of tumors are associated with Proteus syndrome, including lipomas that tend to grow aggressively, ovarian cystadenoma, monomorphic parotid adenoma, testicular tumors, and central nervous system tumors (especially meningiomas).

Cleidocranial Dysplasia

In this autosomal-dominant disorder, the chromosome locus is at 6p21 coding for a gene called CBFA1 (core binding factor a1), also known as RUNX2. This dysplasia is quite common, with marked clinical variability and is often diagnosable at birth. The clinical findings include enlarged skull with large, late-closing fontanels; dental abnormalities; drooping, hypermobile shoulders; mild short stature; and a narrow chest.

Currarino Triad

Currarino triad (hereditary sacral agenesis syndrome) consists of imperforate or stenotic anus, osseous sacral defect, and a presacral mass.³⁸ The presacral mass may be a teratoma (two thirds of cases), a lipoma, a dermoid cyst, an enteric cyst, or an anterior meningocele. The first sacral segment is not affected. The remainder of the sacrum is deformed into a sickle shape because of partial agenesis. Life-threatening meningitis and sepsis may occur, particularly with presacral anterior meningoceles. Moreover, approximately 50% of presacral tumors communicate with the spinal canal in Currarino triad, making surgical repair difficult without neurologic complications. The syndrome is another homeobox type mutation, this one at 7q36 affecting the HLXB9 homeobox gene.

Brachydactyly Group

Limb Hypoplasia—Reduction Defects Group

Fetal Alcohol Spectrum Disorder

Fetal alcohol spectrum disorder (FASD) combines characteristic facies with predominantly neurologic abnormalities. The distinctive facies include thin palpebral fissures, a smooth philtrum, midface hypoplasia, and a thin upper lip. Neurologic abnormalities include microcephaly, agenesis of the corpus callosum, cerebellar hypoplasia, and migrational anomalies. Even in the face of no observable structural changes in the brain, intelligence may be drastically reduced. FASD is thought to be the leading known cause of intellectual disability in the developed world. Interestingly, the level of severity of the syndrome is directly related to the degree of exposure and the more characteristically abnormal the facies, the more brain damage is suspected; that is, the face predicts the brain.

A wide range of anomalies may be present. Skeletal changes include vertebral body segmentation and fusion anomalies, radiolunar synostosis, tibial exostoses, and hand anomalies, including ectrodactyly, brachydactly, and carpal fusions. Cardiac defects include septal defects, tetralogy of Fallot, and aortic arch interruption.

Urogenital anomalies associated with FASD include horseshoe kidneys, ureteral duplications, and renal aplasia. Gastrointestinal tract abnormalities include esophageal atresia with tracheoesophageal fistula, anal and small bowel atresias, and diaphragmatic hernia. Hepatobiliary abnormalities include hepatic dysfunction, biliary atresia, and hepatic fibrosis.

Noonan Syndrome

Noonan syndrome is a relatively common autosomal-dominant disorder caused by mutations in any one of these four genes: KRAS, PTPN11, RAF1, and SOS1. About half of the patients have affected PTPN11. Those with KRAS mutations are more severely affected. Noonan syndrome used to be thought of as a “male Turner syndrome,” and although the two syndromes are genetically distinct, the paradigm has validity as a memory tool.

Short stature, abnormal facies, and distinctive congenital heart defects are seen, typically pulmonic stenosis and hypertrophic cardiomyopathy. In about 20% of patients lymphatic abnormalities are present and echo Turner syndrome. These include lymphangiectasia and lymphedema. Bleeding diathesis occur in about 50% of patients.

VACTERL Association

VATER association, now expanded to VACTERL association, refers to a specific combination of anomalies in multiple organ systems which is believed to represent a developmental defect arising during the fifth week of gestation. The acronym indicates the following:

VACTERL is referred to as an association rather than a syndrome, indicating that the cause is uncertain. The various organ defects occur together and are associated. They are probably caused by a problem in blastogenesis around the fifth week of gestation. It is not associated with facial dysmorphism, learning disability, growth failure, or abnormal head size or shape. If any of these features is present, a genetic condition associated either with esophageal atresia such as Feingold syndrome or CHARGE association or with imperforate anus such as Townes-Brocks syndrome needs to be excluded.

In those patients with imperforate anus, sacral anomalies, and posterior spinal fusion defects, including tethered cord and lipomyelomeningocele, are common.

Hydrocephalus associated with the VACTERL association is known to have a high rate of recurrence in subsequent pregnancies. This is referred to as VACTERL-H association, with hydrocephalus added to the acronym. VACTERL-H is frequently an X-linked disorder, particularly when aqueductal stenosis is present and the prognosis is poor. (Fig. 133-58)

Klinefelter Syndrome

The addition of one or more X chromosomes in the male results in Klinefelter syndrome. Affected patients have greater expression of female characteristics, including gynecomastia, a feminine body fat distribution, small testes, and elevated levels of follicle-stimulating hormone. An increased incidence of male breast cancer, mediastinal germ cell tumor, leukemia, non-Hodgkin lymphoma, and lung cancer is seen, but the risk of prostate cancer is decreased.

