OBJECTIVES: To study the clinical features and fibroblast growth factor receptor 3 (FGFR3) gene mutations of children with achondroplasia (ACH) through an analysis of 17 cases. METHODS: A retrospective analysis was performed on the clinical data and FGFR3 gene detection results of 17 children with ACH who were diagnosed from January 2009 to October 2021. RESULTS: Of the 17 children with ACH, common clinical manifestations included disproportionate short stature (100%, 17/17), macrocephaly (100%, 17/17), trident hand (82%, 14/17), and genu varum (88%, 15/17). The common imaging findings were rhizomelic shortening of the long bones (100%, 17/17) and narrowing of the lumbar intervertebral space (88%, 15/17). Major complications included skeletal dysplasia (100%, 17/17), middle ear dysfunction (82%, 14/17), motor/language developmental delay (88%, 15/17), chronic pain (59%, 10/17), sleep apnea (53%, 9/17), obesity (41%, 7/17), foramen magnum stenosis (35%, 6/17), and hydrocephalus (24%, 4/17). All 17 children (100%) had FGFR3 mutations, among whom 13 had c.1138G>A hotspot mutations of the FGFR3 gene, 2 had c.1138G>C mutations of the FGFR3 gene, and 2 had unreported mutations, with c.1252C>T mutations of the FGFR3 gene in one child and c.445+2_445+5delTAGG mutations of the FGFR3 gene in the other child. CONCLUSIONS This study identifies the unreported mutation sites of the FGFR3 gene, which extends the gene mutation spectrum of ACH. ACH is a progressive disease requiring lifelong management through multidisciplinary collaboration.
Achondroplasia/genetics* ; Child ; Humans ; Mutation ; Osteochondrodysplasias/genetics* ; Receptor, Fibroblast Growth Factor, Type 3/genetics* ; Retrospective Studies

This study aimed to report the clinical characteristics and COMP gene mutation of a family with pseudoachondroplasia (PSACH), a relatively rare spinal and epiphyseal dysplasia that is inherited as an autosomal dominant trait. Clinical information on a 5-year-2-month-old PSACH child and his parents was collected and analyzed. Diagnosis was confirmed by PCR amplification and direct sequencing of all the 19 exons and their flanking sequences of COMP gene, and the mutation was further ascertained by cloning analysis of exon 10. The child presented with short and stubby fingers, bow leg, short limb dwarfism and metaphysic broadening in long bone as well as lumbar lordosis. A mutation c.1048_1116del (p.Asn350_Asp372del) in exon 10, inherited from his father who did not demonstrate any phenotypic feature of PSACH, was detected in the child. PSACH was diagnosed definitively by means of COMP mutation analysis, on the basis of the child's clinical and imaging features. The non-penetrance phenomenon of COMP mutation was described for the first time in PSACH.
Achondroplasia ; genetics ; Cartilage Oligomeric Matrix Protein ; genetics ; Child, Preschool ; Cloning, Molecular ; Humans ; Male ; Mutation

This paper summarizes the clinical features, causative genes and treatment progress of patients with rickets-like genetic diseases, including X-linked hypophosphatemic rickets (XLH), hypophosphatasia, achondroplasia, vitamin D-dependent rickets, pycnodysostosis and ectodermal dysplasia, who visited the pediatric or child health clinic due to the symptoms of rickets, including bow legs, delayed closure of the anterior fontanelle, and sparse hair. Children with XLH usually go to hospital for bow legs and short stature, and biochemical evaluation reveals significantly low serum phosphorus so it is easily diagnosed. This disease is treated using phosphate mixture and 1,25(OH)2D3, which is different from the treatment of nutritional vitamin D deficiency rickets. Hypophosphatasia is characterized by a significant decrease in serum alkaline phosphatase, as well as normal serum calcium and phosphorus. The disease is caused by mutations in TNSALP gene. Patients with achondroplasia show short-limbed dwarfism and special face in addition to bow legs, but with normal serum calcium, phosphorus and alkaline phosphatase. Bone X-ray and FGFR3 gene test contribute to the diagnosis. Vitamin D-dependent rickets is an autosomal recessive disease, and active vitamin D supplement is effective in treatment of the disease. Patients with pycnodysostosis may be first seen at hospital because of large anterior fontanelle; in addition, they also show obtuse mandibular angle, dental abnormalities and dysplastic nails, which are caused by mutations in TSK gene. Children with ectodermal dysplasia may see a doctor for sparse hair, and they are easily misdiagnosed with nutritional vitamin D deficiency rickets. Ectodermal dysplasia is related to EDA, EDAR, EDARADD and WNT 10A genes.
Achondroplasia ; genetics ; therapy ; Ectodermal Dysplasia ; genetics ; therapy ; Familial Hypophosphatemic Rickets ; genetics ; therapy ; Humans ; Hypophosphatasia ; genetics ; therapy ; Pycnodysostosis ; genetics ; therapy

