Hypochondroplasia and stature within normal limits: Another family with an Asn540Ser mutation in the fibroblast growth factor receptor 3 gene

Thauvin‐Robinet, Christel; Faivre, Laurence; Lewin, Patricia; Monléon, Jean-Vital de; François, C; Huet, Frédéric; Couailler, J.-F.; Campos-Xavier, Ana Bélinda; Bonaventure, Jacky; Merrer, Martine Le

doi:10.1002/ajmg.a.10238

Cited by 12 publications

(5 citation statements)

References 17 publications

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“…Furthermore, the same fetus presented mild tibia bowing that has been described in fetuses with more severe phenotype. Although HCH individuals carrying the N540K mutation are characterized by a relatively uniform phenotype [Rousseau et al, 1996; Prinster et al, 1998; Grigelioniene et al, 2000, variable expressivity cannot be excluded as indicated by the report of one patient with the N540K mutation presenting with craniosynostosis [Angle et al, 1998, or considering reports of clinical variability of other HCH FGFR3 mutations, like N540S [Mortier et al, 2000; Thauvin‐Robinet et al, 2003 and N540T [Deutz‐Terlouw et al, 1998. Almost all prenatally diagnosed HCH patients that were studied by molecular methods, including the two fetuses presented here, carried the N540K FGFR3 mutation, with a more severe phenotype compared to patients with other FGFR3 mutations or unlinked to 4p16.3 [Rousseau et al, 1996; Prinster et al, 1998; Grigelioniene et al, 2000.…”

Section: Discussionmentioning

confidence: 99%

Biological fixation of fibrous materials to bone using chitin/chitosan as a bone formation accelerator

et al. 2008

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Biological fixation or anchorage of fibrous materials to bone by bone ingrowth into the spaces between fibers is a major concern in developing novel medical implants, including artificial ligaments. Toward this end, we evaluated the efficacy of chitin/chitosan as a bone formation accelerator. Specimens of polyester nonwoven fabric coated with chitin/chitosan were implanted into holes drilled into the distal ends of rat femora. Uncoated fabric specimens were used as controls. At 1 or 2 weeks after implantation, the specimens were retrieved, and the fixation strength was measured by mechanical testing. Histological sections of 2-week implantation specimens were prepared, and the area of new bone tissue formed in the spaces between the fibers of the fabric was measured. The chitin/chitosan coating significantly increased the fixation strength and the area of bone tissue formed in the spaces between the fibers. The mean fixation strength of chitin/chitosan-coated fabric specimens was more than twice that of the controls at 2 weeks after implantation. These results demonstrated that the chitin/chitosan coating effectively induced bone formation in the spaces between the fibers and enhanced biological fixation of the fibrous materials to the bone.

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Section: Discussionmentioning

confidence: 99%

Biological fixation of fibrous materials to bone using chitin/chitosan as a bone formation accelerator

et al. 2008

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“…In patients with these mutations, growth retardation is less severe and the lumbar interpedicular distances and fibula/tibia length ratios are closer to normal, although disproportion of the upper extremities is as severe as in patients with other HCH mutations. A mild phenotype has also been described in families with a p.N540S mutation (23,24,25). Patients with this mutation may have a height overlapping with the lower end of the normal range, but they all have radiologic abnormalities and some have a large HC.…”

Section: Discussionmentioning

confidence: 94%

A novel variant of FGFR3 causes proportionate short stature

Kant

Cervenkova

Bálek

et al. 2015

European Journal of Endocrinology

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Objective: Mutations of the fibroblast growth factor receptor 3 (FGFR3) cause various forms of short stature, of which the least severe phenotype is hypochondroplasia, mainly characterized by disproportionate short stature. Testing for an FGFR3 mutation is currently not part of routine diagnostic testing in children with short stature without disproportion. Design: A three-generation family A with dominantly transmitted proportionate short stature was studied by whole-exome sequencing to identify the causal gene mutation. Functional studies and protein modeling studies were performed to confirm the pathogenicity of the mutation found in FGFR3. We performed Sanger sequencing in a second family B with dominant proportionate short stature and identified a rare variant in FGFR3. Methods: Exome sequencing and/or Sanger sequencing was performed, followed by functional studies using transfection of the mutant FGFR3 into cultured cells; homology modeling was used to construct a three-dimensional model of the two FGFR3 variants. Results: A novel p.M528I mutation in FGFR3 was detected in family A, which segregates with short stature and proved to be activating in vitro. In family B, a rare variant (p.F384L) was found in FGFR3, which did not segregate with short stature and showed normal functionality in vitro compared with WT. Conclusions: Proportionate short stature can be caused by a mutation in FGFR3. Sequencing of this gene can be considered in patients with short stature, especially when there is an autosomal dominant pattern of inheritance. However, functional studies and segregation studies should be performed before concluding that a variant is pathogenic.

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“…Chen et al have shown that the FGFR2 variants p.(Asn549His) and p.(Asn549Thr) lead likewise to a ligand-independent tyrosine kinase activation by directly disengaging the molecular brake (Chen et al 2007 ). Furthermore, equivalent substitutions in FGFR3 (p.(Asn540Lys), p.(Asn540Thr) and p.(Asn540Ser)) are known to result in gain of function and to cause hypochondroplasia (MIM 146000), an autosomal dominant skeletal dysplasia characterized by disproportionate short stature (Webster and Donoghue 1997 ; Deutz-Terlouw et al 1998 ; Mortier et al 2000 ; Thauvin-Robinet et al 2003 ). The causality of the reported variant is also underscored by a striking genotypic and phenotypic overlap with encephalocraniocutaneous lipomatosis (ECCL; MIM 613001), another mosaic neurocutaneous disorder.…”

Section: Discussionmentioning

confidence: 99%

Expansion of the complex genotypic and phenotypic spectrum of FGFR2-associated neurocutaneous syndromes

Schmidt,

Kaulfuß,

Ott

et al. 2024

Hum. Genet.

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The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. Within this family, FGFR2 is a key regulator in many biological processes, e.g., cell proliferation, tumorigenesis, metastasis, and angiogenesis. Heterozygous activating non-mosaic germline variants in FGFR2 have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes. We report on a girl with cutaneous nevi, ocular malformations, macrocephaly, mild developmental delay, and the initial clinical diagnosis of Schimmelpenning–Feuerstein–Mims syndrome, a very rare mosaic neurocutaneous disorder caused by postzygotic missense variants in HRAS, KRAS, and NRAS. Exome sequencing of blood and affected skin tissue identified the mosaic variant c.1647=/T > G p.(Asn549=/Lys) in FGFR2, upstream of the RAS signaling pathway. The variant is located in the tyrosine kinase domain of FGFR2 in a region that regulates the activity of the receptor and structural mapping and functional characterization revealed that it results in constitutive receptor activation. Overall, our findings indicate FGFR2-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum of FGFR-associated disorders. We conclude that molecular analysis of FGFR2 should be considered in the genetic workup of individuals with the clinical suspicion of a mosaic neurocutaneous condition, as the knowledge of the molecular cause might have relevant implications for genetic counseling, prognosis, tumor surveillance and potential treatment options.

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Hypochondroplasia and stature within normal limits: Another family with an Asn540Ser mutation in the fibroblast growth factor receptor 3 gene

Cited by 12 publications

References 17 publications

Biological fixation of fibrous materials to bone using chitin/chitosan as a bone formation accelerator

Biological fixation of fibrous materials to bone using chitin/chitosan as a bone formation accelerator

A novel variant of FGFR3 causes proportionate short stature

Expansion of the complex genotypic and phenotypic spectrum of FGFR2-associated neurocutaneous syndromes

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