Osseous changes are inconstant and include kyphoscoliosis, radioulnar synostosis, and a short fourth metacarpal. Skeletal findings are more apparent when more than two X chromosomes are present.

Other organ systems also may be affected. The risk of lupus, diabetes mellitus, mitral valve prolapse, bronchiectasis and emphysema, and situs inversus is increased.

Trisomy 13 (Patau Syndrome)

Trisomy 13 occurs as a pure trisomy as well as a mosaic syndrome. Survival beyond the age of 10 years is rare and most die in infancy. Severe intracranial abnormalities, including holoprosencephaly, Dandy-Walker malformation spectrum, agenesis of the corpus callosum, and anencephaly, are often present. Congenital heart disease with various renal anomalies are often present. Additional components of the syndrome include congenital vertical talus (rocker-bottom foot), digital anomalies, micropthalmia, micrognathia, and cleft palate.

Trisomy 18 (Edwards Syndrome)

Abnormalities in trisomy 18 include severe central nervous system changes such as holoprosencephaly and nonspecific migrational disorders, congenital heart disease, clubfeet or rocker-bottom feet, and digital anomalies. The hands are clenched in utero, and at birth, the first finger is adducted, and the second finger overlaps the third. Multiple other organ systems, including genitourinary, gastrointestinal, and biliary systems, are also affected. Life expectancy is short. Very few cases survive childhood. Mosaics may be less affected.

Trisomy 21 (Down Syndrome)

Trisomy 21 is the most common chromosomal syndrome. A host of anomalies involving virtually all organ systems are well described. The most common cause of trisomy 21 is a nondisjunction event during gametogenesis, usually in the mother. At times, a trisomy 21 mosaic situation can occur when the nondisjunction event occurs in an embryo during early cell division. Rarely, trisomy 21 can occur as a result of an unbalanced translocation in one parent when the long arm of chromosome 21 attaches to the long arm of chromosome 14.

Both occipitoatlantal and atlantoaxial instability is found in Down syndrome. Anteroposterior occipitoatlantal instability is defined as more than 2 mm of motion on extension of the occipitoatlantal joints. If present, a neck MRI is recommended to evaluate for signal changes in the cord. An atlantoaxial distance of 4.5 mm or less is considered normal. With a distance from 4.5 to 10 mm and a normal neurologic exam, avoidance of high-risk sports (diving, football) is recommended. If more than 4.5 mm and with a neurological deficit, activities are restricted and MRI recommended to evaluate for cord changes.⁴³ However, the poor reproducibility of findings and both intraobserver and interobserver variability may make it difficult to base surgical and clinical treatment protocols for upper cervical spine instability on measurements alone.

The brains of trisomy 21 patients have smaller than normal volumes, but no other consistent changes occur. The level of intellectual performance of affected individuals varies, but many are able to function normally in society with some assistance.

Turner Syndrome

Turner syndrome is most commonly caused by a 45,XO chromosomal pattern. In 15% of cases, one full X chromosome is present as well as an X isochromosome that contains only the long arms of chromosome X. Although originally it was thought that in the normal 46,XX female, complete inactivation of the second X chromosome occurs, some genes on the short arm of the inactivated X chromosome remain activated and are necessary for proper development, which explains why a patient with an X isochromosome and the classic XO are phenotypically similar.⁴⁴ The locus involved on the short arm of the X chromosome is in the pseudoautosomal region at Xp22 at a gene termed the short stature homeobox gene (SHOX). SHOX was originally determined to be associated with some patients with idiopathic short stature syndrome who have a significantly short stature (>2 SDS), a persistently low growth rate for age and no identifiable cause of a specific metabolic growth retarding condition. Subsequently, SHOX has been found to be active in Turner syndrome.⁴⁵ Later, homozygous loss was found to be the cause of Langer mesomelic dysplasia and heterozygous loss the cause of dyschondrosteosis (Leri-Weill syndrome).^46,47 In each of these last three conditions, the common thread of short stature, a short fourth metacarpal, and a varying degree of Madelung deformity is present.

Turner syndrome, or monosomy X, was initially described as a triad of infertility, webbing of the neck, and cubitus valgus deformity of the elbow. Since that time, a multitude of associated radiographic findings have been described involving most organ systems:

Hand radiographs demonstrate typical changes with osteopenia, shortening of the fourth and fifth metacarpals, delayed maturation, phalangeal predominance, a V-shaped deformity of the distal radiocarpal joint (Madelung deformity), and drumstick-shaped distal phalanges.

