Skeletal Syndromes and Systemic Disorders in Pediatric Orthopaedics

Paul D. Sponseller

5.1 Introduction

This chapter summarizes developmental syndromes that involve skeletal abnormalities. It focuses on focuses on key findings and principles for each syndrome. More detailed discussion of these conditions is available in the cited references if needed.

5.2 Skeletal Dysplasias

Skeletal dysplasias involve abnormalities of bone and cartilage growth and development. Usually, short stature occurs.

Achondroplasia:
1. Autosomal dominant with frequent new mutations. Most common skeletal dysplasia.
2. Genetic defect: Fibroblast growth factor receptor protein 3 (a gain-of-function mutation).
3. Major features:
  1. Midface hypoplasia.
  2. Rhizomelic dwarfism (limb shortening greatest proximally).
  3. Genu varum (variable).
  4. A 3- to 6-month delay in motor milestones.
  5. Thoracolumbar kyphosis, often resolving with growth.
  6. Spinal stenosis is greatest in the lumbar spine, greatest distally, but may affect entire spine, including foramen magnum, and cause severe developmental delay.
4. Height graph (▶ Fig. 5.1).
5. Treatment: Monitor for spinal stenosis and persistent kyphosis. Correction of knee and ankle deformities at patient’s discretion. Limb lengthening is an option and is usually successful but time consuming.
  
  Fig. 5.1 Comparison of growth patterns of normal-stature and achondroplastic persons, in males (a) and females (b).
  
  (Used with permission from Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall JG. Standard growth curves for achondroplasia. J Pediatr 1978;93(3):436, Figs. 1 and 2.)

Bibliography

1. Khan BI, Yost MT, Badkoobehi H, Ain MC. Prevalence of scoliosis and thoracolumbar kyphosis in patients with achondroplasia. Spine Deform 2016;4(2):145–148

