Dysplasias

Achondroplasia

Achondroplasia belongs to group 1 of the osteochondrodysplasias, as listed in the International Nosology and Classification of Genetic Skeletal Disorders.

It is one of the more common skeletal dysplasias, with a prevalence ranging from 1 : 15,000 to 1 : 40,000 live births. The incidence increases with increasing paternal age.

It is usually inherited as a sporadic autosomal-dominant (AD) condition. The homozygous state is lethal.

Achondroplasia arises from a point mutation in the fibroblast growth factor receptor-3 (FGFR3) gene, now a therapeutic target for treating affected patients.

Antenatal diagnosis (by ultrasonography) is possible by detecting shortening of the long bones. Short limbs (specifically short femora) are not apparent until toward the end of the first (homozygous disease) or second trimester (heterozygous disease).

Complications may be common and relatively mild (e.g., otitis media) or less common but more severe (e.g., narrow foramen magnum with compression of the cervicomedullary junction). Complications of orthopedic procedures such as limb lengthening should also be considered.

Radiologic findings for the neonate include:

• 1.

  Skull: Large vault; small foramen magnum

• 2.

  Spine: Bullet-shaped vertebral bodies with posterior vertebral scalloping ( Fig. 104-1 )

  

• 3.

  Chest: Small thorax with short ribs (see eFig. 104-1 )

  

• 4.

  Pelvis: Medial and lateral acetabular spurs (trident acetabula); horizontal acetabular roof; small sacrosciatic notch (see eFig. 104-1 ; Fig. 104-2 )

  

• 5.

  Long bones: Characteristic sloping metaphyses—especially of proximal femora (see Fig. 104-2 )

For the older child:

• 1.

  Skull, chest: As for neonate, plus

• 2.

  Spine: Short pedicles with narrowing of the inter­pedicular distance from L1 to L5 (see eFig. 104-2 ), horizontal sacrum with exaggerated lumbar lordosis (see eFig. 104-3 )

  
  

• 3.

  Pelvis: Squared iliac wings

• 4.

  Long bones: Predominantly rhizomelic shortening (see eFig. 104-4 ); long distal fibula relative to tibia (causing progressive varus deformity); chevron deformity of growth plates (V-shaped notches)

  

• 5.

  Hands: Trident; bullet-shaped phalanges ( Fig. 104-3 )

  

Hypochondroplasia

Hypochondroplasia belongs to the achondroplasia group (group 1) of osteochondrodysplasias. It is allelic to achondroplasia and, like achondroplasia, is inherited as an autosomal dominant trait. The degree of short stature is variable, and the phenotype ranges from near normal to almost as severe as achondroplasia. Although there are reports of antenatal diagnosis, it is more common for the (radiologic) diagnosis to be made in early or even middle childhood when mild short stature or failure of the pubertal growth spurt is noted. FGFR3 mutations are not the only cause of hypochondroplasia, with more than 50% of patients being FGFR3 mutation negative.

Clinical features include short limbs with or without bowing of the lower limbs, a muscular build, lumbar hyperlordosis, and macrocephaly with frontal bossing.

Radiologic findings (see eFig. 104-5A-C ) are similar to but milder than those seen in achondroplasia. They include:

• 1.

  Long bones: Short and relatively broad with prominence of sites of muscular insertion; relatively long distal fibula; long ulna styloid process (see eFig. 104-5A-C )

• 2.

  Hands: Brachydactyly (see eFig. 104-6 )

  

• 3.

  Spine: Loss of the normal widening of the interpedicular distance from L1 to L5 (see eFig. 104-7 )

  

• 4.

  Pelvis: Short, square iliac wings

Thanatophoric Dysplasia

“Thanatophoric” comes from the Greek for “death bearing.” This is the most common lethal osteochondrodysplasia and belongs to the achondroplasia group (group 1) of the International Nosology. It results from a sporadic AD FGFR3 mutation. Antenatal diagnosis is based on identification of short, bowed femora in association with a small thorax.