The classic cardiovascular finding is postductal coarctation of the aorta, but septal defects, aortic coarctation and dissection, and mitral valve prolapse are also common. Renal anomalies include rotational anomalies, bifid renal pelvis, horseshoe kidney (common), and multicystic dysplastic kidney. Autoimmune conditions, including hypothyroidism, diabetes, and juvenile rheumatoid arthritis, have been associated with Turner syndrome. Genital abnormalities, best evaluated with pelvic ultrasound or MRI, include ovarian and uterine absence or hypoplasia. Vascular abnormalities also include intestinal telangiectasia, lymphedema, and an increased incidence of vascular tumors (hemangioma, lymphangioma).

Alman, BA. Skeletal dysplasias and the growth plate. Clin Genet. 2008;73(1):24–30.

Ikegawa, S. Genetic analysis of skeletal dysplasia: recent advances and perspectives in the post-genome-sequence era. J Hum Genet. 2006;51(7):581–586.

McAlister, WH, Herman, TE. Osteochondrodysplasias, dysostoses, chromosomal aberrations, mucopolysaccharidoses, and mucolipidoses. In Resnick D, ed.: Bone and joint disorders, 4th ed, Philadelphia, PA: Elsevier, 2002.

Superti-Furga, A, Bonafe, L, Rimoin, DL. Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet. 2001;106(4):282–293.

Rimoin, DL, Cohn, D, Krakow, D, et al. The skeletal dysplasias: clinical-molecular correlations. Ann N Y Acad Sci. 2007;1117:302–309.

1. Warman, ML, Cormier-Daire, V, Hall, C, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011;155A(5):943–968.

2. Lachman, RS. Taybi and Lachman’s radiology of syndromes, metabolic disorders and skeletal dysplasias, 5th ed. Philadelphia, PA: Mosby; 2007.

3. Spranger, JW, Brill, PW, Poznanski, A. Bone dysplasias: an atlas of genetic disorders of skeletal development, 2nd ed. New York: Oxford University Press; 2002.

4. Bonaventure, J, Rousseau, F, Legeai-Mallet, L, et al. Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. Am J Med Genet. 1996;63(1):148–154.

5. Dakouane Giudicelli, M, Serazin, V, et al. Increased achondroplasia mutation frequency with advanced age and evidence for G1138A mosaicism in human testis biopsies. Fertil Steril. 2008;89(6):1651–1656.

6. Shapiro, R, Robinson, F. Embryogenesis of the human occipital bone. AJR Am J Roentgenol. 1976;126(5):1063–1068.

7. Gordon, N. The neurological complications of achondroplasia. Brain Dev. 2000;22(1):3–7.

8. Matsui, Y, Yasui, N, Kimura, T, et al. Genotype phenotype correlation in achondroplasia and hypochondroplasia. J Bone Joint Surg Br. 1998;80(6):1052–1056.

9. Dwek, JR. Kniest dysplasia: MR correlation of histologic and radiographic peculiarities. Pediatr Radiol. 2005;35(2):191–193.

10. Hastbacka, J, Superti-Furga, A, Wilcox, WR, et al. Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias. Am J Hum Genet. 1996;58(2):255–262.

11. Superti-Furga, A, Rossi, A, Steinmann, B, et al. A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: genotype/phenotype correlations. Am J Med Genet. 1996;63(1):144–147.

12. Karniski, LP. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype. Hum Mol Genet. 2001;10(14):1485–1490.

13. Robertson, SP. Filamin A: phenotypic diversity. Curr Opin Genet Dev. 2005;15(3):301–307.

14. Robertson, SP. Molecular pathology of filamin A: diverse phenotypes, many functions. Clin Dysmorphol. 2004;13(3):123–131.

15. Krakow, D, Robertson, SP, King, LM, et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet. 2004;36(4):405–410.

16. Dai, J, Kim, OH, Cho, TJ, et al. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J Med Genet. 2010;47(10):704–709.

17. Dai, J, Cho, TJ, Unger, S, et al. TRPV4-pathy, a novel channelopathy affecting diverse systems. J Hum Genet. 2010;55(7):400–402.

18. Hall, T, Bush, A, Fell, J, et al. Ciliopathy spectrum expanded? Jeune syndrome associated with foregut dysmotility and malrotation. Pediatr Pulmonol. 2009;44(2):198–201.

19. Dagoneau, N, Goulet, M, Genevieve, D, et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009;84(5):706–711.

20. Mill, P, Lockhart, PJ, Fitzpatrick, E, et al. Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. Am J Hum Genet. 2011;88(4):508–515.

