Achondroplasia

Author:

Introduction
  • Also known as classic dwarfism
    • most common cause of disproportionate dwarfism
  • Genetics
    • autosomal dominant (AD) 
    • caused by G380 mutation of FGFR3 (fibroblast growth factor receptor 3, on chromosome 4P)      
      • an "activation" mutation that leads to abnormal chondroid production by chondroblasts in the proliferative zone during enchondral bone formation at the physis  
      • a quantitative, not qualitative, cartilage defect
      • a sporadic mutation in >80%
        • risk increases with advanced paternal age
  • Associated conditions
    • spinal manifestations
      • lumbar stenosis
        • caused by short pedicles
        • most likely to cause disability 
      • thoracolumbar kyphosis 
        • may cause neurologic symptoms
      • foramen magnum and upper cervical stenosis
        • may cause periods of apnea
    • Pseudoachondroplasia
      • an autosomal dominant condition that is clinically similar to achondroplasia
      • genetics
        • caused by a defect in the cartilage oligomeric matrix protein (COMP) on chromosome 19
      • differs from achondroplasia by
        • normal facies on physical exam
        • associated with cervical instability due to odontoid hypoplasia 
        • absence of spinal stenosis
Presentation 
  • Symptoms
    • normal intelligence 
    • delayed motor milestones
    • symptoms of spinal stenosis
      • pseudoclaudication and standing discomfort
      • numbness and paresthesias
      • subjective weakness
  • Physical exam
    • classic rhizomelic dwarfism  
      • adult height ~ 50 inches
      • humerus shorter than forearm and femur shorter than tibia
      • normal trunk
    • facial features
      • frontal bossing
      • button noses
      • small nasal bridges
    • extremities
      • trident hands (inability to approximate extended middle and ring finger)  
      • bowed legs
      • radial head subluxation
      • muscular hypotonia
    • spine
      • thoracolumbar kyphosis (often resolves at weight-bearing age) 
      • excessive lordosis (due to short pedicles)
Imaging
  • Radiographs
    • CTLS spine
      • recommended views
        •  AP and lateral  
      • lumbar spine findings
        • short pedicles 
        • decreased interpedicular distance from L1-S1 
        • T12/L1 vertebral wedging
        • posterior vertebral scalloping  
    • pelvis and extremities
      • recommended views
        • AP pelvis and weight-bearing hip-to-ankle AP  
      • findings
        • champagne glass pelvis (pelvis is wider than deep) 
  • MRI
    • indications
      • to evaluate spinal stenosis  
      • suspected foramen magnum stenosis  
Treatment
  • Spinal kyphosis
    • nonoperative
      • bracing
        • indicated as first line of treatment in mild curves
    • operative
      • anterior strut corpectomy and posterior fusion
        • indications
          • bracing has failed
          • kyphosis of > 60° by age 5
  • Lumbar stenosis
    • nonoperative
      • weight loss, physical therapy, corticosteroid injections
    • operative
      • multilevel laminectomy and fusion
        • indications
          • spinal stenosis with severe symptoms
          • nonoperative management has failed
  • Foramen magnum stenosis
    • operative
      • urgent decompression
        • indications
          • when cord compression is present
  • Genu varum
    • operative
      • tibial osteotomies or hemiepiphysiodeses
        • indications
          • symptoms are severe
          • nonoperative modalities have failed
  • Short stature
    • operative
      • limb lengthening through a metaphyseal corticotomy
        • indications
          • controversial due to high rate of complications
 

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Questions (5)

(OBQ12.82) Which of the following radiographs represents the condition associated with the genetic mutation G380R in the transmembrane domain of fibroblast growth factor 3 (FGFR3)? Topic Review Topic

QID:4442
FIGURES:
1

Figure A

5%

(152/3012)

2

Figure B

6%

(191/3012)

3

Figure C

75%

(2249/3012)

4

Figure D

10%

(297/3012)

5

Figure E

2%

(71/3012)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Figure C shows the classic radiograph found in a child with achondroplasia, which is caused by a mutation in the fibroblast growth factor 3 (FGFR3). Characteristic features include the "champagne glass" pelvis, squared iliac wings, and a flat acetabular roof.

Achondroplasia is an autosominal dominant condition caused by a mutation in fibroblast growth factor 3. The mutation causes a change in the genetic make-up of a single protein, changing glycine to arginine at position 380. Characteristic clinical features include rhizomelic dwarfism, frontal bossing, trident hands, and excessive lordosis secondary to congenitally short pedicles.

