I. Normal Growth
1. Long-bone growth/fracture healing is endochondral.
a. Vessel invades cartilage in the primary ossification center and growth occurs longitudinally at either end as chondrocytes proliferate, hypertrophy, die, and are replaced by calcified matrix and osteoblasts.
b. Widening of the bone is achieved by osteoblasts differentiating from stem cells from the ring of Lacroix/node of Ranvier.
Figure 1. Photomicrograph showing the structure and zones of the growth plate, ×220.]
2. Flat bone growth/distraction osteogenesis is intramembranous.
a. The skull is formed by neural crest cells invading a connective tissue scaffold.
b. The clavicle has both intramembranous and endochondral ossification.
c. The scapula has seven ossification centers.
1. An endochondral growth plate is divided into four main zones (Figure 1).
a. Reserve zone—No diseases are associated with this zone.
b. Proliferative zone—Achondroplasia and spondyloepiphyseal dysplasia (SED) affect this zone.
c. Hypertrophic zone—Fractures occur in this zone.
d. Zone of calcification—Type X collagen is present, but type II collagen is still predominant.
2. Calcifying fracture callus has some type IV collagen.
II. Skeletal Dysplasias
A. Achondroplasia (
a. Short-limbed dwarfism with abnormal facial features
b. The most common skeletal dysplasia
c. Autosomal dominant, but 90% are new mutations
Mutation affects a single protein in fibroblast growth factor receptor-3 (FGFR-3) gene, changing glycine to arginine at position 380.
[Table 1. Skeletal Dysplasias: Genetics and Features]
Result is growth retardation of the proliferative zone of the growth plate, resulting in short limbs.
The growth plates with the most growth (proximal humerus/distal femur) are most affected, resulting in rhizomelic (proximal more than distal) short stature.
a. Features include rhizomelic shortening with a normal trunk, frontal bossing, button nose, trident hands (cannot approximate middle and ring fingers), thoracolumbar kyphosis (usually resolves with ambulation), lumbar stenosis with lordosis and short pedicles, posterior radial head dislocation, "champagne glass" pelvic outlet, and genu varum (
b. Foramen magnum stenosis and upper cervical stenosis may be present and cause central apnea and weakness in the first few years of life.
[Figure 2. Weight-bearing hip-to-ankle AP radiograph of a child with achondroplasia demonstrates the classic lower extremity features of a champagne glass pelvic outlet and genu varum.]
Figure 3. Radiographs of the cervical spine of a patient with Hurler syndrome who had cervical instability that was corrected surgically. A, Extension lateral view demonstrates cervical instability. B,Flexion lateral view shows the widened atlanto-dens interval (arrow). C, Postoperative flexion lateral view shows a stable atlanto-dens interval.]
a. Nonsurgical treatment is usual for the thoracolumbar kyphosis present early on. Avoidance of unsupported sitting may help prevent it.
b. Genu varum is treated with osteotomies if symptomatic.
c. Foramen magnum/upper cervical stenosis may require urgent decompression if cord compression is present; this area does grow bigger in later life.
d. The main issue in adult life is lumbar stenosis requiring decompression and/or fusion.
e. Limb lengthening is controversial and does not treat the other dysmorphic features; if lower limb lengthening is done, humeral lengthening is indicated too.
f. Growth hormone is not effective at increasing stature.
B. Pseudoachondroplasia (Table 1)
a. Short-limbed rhizomelic dwarfism with normal facial features
b. Normal development up to age 2 years
a. Autosomal dominant
b. Mutation is in cartilage oligomeric matrix protein (COMP) on chromosome 19.
c. Epiphyses are delayed and abnormal, metaphyseal flaring is present, and early onset osteoarthritis (OA) is common.
a. Cervical instability is common and must be looked for (Figure 3, A and B).
b. Lower extremity bowing may be valgus, varus, or windswept.
c. Joints may be hyperlax in early life but later develop flexion contractures and early OA.
d. Platyspondyly is always present, but spinal stenosis is not present.
a. Cervical instability should be stabilized (Figure 3, C).
b. Symptomatic limb bowing should be surgically corrected, but recurrence is common and OA progressive.
C. Diastrophic dysplasia (Table 1)
1. Overview—Short-limbed dwarfism apparent from birth. Other common findings include cleft palate and hitchhiker thumbs (
a. Autosomal recessive
b. Mutation in sulfate transport protein that primarily affects cartilage matrix. Present in 1 in 70 Finnish citizens.
a. Cleft palate is present in 60%.
b. Cauliflower ears are present in 80% and develop after birth from cystic swellings in the ear cartilage (
Figure 5, A).
[Figure 4. Photograph of the hands of a child with diastrophic dysplasia. Note the hitchhiker thumbs.]
c. Cervical kyphosis and thoracolumbar scoliosis are often present.
d. Joint contractures (hip flexion, genu valgum with dislocated patellae) and rigid clubfeet or skewfeet are often present.
a. Surgery is indicated for progressive spinal deformity or cord compromise; note that cervical kyphosis often resolves spontaneously.
b. Surgery is also indicated for progressive, symptomatic lower extremity deformity; recurrence is common.
c. Compressive wrapping is used for cystic swelling of the ears (Figure 5, B).
