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Which of the following radiographs represents the condition associated with the genetic mutation G380R in the transmembrane domain of fibroblast growth factor 3 (FGFR3)?
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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.
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.
He L, Shobnam N, Wimley WC, Hristova K
J. Biol. Chem.. 2011 Apr;286(15):13272-81. 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.
Genet Med. 2010 Nov;12(11):736-41. PMID: 21113976 (Link to Abstract)
Engberts AC, Jacobs WC, Castelijns SJ, Castelein RM, Vleggeert-Lankamp CL
J Child Orthop. 2012 Mar;6(1):69-73. PMID: 22442656 (Link to Abstract)
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Dwarfism caused by a defect of fibroblast growth factor receptor-3 (FGFR3) is associated with all of the following traits EXCEPT:
Rhizomelic limb shortening
Cervical spine instability
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.
Shirley ED, Ain MC
J Am Acad Orthop Surg. 2009 Apr;17(4):231-41. PMID: 19307672 (Link to Abstract)
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Which of the following conditions is associated with a mutation in fibroblast growth factor receptor-3 (FGFR3)?
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.
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.
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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?
Zone of hypertrophy
Zone of proliferation
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.
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
Aviezer D, Golembo M, Yayon A
Curr Drug Targets. 2003 Jul;4(5):353-65. PMID: 12816345 (Link to Abstract)
Chen L, Adar R, Yang X, Monsonego EO, Li C, Hauschka PV, Yayon A, Deng CX
J. Clin. Invest.. 1999 Dec;104(11):1517-25. PMID: 10587515 (Link to Abstract)
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Achondroplasia results from abnormal chondrocyte function in the physis. What receptor is defective and what region of the physis is affected?
FGFR-3, zone of proliferation
FGFR-2, zone of proliferation
FGFR-3, zone of hypertrophy
FGFR-2, zone of hypertrophy
COMP, zone of hypertrophy
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.
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.
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