Achondroplasia ; genetics ; Adult ; Amino Acid Sequence ; Genes, Dominant ; Humans ; Male ; Molecular Sequence Data ; Mutation ; Polymorphism, Restriction Fragment Length ; Receptor, Fibroblast Growth Factor, Type 3 ; chemistry ; genetics ; physiology

OBJECTIVETo research on the reliability of diagnosing achondroplasia (ACH) on single cell level and to provide a basis for preimplantation genetic diagnosis(PGD).

METHODSThe high-frequency mutation region G380R of fibroblast growth factor receptor 3(FGFR3) gene was amplified by nested-PCR with single lymphocyte and single blastomere. The products of PCR were digested by restriction enzyme Bfm I, then the digested products were detected by 10% polyacrylamida gel electrophoresis(PAGE).

RESULTSThe amplification success rate, allele dropout rate and correct diagnosis rate of single lymphocyte's PCR were 90.4%, 8.2% and 91.8%,respectively. The amplification success rate of single blastomere was 75.4%.

CONCLUSIONThe diagnosis of ACH by single cell nested-PCR is comparatively stable and reliable.

Achondroplasia ; diagnosis ; genetics ; DNA Mutational Analysis ; Humans ; Molecular Diagnostic Techniques ; methods ; Mutation ; Polymerase Chain Reaction ; methods ; Preimplantation Diagnosis ; Receptor, Fibroblast Growth Factor, Type 3 ; genetics ; Sensitivity and Specificity

OBJECTIVETo diagnose achondroplasia prenatally by FGFR3 gene detection.

METHODSSeventy-eight fetuses affected by short-limb dysplasias were recruited. Umbilical blood sampling was employed to obtain fetal blood for karyotyping and FGFR3 gene detection. Genomic DNA was extracted, and the exon 10 of the FGFR3 gene was amplified. PCR amplicons were analyzed by DNA sequencing and restriction fragment length polymorphism with Bfm I. The FGFR3 exon 10 from the parents of the positive fetuses was screened by the same method.

RESULTSIn 78 fetuses affected with short-limb dysplasias, 8 cases had G1138A heterozygotic mutation and normal karyotype, and were diagnosed as achondroplasia. The other 70 fetuses had normal nucleotide at nucleotide 1138 in exon 10 of FGFR3, therefore were excluded from achondroplasia. Only one father in parents of the 8 achondroplasia fetuses also had the G1138A mutation.

CONCLUSIONAchondroplasia could be diagnosed prenatally in the fetuses affected with short-limb dysplasias by using PCR-RFLP and DNA sequencing of the exon 10 of the FGFR3 gene.

Achondroplasia ; diagnosis ; genetics ; DNA Mutational Analysis ; Female ; Humans ; Male ; Polymorphism, Restriction Fragment Length ; Pregnancy ; Prenatal Diagnosis ; methods ; Receptor, Fibroblast Growth Factor, Type 3 ; genetics

OBJECTIVETo analyze the clinical manifestations, bone X-ray findings and genetic analysis results of three short-limb inherited short stature diseases: achondroplasia (ACH), hypochondroplasia (HCH) and pseudoachondroplasia (PSACH).

METHODSThe clinical manifestations, bone X-ray findings, and genetic analysis results of 10 children with genetically confirmed short-limb inherited short stature diseases, including 4 cases of ACH 3 cases of HCH, and 3 cases of PSACH, were analyzed.