He et al. discuss the role of the G380R mutation in the transmembrane domain of fibroblast growth factor 3 (FGFR3), which is associated with achondroplasia. They demonstrated that FGFR3 WT/G380R heterodimers form with lower probability than wild-type FGFR3 homodimers at low ligand concentration.

Van Dijk et al. performed multiplex ligation-dependent probe amplification analysis of the COL1A1 gene in a group of 106 patients with a clinical suspicion of osteogenesis imperfecta (OI). They found a deletion of the complete COL1A1 gene on one allele in four families with mild OI.

Incorrect Answers:
Answer 1: Figure A represents rickets with metaphyseal cupping and fraying in the distal radius and ulna.
Answer 2: Figure B shows a radiographic representation of osteopetrosis.
Answer 4: Figure D represents osteogenesis imperfecta, with marked osteopenia, anterior and medial bowing, and focal sclerosis in the midshaft of the tibia due to prior fracture. Osteogenesis imperfecta is associated with a gene mutation in collagen type I (COL1A2).
Answer 5: Figure E repesents cleidocranial dysplasia, with hypoplasia of the clavicles.

References:

Complete COL1A1 allele deletions in osteogenesis imperfecta.

Pediatrics - Journal Club - Osteogenesis Imperfecta

van Dijk FS, Huizer M, Kariminejad A, Marcelis CL, Plomp AS, Terhal PA, Meijers-Heijboer H, Weiss MM, van Rijn RR, Cobben JM, Pals G.
Genet Med. 2010 Nov;12(11):736-41. PMID: 21113976 (Link to Abstract)
POSTS
Question COMMENTS

(OBQ10.161) Dwarfism caused by a defect of fibroblast growth factor receptor-3 (FGFR3) is associated with all of the following traits EXCEPT: Topic Review Topic

QID:3254
1

Rhizomelic limb shortening

6%

(123/1906)

2

Normal intelligence

3%

(63/1906)

3

Frontal bossing

4%

(72/1906)

4

Cervical spine instability

78%

(1481/1906)

5

Spinal stenosis

9%

(165/1906)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

Characteristic findings of achondroplasia include rhizomelic limb shortening, normal intelligence, frontal bossing, and spinal stenosis. Cervical spine instability is not prevalent in achondroplasia, but is is present in pseudoachondroplasia, a skeletal dysplasia due to cartilage oligometric matrix protein (COMP) gene.

Achondroplasia, caused by a defective FGFR3 affecting the proliferative zone of the physis, is characterized by rhizomelic shortening of the extremities. Rhizomelic shortening is defined as disproportionate shortening of the proximal segment of limbs, and is characteristically found in achondroplastic patients. Inheritance is typically autosomal dominant, although spontaneous mutations are not uncommon. Characteristic findings include frontal bossing, trident hands, thoracolumbar kyphosis, shortened pedicles causing spinal stenosis, genu varum, muscular hypotonia, and normal intelligence.

Shirley et al report achondroplasia, the most common skeletal dysplasia, is caused by a mutation of fibroblast growth factor receptor-3. This disorder is characterized by frontal bossing, midface hypoplasia, otolaryngeal system dysfunction, and rhizomelic short stature."

Illustration A is a clinical example of achondroplasia. Illustration B demonstrates the difference between different forms of dwarfism.

ILLUSTRATIONS:
  • A
  • B
  • C
  • D
  • E
  • F
  • V
Question COMMENTS

(OBQ09.10) Which of the following conditions is associated with a mutation in fibroblast growth factor receptor-3 (FGFR3)? Topic Review Topic

QID:2823
1

Marfan syndrome

2%

(16/869)

2

Gaucher's disease

0%

(0/869)

3

Fibrous dysplasia

4%

(39/869)

4

Achondroplasia

91%

(794/869)

5

Diastrophic dysplasia

2%

(20/869)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

Achondroplasia results from a mutation in fibroblast growth factor receptor-3.

Achondroplasia, the most common skeletal dysplasia, is caused by a mutation of fibroblast growth factor receptor-3. This disorder is characterized by frontal bossing, midface hypoplasia, otolaryngeal system dysfunction, and rhizomelic short stature. Orthopaedic manifestations are exhibited in the spine and the extremities.

Shirley et al discuss different orthopaedic manifestations of achondroplasia and their treatment. They report thoracolumbar kyphosis is seen in most infants, but typically it resolves when the child begins to walk. Anatomic anomalies of the vertebral column place the patient at risk for spinal stenosis as early as the first decade and especially during adulthood.

Illustration A shows characteristic findings of the vertebral body. Notice the short pedicles, which often leads to spinal stenosis in these patients.