The role of 3D compared with 2D ultrasonography and CT and MRI in the antenatal diagnosis of skeletal dysplasias including thanatophoric dysplasia continues to be evaluated.

Radiologic findings include:

• 1.

  Skull: Relative macrocephaly; in type 1 ( Fig. 104-4 ) the skull is of normal shape; in type 2 ( Fig. 104-5 ) there is premature fusion of the temporoparietal sutures and frontal bossing, giving rise to the “cloverleaf” skull or Kleeblattschädel

  
  

• 2.

  Spine: Severe platyspondyly with “wafer thin” or H-shaped vertebral bodies on lateral (see Figs. 104-4 and 104-5 and eFig. 104-8 ) and anteroposterior (see eFig. 104-9 ) spine radiographs

  
  

• 3.

  Chest: Small thorax; short horizontal ribs with cupped costochondral junctions (see eFigs. 104-9 and 104-10 )

  

• 4.

  Pelvis: Small, square iliac wings; small sacrosciatic notch; trident acetabula (see eFig. 104-11 )

  

• 5.

  Long bones: Significant micromelia; irregular, flared metaphyses; bowed “telephone receiver” femora (see eFigs. 104-9 and 104-11 ), but not in all cases

• 6.

  Hands: Short, broad tubular bones (see eFig. 104-12 )

  

Kniest Dysplasia

Kniest dysplasia belongs to group 2 of the osteochondrodysplasias—the type II collagenopathies. Other type II collagenopathies include achondrogenesis type II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita (SEDC), and Stickler syndrome type I.

Kniest dysplasia is inherited as an AD trait.

Clinical features include short stature, enlarged joints, cleft palate, severe myopia, retinal detachment, hearing loss from recurrent ear infections, and tracheomalacia.

Histopathologic examination of unossified cartilage reveals a characteristic “Swiss cheese” appearance that has also been documented on MRI.

Radiographic findings include:

• 1.

  Spine: Mild platyspondyly; irregular end plates; coronal clefts; kyphoscoliosis in older children and adults (see eFig. 104-13 )

  

• 2.

  Chest: Short, broad thorax

• 3.

  Pelvis: Sloping acetabular roofs

• 4.

  Long bones: Short; wide metaphyses giving a “dumbbell” appearance; delayed ossification of epiphyses; stippled epiphyses ( Fig. 104-6 )

  

• 5.

  Hands: Pseudoepiphyses of proximal and middle phalanges, broad metaphyses ( Fig. 104-7 )

  

Spondyloepiphyseal Dysplasia Congenita

Like Kniest dysplasia, SEDC is an AD type II collagenopathy. Affected patients are short at birth with a flat face and may have a cleft palate. There is severe myopia, and retinal detachment may develop. Respiratory complications requiring long-term ventilation have been described.

Radiologic findings include:

• 1.

  Spine:

  • a.

    Infancy: Platyspondyly; anisospondyly with L5 being smaller than L1 ( Fig. 104-8A ); oval vertebral bodies; hypoplastic peg (see eFig. 104-14 ) and/or cervical vertebral body (usually C3)

    
    

  • b.

    Childhood: Pear-shaped vertebral bodies (see Fig. 104-8B ); cervical kyphosis and instability as a result of a hypoplastic peg/vertebral body; progressive kyphoscoliosis may develop

• 2.

  Chest: Small thorax with short ribs

• 3.

  Pelvis: At birth there is absent ossification of the pubic rami; horizontal acetabular roofs (see eFig. 104-15 )

  

• 4.

  Long bones: Absent ossification of epiphyses of the knees at birth; micromelia; short or absent femoral necks; delayed ossification of proximal femoral epiphyses (see eFig. 104-16 ); significant coxa vara deformity with waddling gait and high-riding greater trochanters; posterior dislocation of the hips

  

• 5.

