Novel FGFR3 Mutations in Hypochondroplasia

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The vast majority of patients with disorders in the achondroplasia (ACH) class of human chondrodysplasias have one of a very limited number of recurrent mutations in the gene encoding FGFR3 (fibroblast growth factor receptor 3). The strongest correlation is with ACH proper; over 98% of patients have the same glycine to arginine substitution at amino acid position 380 (G380R). Similarly, infants with thanatophoric dysplasia have mutations that map to a limited number of sites on FGFR3. To some extent, the exception to this rule is hypochondroplasia (HCH) in which 60% to 65% of clinically diagnosed patients share a common FGFR3 asparagine to lysine or serine mutation (N540K/S) leaving almost a third without a common mutation. However, DNA testing FGFR3 mutations is often focused on regions of recurrent mutation, the observations in HCH has raised the question of whether the patients in whom the common mutations are not detected have mutations in regions of FGFR3 that are not usually tested or, alternatively, have mutations in genes other that FGFR3 that give rise to a clinical phenotype indistinguishable from that associated with mutation of FGFR3.


Figure 1. Schematic representation of the receptor- and structure-based sequence alignment. (a) Distribution of novel FGFR3 mutations identified in this study. Mutations causing HCH are shown in green and the mutation causing ACH is shown in red. The different domains of the receptor are indicated: Ig I – III1/4immunoglobulin-like domains; A1/4acid box; TM1/4transmembrane domain; TK1, 21/4Tyrosine kinase sub-domains. Numbers at the extremities of Ig loops represent conserved cysteine residues involved in the formation of disulfide bonds.
Reprinted with permission from: Heuertz S, et al. Eur J Hum Genet. 2006;14:1240-7. Copyright © NPG 2006. All rights reserved.

To resolve this question, Heuertz and colleagues sequenced the entire coding sequence including all 18 exons and intron-exon boundaries of FGFR3 in 25 patients with HCH and one with ACH in whom mutations had not been detected by routine testing. They identified seven novel missense mutations, one causing ACH and 6 causing HYP as shown in Figure 1. None of the mutations were detected in unaffected parents indicating that they had arisen de novo. The authors also observed several polymorphisms. However, no FGFR3 mutations were detected in 19 patients clinically diagnosed with HCH. They emphasize that the latter patients did not differ clinically from those with FGFR3 mutations.

The authors concluded that the spectrum of FGFR3 mutations that cause HCH is wider that previously recognized, but that mutations in other genes can produce the HCH clinical phenotype. They recommended a two-step protocol for DNA diagnosis. The first step would analyze the hot spots for known recurrent mutations of FGFR3; the second step would involve sequencing the entire coding sequence.

Heuertz S, Le Merrer M, Zabel B, et al. Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia and severe forms of hypochondroplasia. Eur J Hum Genet. 2006;14:1240-7.

Editor’s Comment

This report helps to resolve the question surrounding DNA diagnosis of HCH suggesting that some patients have atypical mutations of FGFR3 and that other patients apparently have mutations elsewhere, ie, genetic heterogeneity. The two-step protocol for DNA testing seems reasonable if sequencing is available. It will be interesting to see if mutations in HCH patients lacking FGFR3 mutations map to genes whose products are functionally related to FGFR3 as predicted. The evolving nature of the radiographic finings of HCH is shown in Figure 2.

William A. Horton, MD


Figure 2. Radiographs of HCH Patients (a) Pelvis of patient 2 at 4 weeks with oval radiolucent area in the proximal femora. (b) Pelvis at 3.5 years. Femoral necks are short and in valgus position. (c) Short tibia and disproportionately long fibula in patient 2 at 3.5 years. (d) Lateral view of the spine with rounded vertebral bodies and dorsal scalloping in the lumbar region in patient 2 at 3.5 years. (e) Lower limbs of patient 3 at 18 months illustrating exaggerated flaring of femoral and tibial metaphyses. (f) Short hand with reduction of metacarpal bones in patient 3 at 30 years. (g) Lateral spine view showing short lumbar pedicles in patient 3 at 30 years. (h) Skeleton of patient 4 at birth. Internally truncated femoral metaphyses are noticeable. (i) Short hand of patient 4 at 6 months with mild metaphyseal flaring. (j) Short tibiae and femora with marked metaphyseal flaring in patient 4 at 3 years. (k) Left femur of patient 5 at 5 years showing moderate flaring of the distal metaphysis. (l) Disproportionately long fibula of patient 5 at 5 years. (m) Lateral view of the spine showing short lumbar pedicles in patient 5 at 12 years. (n) Pelvis of patient 6 at 3 years showing short and wide femoral necks. (o) Short lumbar pedicles are seen on the lateral spine view of the affected mother of patient 6. (p) Femurs of patient 7 at 4 years are slightly bowed. (q) Flaring of the tibial metaphyses is mild but the fibulae are longer than the tibiae in patient 7 at 4 years. (r) Mild metaphyseal cupping of metacarpals is visible in patient 7 at 8 years.

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Last Updated: 04/30/2008