Achondroplasia

Author: Deborah Allen

Topic updated on 06/09/13 6:15pm

Introduction

Also known as classic dwarfism
- it is the most common cause of disproportionate dwarfism.
Genetics
- autosomal dominant (AD)
- caused by 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 spinal conditions
- lumbar spinal 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
- be alert for symptoms of spinal stenosis
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
- spine
  - lumbar spine xrays reveal
    - short pedicles with decreased interpedicular distance from L1-S1
    - T12/L1 vertebral wedging
    - posterior vertebral scalloping
- pelvis
  - xrays show champagne glass pelvis (pelvis is wider than deep)
MRI
- may be indicated to evaluate spinal 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 and has failed nonoperative management
Foramen magnum stenosis
- operative
  - urgent decompression
    - indicated if cord compression is present
Genu varum
- operative
  - tibial osteotomies or hemiepiphysiodeses
    - indicated when severe symptoms and nonoperative modalites fail
Short stature
- operative
  - limb lengthening through a metaphyseal corticotomy
    - indications
      - controversial due to high rate of complications

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Qbank (5 Questions)

TAG

(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

1. Rhizomelic limb shortening
2. Normal intelligence
3. Frontal bossing
4. Cervical spine instability
5. Spinal stenosis

PREFERRED RESPONSE ▶

DISCUSSION: 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

REFERENCES:

1. Shirley ED, Ain MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg. 2009 Apr;17(4):231-41. Review. PubMed PMID: 19307672. PMID:19307672 (Link to Abstract)

Question Authors:

John Badylak MD, Eric Shirley MD, Michael Hughes MD,

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TAG

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

Review Topic

1. Marfan syndrome
2. Gaucher's disease
3. Fibrous dysplasia
4. Achondroplasia
5. Diastrophic dysplasia

PREFERRED RESPONSE ▶

DISCUSSION: 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 achondroplasi 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

REFERENCES:

1. Shirley ED, Ain MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg. 2009 Apr;17(4):231-41. Review. PubMed PMID: 19307672. PMID:19307672 (Link to Abstract)

Question Authors:

Eric Shirley MD, Patrick McCulloch MD, Derek Moore,

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TAG

(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

1. FGFR-3, zone of proliferation
2. FGFR-2, zone of proliferation
3. FGFR-3, zone of hypertrophy
4. FGFR-2, zone of hypertrophy
5. COMP, zone of hypertrophy

PREFERRED RESPONSE ▶

DISCUSSION: 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

REFERENCES:

1. Shirley ED, Ain MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg. 2009 Apr;17(4):231-41. Review. PubMed PMID: 19307672. PMID:19307672 (Link to Abstract)

Question Authors:

Eric Shirley MD, Derek Moore, Eric Shirley MD,

Please Rate Educational Value!

3.0

Average 3.0 of 15 Ratings

Posts

Fibroblast Growth Factor Receptor-3 as a Therapeutic Target for Achondroplasia--Genetic Short Limbed Dwarfism. Includes Poll

Aviezer D, Golembo M, Yayon A
Curr Drug Targets. 2003 Jul;4(5):353-65. PMID: 12816345 (Link to Pubmed)

Pediatrics - Journal Club - Achondroplasia

4/26/2013

14 responses

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ABOS II: Achondroplasia

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Evidence & References Show References

Level of Evidence 5 and Other Journal Articles (includes Case Reports, Expert Opinions, Personal Observations, and Biomechanic Studies)

Shirley ED, Ain MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg. 2009 Apr;17(4):231-41. Review. PubMed PMID: 19307672. PMID:19307672 (Link to Abstract)

Textbooks

Review of Orthopaedics, 6th Edition, Mark D. Miller MD, Stephen R. Thompson MBBS MEd FRCSC, Jennifer Hart MPAS PA-C ATC, an imprint of Elsevier, Philadelphia, Copyright 2012
AAOS Comprehensive Orthopaedic Review, Jay R. Leiberman. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2009
Orthopaedic Knowledge Update 10, John M Flyn. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2011
Hoppenfeld SP. Surgical Exposures in Orthopaedics: The Anatomic Approach. Lipponcott, Williams, and Wilkins, Philadelphia, PA, Copyright 2009
Orthopaedic In-training Examination (OITE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Self-Assessment Examination (SAE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012

Undefined

Aviezer D, Golembo M, Yayon A. Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia-genetic short limbed dwarfism. Curr Drug Targets 2003; 4: 353-365. PMID:12816345 (Link to Abstract)
Chen L, Adar R, Yang X, Monsonego EO, Li C, Hauschka PV, Yayon A, Deng CX. Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. J Clin Invest 1999; 104: 1517-25. PMID:10587515 (Link to Abstract)
He L, Shobnam N, Wimley WC, Hristova K. FGFR3 heterodimerization in achondroplasia, the most common form of human dwarfism. J Biol Chem. 2011 Apr 15;286(15):13272-81. Epub 2011 Feb 15. PMID:21324899 (Link to Abstract)
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. Complete COL1A1 allele deletions in osteogenesis imperfecta. Genet Med. 2010 Nov;12(11):736-41. PMID:21113976 (Link to Abstract)

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Achondroplasia

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