  Hands: Delayed maturation of carpal bones on the radial side of the hand

Stickler Syndrome

Stickler syndrome is an AD disorder with characteristic eye and facial features, deafness, and arthritis.

There are three types, with Stickler dysplasia type I (and various Stickler-like syndromes) belonging to group 2—type II collagenopathies, and Stickler dysplasia types II and III belonging to group 3—type XI collagenopathies. Types II and III are differentiated by the absence of ocular involvement in the former.

Clinical features include midface hypoplasia with a depressed nasal bridge and micrognathia. Midline abnormalities may be absent or range from a cleft soft palate to the Pierre Robin sequence. Patients have a congenital nonprogressive high myopia, and the associated abnormality of the vitreous gel is said to be pathognomonic. Retinal detachment is a recognized complication. Sensorineural deafness is another finding. There is joint hypermobility that improves with age, but early osteoarthritis may develop.

Patients are usually of normal stature and normal intelligence.

Infants with the Zweymüller-Weissenbacher (ZW) syndrome (Pierre Robin sequence, mild platyspondyly, and flared metaphyses) are later diagnosed (around the age of 3 years) either with Stickler syndrome or with otospondylomegaepiphyseal dysplasia (OSMED). However, not all patients with Stickler syndrome will have had the ZW phenotype.

Radiologic findings in Stickler syndrome (all types) may be subtle and include:

• 1.

  Spine: Mild platyspondyly (localized or generalized); irregular end plates; kyphoscoliosis

• 2.

  Pelvis: Tilted acetabular roofs ( Fig. 104-9 )

  

• 3.

  Long bones: Flared, wide metaphyses in infancy (ZW syndrome—see eFig. 104-17 ); wide femoral necks; early osteoarthritis

  

• 4.

  Hands: Advanced bone age (see eFig. 104-18 )

  

Asphyxiating Thoracic Dystrophy

This autosomal-recessive (AR) disorder belongs to group 9 of the osteochondrodysplasias—the short rib conditions with or without polydactyly. Asphyxiating thoracic dystrophy and chondroectodermal dysplasia are nonlethal, compared with short rib dysplasia types I/III, IV, and II, which are perinatally lethal.

Asphyxiating thoracic dystrophy may be diagnosed antenatally with identification of a small thorax and postaxial polydactyly (in 10% of cases).

Death is usually a result of respiratory distress associated with the small thorax and hypoplastic lungs.

Various approaches and materials for thoracoplasty have been devised to increase chest size and improve the survival rate in patients with asphyxiating thoracic dystrophy.

Pancreatic cysts, retinal abnormalities, and hepatic complications have also been described.

Long-term survivors develop renal cystic disease and will not survive without renal transplantation.

Radiologic findings include:

• 1.

  Chest: Small thorax; short horizontal ribs ( Fig. 104-10 )

  

• 2.

  Pelvis: Short iliac bones; trident acetabula with medial and lateral spurs

• 3.

  Long bones: Mild micromelia; bowed; metaphyseal spurs; premature ossification of proximal femoral epiphyses

• 4.

  Hands: Cone-shaped epiphyses of phalanges (see eFig. 104-19 ); postaxial polydactyly (10%)

  

It is worth noting that in survivors these features resolve, with the only radiographic abnormalities that persist into childhood being short middle and distal phalanges associated with cone-shaped epiphyses.

Ellis-Van Creveld Syndrome

This is an AR, nonlethal short rib syndrome with polysyndactyly occurring in 90% of patients. It belongs to the same group (group 9) of osteochondrodysplasias as asphyxiating thoracic dystrophy. The small thorax and polydactyly in addition to mesomelic shortening and an atrial (occasionally ventricular) septal defect allow antenatal diagnosis.

Clinical findings include natal teeth, abnormally shaped microdontic teeth, dystrophic nails, fusion of the upper lip to the gingival margin, and oral frenula.