Incorrect Answers:
Answer 1. Marfan syndrome is caused by a mutation in the fibrillin gene.
Answer 2. Gaucher's disease results from a mutation in glucocerebrosidase.
Answer 3. Fibrous dysplasia results from a mutation in cAMP.
Answer 5. Diastrophic dysplasia most commonly results from a mutation in the SLC26A2 gene which affects a sulfate transporter.

ILLUSTRATIONS:
  • A
  • B
  • C
  • D
  • E
  • F
  • V
Question COMMENTS

(OBQ06.139) A 7-year-old presents to your office for general orthopedic evaluation at the request of his primary care physician. A clinical picture of the patient with his taller sibling is shown in Figure A. What physeal zone is affected by the mutation leading to this patient's condition? Topic Review Topic

QID:325
FIGURES:
1

Zone of hypertrophy

25%

(471/1859)

2

Reserve zone

2%

(29/1859)

3

Zone of proliferation

71%

(1327/1859)

4

Primary spongiosa

1%

(16/1859)

5

Secondary spongiosa

0%

(4/1859)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Based on the clinical photo shown, the patient has rhizomelic dwarfism and frontal bossing. The most common cause of this is achondroplasia. Achondronplasia results from a mutation in the FGFR3 gene. This leads to abnormal chondroid production in the zone of proliferation of the physis.

Achondroplasia is an autosomal dominant condition that results from sporadic mutations in FGFR3. Patients classically have rhizomelic dwarfism. Frontal bossing of the forehead, trident hands, bowing of the legs, thoracolumbar kyphosis and hyperlordosis are some of the characteristic clinical findings in this patient population.

Aviezer et al. discuss some of the molecular abnormalities related to mutations in the FGFR3 gene. Disruption of this gene in mice leads to an increased length of long bones and the vertebral column. They indicate that treatment strategies for achondroplasia may ultimately take advantage of blocking FGFR3 signaling mechanisms.

Chen et al. induced achondroplastic changes in a mouse model. The found that mutant mice had macropcephaly and shortened limbs secondary to limited enchondral bone growth. Relative to wild types, there was a narrowed physeal zone of proliferation. Their findings suggest a critical role for FGFR3 signaling during enchondral ossification.

Figure A shows a clinical photo of a child with rhizomelic dwarfism, short limbs and frontal bossing consistent with achondroplasia.

Illustration A shows a pelvic radiograph demonstrative of a champagne shaped pelvis, where the pelvis is wider than deep. This is consistent with the diagnosis of achondroplasia.

Incorrect Answers
Answer 1: The zone of hypertrophy is affected with fractures and SCFE
Answer 2: The reserve zone has a low oxygen tension and is implicated in Gaucher's disease.
Answer 4: The primary spongiosa is located in the metaphysis and is implicated in the formation of metaphyseal corner fractures seen in child abuse
Answer 5: The secondary spongiosa is located in the metaphysis and is implicated in SCFE associated with renal osteodystrophy

ILLUSTRATIONS:
  • A
  • B
  • C
  • D
  • E
  • F
  • V
Question COMMENTS

(OBQ06.226) Achondroplasia results from abnormal chondrocyte function in the physis. What receptor is defective and what region of the physis is affected? Topic Review Topic

QID:237
1

FGFR-3, zone of proliferation

80%

(560/701)

2

FGFR-2, zone of proliferation

5%

(35/701)

3

FGFR-3, zone of hypertrophy

13%

(90/701)

4

FGFR-2, zone of hypertrophy

2%

(14/701)

5

COMP, zone of hypertrophy

0%

(1/701)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

Achondropasia is caused by a mutation in the FGFR-3 receptor in the zone of proliferation. This is a gain of function mutation which enhances tyrosine kinase activity resulting in increased inhibition of chondrocyte proliferation and differentiation.

Shirley and Ain reviewed the features of achondroplasia which include rhizomelic dwarfism (proximal shortening) and genu varum. It is helpful to remember that spinal manifestations develop at different ages: foramen magnum stenosis during infancy, thoracolumbar kyphosis when sitting begins, and spinal stenosis as early as the second decade.

Illustration A shows the zone of proliferation, which is affected in Achondroplasia.

Incorrect Answers:
Answer 2 & 4: Apert's syndrome is caused by a genetic defect in the FGFR-2
Answer 5: COMP defects cause pseudoachondroplasia, multiple epiphyseal dysplasia type I, and McKusick's metaphyseal chondrodysplasia.

ILLUSTRATIONS:
  • A
  • B
  • C
  • D
  • E
  • F
  • V
Question COMMENTS
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