Pseudo-achondroplasia:
1. Although these patients are also rhizomelic, the epiphyseal involvement in this syndrome causes arthrosis—a major difference from achondroplasia.
2. Genetic defect: Cartilage oligomeric matrix protein (COMP); found in extraterritorial matrix.
3. Major features:
  1. Rhizomelic shortening of extremities.
  2. Variable knee deformities (often varus on one side, valgus on the other).
  3. Mild platyspondyly; minimal scoliosis; no stenosis.
  4. Odontoid hypoplasia, possible C1–C2 instability.
  5. Epiphyseal deformation; eventual degeneration.
  6. Ligamentous laxity.
4. Treatment: Screen cervical spine; correct major limb malalignment. Many patients will require joint arthroplasty as adults.
Diastrophic dysplasia:
1. Autosomal recessive.
2. Genetic defect: Diastrophic sulfate transporter (DTST).
3. Major features:
  1. “Cauliflower ear” developing at around 6 months of age.
  2. Rhizomelic shortening of extremities.
  3. Contractures of major joints with later degenerative joint disease (DJD).
  4. Hands: Hitchhiker thumb, symphalangism.
  5. Dislocated hips: Occasionally.
  6. Equinovarus or other foot deformities.
  7. Cervical spina bifida with severe kyphosis: Sometimes resolves.
  8. Scoliosis of thoracic and lumbar spine.
4. Treatment: Screen and monitor the cervical spine. Correct foot deformities, scoliosis, and limb contractures. Arthroplasty as indicated.
Spondyloepiphyseal dysplasia congenita:
1. Autosomal dominant with frequent new mutations.
2. Genetic defect: Collagen 2A1.
3. Major features:
  1. Extreme short stature.
  2. Odontoid hypoplasia/os odontoideum: May have instability.
  3. Platyspondyly, scoliosis.
  4. Coxa vara, epiphyseal irregularity, DJD.
4. Treatment: Screen or stabilize the cervical spine. Correct scoliosis as indicated. Treatment for hip dysplasia is of uncertain benefit. Joint arthroplasty is often indicated in adulthood.
Spondyloepiphyseal dysplasia tarda:
1. Variable transmission; diagnosis late in childhood.
2. Genetic defect: SEDL (a tracking protein) or others.
3. Major features:
  1. Irregular ossification, DJD.
  2. Hips may resemble Perthes, but in SED bilaterally synchronous.
  3. Osteoarthritis of other joints.
  4. Scoliosis.
Multiple epiphyseal dysplasias:
1. Autosomal dominant.
2. Gene defect: COMP (found in matrix) or collagen 9 or DTST.
3. Major features:
  1. Variable; usually mild short stature because of short limbs.
  2. Irregular epiphyseal ossification with deformity, pain, DJD.
  3. Hips, knees, and ankles are most involved. Patella may show “double layer.”
  4. Usually presents in late childhood to adulthood.
Metatropic dysplasia:
1. Major features:
  1. Epiphyseal or metaphyseal enlargement: “Knobby” joints with contractures.
  2. Cervical stenosis, instability.
  3. Scoliosis, kyphosis, later onset.
  4. Coccygeal tail.
  5. Thoracic hypoplasia; may cause respiratory compromise.
  6. Initially short-limb dwarfism; becomes short-trunk type with onset of scoliosis.
Chondrodysplasia punctata (Conradi–Hünermann syndrome).
1. Autosomal dominant, recessive, and X-linked.
2. Major features:
  1. Multiple asymmetric epiphyseal calcifications.
  2. Rhizomelic form may have cervical stenosis or kyphosis as well as thoracolumbar scoliosis.
  3. Good prognosis for dominant form. Decreased life expectancy for other forms.
Multiple hereditary exostoses (MHE):
1. Inheritance: Autosomal dominant.
2. Genetic defect: At least three have been described; EXT-1 and -2 on different chromosomes. EXT-1 produces more serious form.
3. Clinical appearance: Mild short stature.
4. Categories of problems:
  1. Local impingement on tendons, nerves, spinal canal, and ribs.
  2. Asymmetrical growth in two-bone segments (forearms and legs) leading to valgus at knees, ankles, elbow, and wrists and possibly radial head dislocation.
  3. Leg-length inequality (usually <4 cm).
  4. Risk of malignant degeneration (in about 1% of patients).
  5. Osteochondromas may grow silently in spinal canal; monitor neurologic examination.
  6. Patients with MHE often heal incisions with wide scars or keloids.
5. Radiographic features:
  1. Osteochondromas in metaphysis, pointing away from joint.
  2. Cortex of osteochondroma is confluent with that of host bone.
  3. May be sessile or pedunculated.
6. Treatment:
  1. Resect lesions only when symptomatic. Increased rotation not predictable in forearm.
  2. Correct knee and ankle valgus when greater than 10 degrees.
  3. Monitor in adulthood every 2 years, possibly with bone scan.
  4. Obtain spine MRI when patient is old enough to undergo without anesthesia, or if there is any question of involvement.
Dysplasia epiphysialis hemimelica (Trevor disease):
1. Definition: Epiphyseal osteochondroma; no genetic pattern.
2. Clinical features: Presents in the first decade of life; restricted joint motion, enlarged joint, or locking. Knee, foot, and ankle are most commonly involved.
3. Radiographs: Multiple opacities in exostotic cartilage; these eventually coalesce.
4. Treatment: Resection, attempting to preserve normal cartilage.
  
  Bibliography
  
  1. Kettelkamp DB, Campbell CJ, Bonfiglio M. Dysplasia epiphysealis hemimelica. A report of fifteen cases and a review of the literature. J Bone Joint Surg Am 1966;48(4):746–765, discussion 765–766
Multiple enchondromas (Ollier disease):
1. Genetic defect: PTH/PTHRP.
2. Clinical presentation:
  1. Angular deformity.
  2. Bony irregularity.
  3. Limb-length inequality.
3. Radiographic features:
  1. Diffuse enchondromas in metaphysis; occasionally epiphyses. Usually asymmetrical.
4. Treatment:
  1. Angular or length correction of limb.
  2. Monitor for malignancy, especially in Maffucci syndrome.
Cleidocranial dysplasia:
1. Autosomal dominant.
2. Genetic defect: CBFA1, a transcription factor.
3. Clinical features:
  1. Persistently open skull sutures with bulging calvarium.
  2. Hypoplasia or aplasia of clavicles.
  3. Wide symphysis pubis.
  4. Hip abnormalities (coxa vara).
  5. Short middle phalanx of fifth finger.
  6. Scoliosis with or without syringomyelia.
  7. Multiple dental abnormalities.
    