As with asphyxiating thoracic dystrophy, perinatal death may result from pulmonary hypoplasia.

Radiologic features include:

• 1.

  Chest: Small thorax; short horizontal ribs

• 2.

  Pelvis: Short iliac bones; trident acetabula with medial and lateral spurs; narrow sacrosciatic notch (see eFig. 104-20 )

  

• 3.

  Long bones: Mesomelic shortening; sloping proximal humeral metaphyses and “chicken drumstick” appearance of forearm bones ( Fig. 104-11 ); smooth rounded metaphyses (see eFig. 104-21 ); deficient ossification of the lateral aspect of the proximal tibial metaphysis leading to gradual genu valgum

  
  

• 4.

  Hands: Cone-shaped epiphyses of middle and distal phalanges; short middle and distal phalanges; postaxial polysyndactyly in up to 90% of patients ( Fig. 104-12 )

  

The chest and pelvic changes improve with age (similar to asphyxiating thoracic dystrophy), leaving the older child with residual mesomelic shortening (most pronounced in the lower limbs) and short middle and distal phalanges with cone-shaped epiphyses.

Multiple Epiphyseal Dysplasia

There are various types of multiple epiphyseal dysplasia (MED) each caused by a specific mutation. Autosomal-recessive MED belongs to group 4 of the classification system (the sulfation disorders group); other AD forms of MED belong to group 10 of the classification system (multiple epiphyseal dysplasia and pseudoachondroplasia group) and are due to mutations in COMP (as is pseudoachondroplasia), type IX collagen, and matrilin-3.

Clinically, patients are of normal intelligence. They may be of normal height or have mild short stature. They present with prominent, stiff painful joints with contractures and premature osteoarthritis.

Genotype/phenotype studies have revealed significant patterns ; however, in all cases, radiologic findings mainly involve hips, knees, and hands complicated by early osteoarthritis (see eFig. 104-22 ).

Radiographic findings include:

• 1.

  Hips: Small, flattened, fragmented, irregular and sclerotic proximal femoral epiphyses ( Fig. 104-13 ; see eFig. 104-22 )

  

  The differential diagnosis is bilateral Legg-Calvé-Perthes disease (however, this disorder is rarely synchronous).

• 2.

  Knees:

  • a.

    AD (see eFig. 104-23 ) and AR forms: Small, flattened epiphyses

  • b.

    AR form: Multilayered patellae ( Fig. 104-14 ); these patients may also have brachydactyly and talipes

    

• 3.

  Hands:

  • a.

    Children (see eFig. 104-24 ): Delayed appearance of epiphyses; small irregular/angulated epiphyses

  • b.

    Adults (see eFig. 104-25 ): Small broad tubular bones; flattened joint surfaces; premature osteoarthritis; contractures

    

• 4.

  Spine: Normal; mild changes including end-plate irregularity; platyspondyly; dorsal wedging

Pseudoachondroplasia

Pseudoachondroplasia belongs to group 10 of the osteochondrodysplasias (multiple epiphyseal dysplasia and pseudoachondroplasia group). It is inherited as an AD trait and, like some cases of MED, is due to a mutation in the COMP gene. The phenotype is more severe than that of MED.

Patients present around the age of 2 years with short-limbed short stature, ligamentous laxity, and a waddling gait. Like patients with MED, they develop premature osteoarthritis.

Radiographic findings include:

• 1.

  Long bones: Small, flattened, irregular epiphyses; flared irregular metaphyses (see eFig. 104-26 )

  
  
  

• 2.

  Spine: In children there is mild platyspondyly; biconvex end plates; anterior tongues of the vertebral bodies (see eFig. 104-27 )

  

• 3.

  Pelvis: Wide triradiate cartilage ( Fig. 104-15 )

  

• 4.

  Chest: Cupping of the posterior rib ends

• 5.

  Hands: Short metacarpals and phalanges, pointing of bases of metacarpals ( Fig. 104-16 )