21. Krakow, D, Salazar, D, Wilcox, WR, et al. Exclusion of the Ellis-van Creveld region on chromosome 4p16 in some families with asphyxiating thoracic dystrophy and short-rib polydactyly syndromes. Eur J Hum Genet. 2000;8(8):645–648.

22. Kruse, K, Schutz, C. Calcium metabolism in the Jansen type of metaphyseal dysplasia. Eur J Pediatr. 1993;152(11):912–915.

23. Bastepe, M, Raas-Rothschild, A, Silver, J, et al. A form of Jansen’s metaphyseal chondrodysplasia with limited metabolic and skeletal abnormalities is caused by a novel activating parathyroid hormone (PTH)/PTH-related peptide receptor mutation. J Clin Endocrinol Metab. 2004;89(7):3595–3600.

24. Hermanns, P, Tran, A, Munivez, E, et al. RMRP mutations in cartilage-hair hypoplasia. Am J Med Genet A. 2006;140(19):2121–2130.

25. Hermanns, P, Bertuch, AA, Bertin, TK, et al. Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. Hum Mol Genet. 2005;14(23):3723–3740.

26. Sulisalo, T, Francomano, CA, Sistonen, P, et al. High-resolution genetic mapping of the cartilage-hair hypoplasia (CHH) gene in Amish and Finnish families. Genomics. 1994;20(3):347–353.

27. Bowen, P, Biederman, B, Hoo, JJ. The critical segment for the Langer-Giedion syndrome: 8q24.11-q24.12. Ann Genet. 1985;28(4):224–227.

28. Vickers, D, Nielsen, G. Madelung deformity: surgical prophylaxis (physiolysis) during the late growth period by resection of the dyschondrosteosis lesion. J Hand Surg Br. 1992;17(4):401–407.

29. Cook, PA, Yu, JS, Wiand, W, et al. Madelung deformity in skeletally immature patients: morphologic assessment using radiography, CT, and MRI. J Comput Assist Tomogr. 1996;20(4):505–511.

30. Bartsocas, CS. Pycnodysostosis: Toulouse-Lautrec’s and Aesop’s disease? Hormones (Athens). 2002;1(4):260–262.

31. Ben-Asher, E, Zelzer, E, Lancet, D. LEMD3: the gene responsible for bone density disorders (osteopoikilosis). Isr Med Assoc J. 2005;7(4):273–274.

32. Isidor, B, Le Merrer, M, Exner, GU, et al. Serpentine fibula-polycystic kidney syndrome caused by truncating mutations in NOTCH2. Hum Mutat. 2011;32(11):1239–1242.

33. Zanotti, S, Smerdel-Ramoya, A, Stadmeyer, L, et al. Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology. 2008;149(8):3890–3899.

34. Zanotti, S, Canalis, E. Notch and the skeleton. Mol Cell Biol. 2010;30(4):886–896.

35. Zhang, P, Yang, Y, Zweidler-McKay, PA, et al. Critical role of notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res. 2008;14(10):2962–2969.

36. Ramirez, F. Fibrillln mutations in Marfan syndrome and related phenotypes. Curr Opin Genet Dev. 1996;6(3):309–315.

37. Ramirez, F, Pereira, L, Zhang, H, et al. The fibrillin-Marfan syndrome connection. Bioessays. 1993;15(9):589–594.

38. Currarino, G, Coln, D, Votteler, T. Triad of anorectal, sacral, and presacral anomalies. AJR Am J Roentgenol. 1981;137(2):395–398.

39. Kirks, DR, Merten, DF, Filston, HC, et al. The Currarino triad: complex of anorectal malformation, sacral bony abnormality, and presacral mass. Pediatr Radiol. 1984;14(4):220–225.

40. Bell, J, On brachydactyly and Symphalangism. Treasury of human inheritance. Pensore, LS, eds. Treasury of human inheritance, London, U.K., Cambridge University Press, 1951;vol 5:1–31.

41. Temtamy, SA, McKusick, VA, Bergsma, D Genetics of hand malformations, New York, A. R. Liss, 1978;vol 14.

42. Temtamy, SA, Aglan, MS. Brachydactyly. Orphanet J Rare Dis. 2008;3:15.

43. Pizzutillo, PD, Herman, MJ. Cervical spine issues in Down syndrome. J Pediatr Orthop. 2005;25(2):253–259.

44. Brown, CJ, Willard, HF. Localization of a gene that escapes inactivation to the X chromosome proximal short arm: implications for X inactivation. Am J Hum Genet. 1990;46(2):273–279.

45. Rao, E, Weiss, B, Fukami, M, et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet. 1997;16(1):54–63.

46. Belin, V, Cusin, V, Viot, G, et al. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet. 1998;19(1):67–69.

47. Shears, DJ, Vassal, HJ, Goodman, FR, et al. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet. 1998;19(1):70–73.