D. Cleidocranial dysostosis (Table 1)
1. Overview—Proportionate dwarfism characterized by mildly short stature, a broad forehead, and absent clavicles.
a. Autosomal dominant
b. Defect in core-binding factor alpha 1 (CBFA-1), which is a transcription factor for osteocalcin
c. Affects intramembranous ossification: skull, clavicles, pelvis
a. Delayed skull suture closure with frontal bossing is present, and delayed eruption of the permanent teeth is found.
b. Aplasia of the clavicles with ability to appose the shoulders in front of the chest is present.
c. Symphysis pubis is widened.
d. Coxa vara may be present.
e. Shortening of the middle phalanges of the long, ring, and little fingers is seen.
[Figure 5. Clinical photographs of the ear of a child with diastrophic dysplasia. A, The classic cauliflower ear appearance is observed in the neonate. B, The same ear several years later, after early treatment with compressive bandages.]
a. Progressive and/or symptomatic coxa vara is treated with intertrochanteric osteotomy.
b. The other features are treated supportively.
E. Mucopolysaccharidoses (
1. Overview—All patients are short statured; additional features vary but often include corneal clouding, enlarged skull, bullet-shaped phalanges, mental retardation, visceromegaly, cervical instability, genu valgum, and developmental dysplasia of the hip (DDH) that is later in onset.
a. Mucopolysaccharidoses are lysosomal storage diseases that result in the intracellular accumulation of mucopolysaccharides in multiple organs.
b. All are autosomal recessive except Hunter syndrome type II, which is X-linked recessive.
a. Urine test to see which mucopolysaccharide breakdown products are present
b. Testing enzyme activity in skin fibroblast culture
c. Chorionic villous sampling
Hurler syndrome is now treated with a bone marrow transplant in the first year of life; intelligence is normal in some affected individuals,
[Table 2. Mucopolysaccharidoses Subtypes]
but short stature and orthopaedic deformities are always present.
Surgery is indicated for cervical instability (often atlantoaxial—assess with dynamic MRI) and progressive lower extremity deformity (Figure 3, C).
F. Multiple epiphyseal dysplasia (MED) (Table 1)
a. Proportionate dwarfisim with multiple epiphyses involved but no spinal involvement.
b. Often diagnosed in midchildhood
a. Autosomal dominant
b. Genes identified causing this phenotype include COMP; COL9A2, which encodes a chain for type IX collagen (a link protein for type II collagen); and, recently, a similar gene, COL9A3.
a. Multiple abnormal epiphyses
b. Shortened metacarpals and metatarsals are present.
c. Valgus knees with a double-layer patella are found (
Figure 6, A).
d. May be mild to severe involvement of epiphyses; long-term prognosis ranges from mild joint problems to end-stage OA with severe joint contractures at a young age.
e. No spinal involvement
f. For any bilateral Legg-Calve-Perthes patients, rule out MED.
a. Progressive genu valgum can be managed by staple hemiepiphysiodesis or osteotomy (Figure 6, B).
b. Painful, stiff joints are managed with therapy and nonsteroidal anti-inflammatory drugs; end-stage OA with joint arthroplasty.
G. Spondyloepiphyseal dysplasia (SED) (Table 1)
1. Overview—Proportionate dwarfism with spinal involvement and a barrel chest.
a. Most common autosomal dominant form is SED congenital, which is apparent from birth and caused by mutations in COL2A1, which encodes type II collagen found in articular cartilage and vitreous humor of the eyes. The proliferative zone of the growth plates is affected.
b. Rarer, X-linked recessive form is SED tarda, which is milder, with later onset from age 8 to 10 years and is thought to involve the SEDL gene.
a. Cervical instability is common in both forms.
b. Platyspondyly and delayed epiphyseal ossification are present in both, as is premature OA.
c. SEDcongenita—Coxa vara, genuvalgum, planovalgus feet, retinal detachment, myopia, and hearing loss also present.
d. SED tarda—No lower limb bowing, but dislocated hips are sometimes seen.
a. Cervical instability should be stabilized.
b. Progressive, symptomatic lower extremity deformity should be corrected with osteotomies, being careful to assess the whole limb for deformities in joints above and below, and recognizing that early OA and joint arthroplasty is still likely.
[Figure 6. Radiographs of a patient with SED. A, Preoperative weight-bearing hip-to-ankle AP radiograph demonstrates classic epiphyseal irregularities and significant right genu valgum. B, Postoperative weight-bearing hip-to-ankle AP radiograph of the same patient after varus distal femoral osteotomy.]
Top Testing Facts
1. Achondroplasia affects the proliferative zone of the growth plate.
2. Achondroplasia is the most common skeletal dysplasia.
3. Achondroplasia is caused by an autosomal dominant mutation in FGFR-3; 90% are sporadic mutations.
4. Subluxation of the radial head is common in achondroplasia and nail-patella syndrome.
5. Diastrophic dysplasia is associated with a mutation in the sulfate transporter gene, which affects proteoglycan sulfate groups in cartilage.
6. Cauliflower ears and hitchhiker thumbs are characteristic of diastrophic dysplasia.
7. Atlantoaxial instability is common in pseudoachondroplasia, SED, mucopolysaccharidoses, trisomy 21, and McKusick type metaphyseal dysplasia.
8. The most serious complications of achondroplasia in the infant and toddler are cervical spine and foramen magnum stenosis, which may cause apnea, weakness, and sudden death.
9. The most common disabling feature of achondroplasia in the adult is lumbar stenosis due to decreased interpedicular distance and shortened pedicles.
10. Pseudochondroplasia is associated with a mutation in COMP.
11. Cleidocranial dysplasia is caused by a defect in CBFA-1, which is a transcription factor for osteocalcin.
12. The mucopolysaccharidoses are all autosomal recessive except for Hunter syndrome, which is X-linked recessive.
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