    Bibliography
    
    1. Brigham EM, Hennrikus WL. Like father, like son: cleidocranial dysplasia: a case report. JBJS Case Connect 2015;5(4):e94
    
    2. Jensen BL. Somatic development in cleidocranial dysplasia. Am J Med Genet 1990;35(1):69–74
Dyschondrosteosis (Léri-Weill disorder):
1. Genetic defect: SHOX pseudoautosomal genes.
2. Major features:
  1. Mild short stature (<25 percentile).
  2. Madelung deformity (dorsoulnar deficiency of distal radial growth).
  3. Relative shortening of forearm and leg; varus or valgus deformity.
  4. Females predominant.

5.3 Other Syndromes Involving Short Stature

5.3.1 Cornelia de Lange (Brachmann de Lange Type)

Genetic defect: NIPBL or microdeletion on chromosome 3.
Major features:
1. Synophrys (single eyebrow).
2. Down-turned mouth.
3. Mandibular spur in infancy.
4. Hirsutism.
5. Gastroesophageal reflux.
6. Small for gestational age, with continued growth retardation.
7. Motor, speech, and intellectual delay.
8. Cardiac abnormalities.
Orthopaedic involvement:
1. Upper extremity anomalies (~100%):
  1. Micromelia, phocomelia.
  2. Decreased number of fingers.
  3. Lobster-claw hand.
  4. Proximally placed thumb.
  5. Elbow anomalies.
2. Lower extremities:
  1. Miscellaneous foot deformities and contracture.
  2. Avascular necrosis (AVN) of femoral head in 10%.
Treatment: Correct lower extremity abnormalities if limiting ambulation; upper extremities: individualized treatment.

5.3.2 Riley-Day Familial Dysautonomia

Ashkenazi Jews only: Autosomal recessive.
Sympathetic overactivity is key feature.
Major features:
1. Deficient sensation of pain and proprioception.
2. Gastroesophageal reflux, pneumonia.
3. Variable life expectancy.
Orthopaedic abnormalities and implications:
1. Scoliosis/kyphosis before age 8; poor brace tolerance; fuse early.
2. Fractures from osteopenia or dyscoordination.
3. AVN of femoral head, distal femur, talus.
4. Hip dysplasia.

5.3.3 Nail-Patella Syndrome

Autosomal dominant, normal life expectancy.
Orthopaedic features:
1. Nails grooved, small, or absent, especially on thumb.
2. Multiple knee anomalies: Patella tripartite, small, or absent, lateral femoral condyle hypoplastic, (valgus) osteochondritis dissecans of lateral femur and talus.
3. Elbow: Capitellar hypoplasia, cubitus valgus, flexion contracture.
4. Iliac horns.
5. X-linked hypophosphatemic rickets.

5.4 Sclerosing Bone Disorders

Fibrodysplasia ossificans progressiva
1. Progressive, disabling heterotopic ossification or ankylosis. Incidence—1:1,000,000.
2. Etiology: Enhanced signaling of BMP4.
3. Characteristic shortening/valgus of great toe (▶ Fig. 5.2).
4. Ossification starts as tender, hard nodule; progresses proximal to distal, posterior to anterior.
5. Do not biopsy; may accelerate the process.
6. Genetics: Usually a spontaneous mutation but may be transmitted as autosomal dominant.
Progressive diaphyseal dysplasia (Camurati–Engelmann disease):
1. Clinical features: Pain, fatigue, muscle atrophy
2. Etiology: Activating mutation in transforming growth factor beta (TGF-β) genes.
3. Radiographs: Symmetrically widened, sclerotic diaphyses and epiphyses, spared tibia, femur most commonly involved.
4. Treatment: Osteotomies only if marked deformity. Possible role for bisphosphonates.
Melorheostosis:
1. Syndrome involving asymmetrical extraosseous longitudinal hyperostotic streaks resembling molten wax; limb pain and soft-tissue contracture.
2. Treatment: Analgesics, bracing contracture releases, and bone shortening.
Osteopathia striata:
1. Linear intraosseous metaphyseal striations.
2. Autosomal dominant.
3. Asymptomatic.
4. No treatment required.
Osteopoikilosis:
1. Multiple symmetrical intraosseous epiphyseal–metaphyseal “spots.”
2. Autosomal dominant.
3. Asymptomatic.
  
  Fig. 5.2 Characteristic shortening/alus of great toe in Fibrodysplasia Ossificans Progressiva.

5.5 Fibrous Dysplasia

Background: Inheritance—somatic mutation that produces mosaic distribution of lesions in one (monostotic) or many (polyostotic) bones:
1. The molecular basis is a postzygotic activating mutation in the GNAS1 gene, which encodes for the cyclic adenosine monophosphatase–regulating α subunit of the Gs protein complex.
2. Histologically, the fibrous tissue undergoes ossification to small, irregular trabeculae (“alphabet soup”). The disease process is most active during growth and causes weakening of the bone and pathologic fracture.
Clinical manifestations: Monostotic form accounts for 80% of cases. Polyostotic is found in several bones on one side of the skeleton or scattered throughout the skeleton. In the axial skeleton, the craniofacial bones and the ribs are the most common sites; in the appendicular skeleton, the tibia and proximal femur are the most common sites.
1. Monostotic fibrous dysplasia usually presents without symptoms, and the lesion is found when a radiograph is taken for unrelated reasons.
2. Polyostotic fibrous dysplasia often results in distortion of the skeletal and facial configuration. The peak incidence of fractures is during the first decade of life, followed by a decrease thereafter. Lesions of the femoral neck may cause progressive coxa vara, leading to the shepherd’s crook deformity; this is the most common angular deformity in polyostotic fibrous dysplasia. Spinal involvement and scoliosis may also occur.
3. Skin lesions include café-au-lait spots with an irregular border (“coast of Maine”).
4. Fibrous dysplasia may be associated with significant endocrine disturbances: hyperthyroidism, phosphaturia, precocious puberty, and diabetes mellitus. The McCune–Albright syndrome includes the triad of polyostotic fibrous dysplasia, café-au-lait spots, and precocious puberty.
Imaging findings: Elongated lesion with symmetric cortical thinning and outward expansion, the characteristic of diaphyseal “long lesion in a long bone.” Lesion shows few trabecular markings and has a ground-glass appearance. Some may be entirely radiolytic or radiodense. There may be an associated angular deformity. Fibrous dysplasia shows excessive uptake on bone scan.
Treatment: Unnecessary for asymptomatic lesions of fibrous dysplasia. Large or symptomatic lesions may be treated by curettage and allografting. Lesions of the femoral neck should be treated with metallic support with or without cortical bone grafting because of the risk of fatigue fracture. If symptomatic varus deformity is present, then treatment should include valgus osteotomy with cortical bone grafting and rigid internal fixation. Because of poor bone quality, intramedullary fixation is preferable to plates and screws alone for lesions of the femoral shaft. Deformity may occur at stress risers, similar to osteogenesis imperfecta. Medical management includes the use of bisphosphonates. Early studies suggest that bisphosphonates decrease pain, improve the radiologic appearance of the lesions, and decrease the fracture rate.

5.6 Marfan and Related Disorders

5.6.1 Marfan Syndrome (MFS)

This is a disorder of fibrillin-1, which also affects TGF-β distribution and has multiple effects on the skeleton and connective tissue. Because some features may be seen in the general population, the following diagnostic criteria have been developed.
Diagnostic (Ghent) criteria: Two major criteria and involvement of another system. The asterisks below indicate major manifestations, of which there are four possibilities.
1. Genetic: MFS diagnosis in first-degree relative or fibrillin gene mutation known to cause MFS.*
2. Skeletal:
  1. Pectus excavatum or carinatum.
  2. Dolichostenomelia (long, narrow limbs; arm span-height >1.05).
  3. Arachnodactyly (long, narrow digits with positive thumb and wrist sign). “Thumb” or Steinberg sign is when the entire distal phalanx of the thumb protrudes beyond the ulnar border of the clenched fist. “Wrist” or Walker-Murdoch sign is positive when the thumb can overlap the nail of the fifth finger when clasping the opposite wrist (▶ Fig. 5.3).
  4. Vertebral column deformity (increased kyphosis, scoliosis >20 degrees).
  5. Significant hindfoot valgus.
  6. Facial features including a high narrow cranium, down-slanting eyes, narrowly arched palate.
  7. Elbow flexion contracture.
  8. Protrusio acetabula.
3. Ocular (*major involvement if any four of the skeletal features below are present):
  1. *Ectopia lentis (superolateral dislocation).
  2. Flat cornea.
  3. Retinal detachment.
  4. Myopia.
4. Cardiovascular:
  1. *Dilation of aortic root with ascending arch aneurysm.
  2. *Aortic dissection: Usually ascending segment.
  3. Aortic valve regurgitation.
  4. Mitral valve regurgitation.
  5. Abdominal aortic aneurysm.
5. Pulmonary:
  1. Spontaneous pneumothorax.
  2. Apical bleb.
6. Skin:
  1. Striae atrophicae (“stretch marks”).
  2. Hernia.
7. Central nervous system:
  1. Dural ectasia.
  2. Learning disability.
  3. Hyperactivity.
Implications:
1. Monitor aortic and cardiac status.
2. β-Blocker or losartan for aortic dilation.
3. Restrict from vigorous exertion.
4. Counsel regarding genetics.
5. Treat skeletal deformity if symptomatic. Bracing does not usually control spinal deformity.
  
  Fig. 5.3 Illustration of the thumb and wrist signs. Thumb sign: The entire distal phalanx of the thumb protrudes beyond the ulnar border of the clenched fist. Wrist sign: Thumb covers the entire fifth fingernail when wrapped around the opposite wrist.

5.6.2 Homocystinuria

This disorder may be mistaken for MFS but is most readily distinguished by mental retardation. It has the following major features:

Mental retardation.
Dislocated lens (inferomedial).
Arachnodactyly.
Joint stiffness.
Cavus feet.
Scoliosis or kyphosis.
Diagnosis: Urine amino acid screen.
Treatment: Vitamin B6 administration, methionine restriction.

5.6.3 Congenital Contractural Arachnodactyly (Beals Syndrome)

This is also an MFS lookalike, so much so that the original MFS patient had this syndrome.
Genetic defect: Fibrillin-2.
Clinical features:
1. Face: Oval with recessed jaw, flattened ears.
2. Eyes: Occasional intraocular coloboma.
3. Heart: Congenital septal and valve defects.
4. Skeleton: Flexion contractures, which partially improve with time.
5. Hands: Contracture of proximal interphalangeal and distal interphalangeal joints.
6. Scoliosis: Appears by mid-childhood.

5.6.4 Achard Syndrome

Clinical features:
1. Arachnodactyly.
2. Generalized ligamentous laxity.
3. Mandibular hypoplasia.

5.6.5 Stickler Syndrome (Hereditary Arthro-ophthalmopathy)

Genetic etiology: A mutation in type II collagen.
Clinical features:
1. Progressive myopia beginning in first decade.
2. Retinal detachment.
3. Abnormal epiphyseal development, eventual DJD. May resemble Perthes.
4. With or without mild joint hypermobility.
5. With or without marfanoid habitus.
6. Autosomal dominant.
  Bibliography
  
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Tags: Handbook of Pediatric Orthopaedics

Mar 20, 2020 | Posted by admin in ORTHOPEDIC | Comments Off

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Skeletal Syndromes and Systemic Disorders in Pediatric Orthopaedics

5.1 Introduction

5.2 Skeletal Dysplasias

5.3 Other Syndromes Involving Short Stature