RESULTSThe 10 patients had a mean body height of -3.69±1.79 SD, a mean sitting height/standing height ratio of 0.65±0.03, and a mean finger spacing/body height ratio of 0.93±0.04. Four ACH cases and 3 PSACH cases showed typical bone X-ray findings; one HCH case showed a smaller sciatic notch, and another HCH case showed no widening of interpedicular distance. G380R mutation in FGFR3 gene was detected in 3 of 4 ACH cases, and Y278C mutation in the other ACH case, N540K mutation in FGFR3 gene was detected in 3 HCH cases, and heterozygous mutations in COMP gene were detected in 3 PSACH cases.

CONCLUSIONSChildren with ACH and PSACH have severer short stature and skeletal deformities than children with HCH, who have mild, atypical clinical manifestations. Bone X-ray and genetic analysis are helpful for the diagnosis and differential diagnosis of the three diseases. The mutational hotspots in two genes are involved in the three diseases, which is conducive to clinical genetic diagnosis.

Achondroplasia ; diagnostic imaging ; genetics ; Bone and Bones ; abnormalities ; diagnostic imaging ; Child ; Child, Preschool ; Dwarfism ; diagnostic imaging ; genetics ; Female ; Humans ; Limb Deformities, Congenital ; diagnostic imaging ; genetics ; Lordosis ; diagnostic imaging ; genetics ; Male ; Mutation ; Radiography ; Receptor, Fibroblast Growth Factor, Type 3 ; genetics

OBJECTIVETo establish the mouse model of Gly374Arg mutation in fibroblast growth factor receptor 3(Fgfr3) and to analyze the phenotype of the mutant mice.

METHODSThe double PCR was used to introduce Gly374Arg point mutation into mouse Fgfr3. The electroporation of embryonic stem(ES) cells was carried out with targeting vector. The targeted ES cells were screened by Positive-Negative Selection of G418 and Ganciclovir, and Southern blot. The correct targeted ES cells were microinjected into blastula. Finally, mutant mice were obtained by crossing between EIIa-Cre transgenic mice and mice carrying recombined mutant Fgfr3 allele. The mice were genotyped by PCR, and phenotype was observed by skeleton staining, histology, etc.

RESULTSFgfr3-Gly374Arg mutant mice exhibited small size, short tail, macrocephaly and had dome-shaped heads, the epiphyseal growth plates of mutant mice were narrower, and the hypertrophic chondrocyte zone was also obviously decreased. Meanwhile, the majority of female mice were infertile, and the uterus, ovary and mammal gland in mutant female mice were also smaller and underdeveloped.

CONCLUSIONThe model of Fgfr3-Gly374Arg mutation causing achondroplasia in mice has been established successfully.

Achondroplasia ; genetics ; pathology ; Amino Acid Substitution ; Animals ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Ovary ; pathology ; Point Mutation ; Protein-Tyrosine Kinases ; genetics ; Receptor, Fibroblast Growth Factor, Type 3 ; Receptors, Fibroblast Growth Factor ; genetics ; Uterus ; pathology

OBJECTIVE[corrected] To investigate the mutation at the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) nucleotide 1138 site for identifying the major pathologic mechanism of achondroplasia (ACH) and to evaluate the efficacy of denaturing gradient gel electrophoresis(DGGE) method for screening the point mutations.

METHODSThe genomic DNA from 17 clinically diagnosed ACH patients where analysed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) with Sfc I and Msp I restriction endonucleases and by PCR-DGGE technique for screening.

RESULTSG to A transition mutation at nucleotide 1138 was detected in 14/17 of the ACH patients as heterozygotes by PCR-RFLP with Sfc I digestion. No 1138 G to C transition was detected by Msp I digestion. All of the 14 samples with G to A mutation were also found to be positive for point mutation by PCR-DGGE. No mutation was detected in 3 negative samples by PCR-RFLP, implying that there was actually no point mutation in this amplified region.

CONCLUSIONNucleotide 1138 in transmembrane domain of FGFR3 gene is the hot point for mutation in ACH and hence its major pathologic cause. PCR-DGGE is a sensitive and reliable technique for point mutation screening, especially for the heterozygotes.

Achondroplasia ; genetics ; DNA ; chemistry ; genetics ; DNA Mutational Analysis ; Female ; Humans ; Male ; Point Mutation ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single-Stranded Conformational ; Protein-Tyrosine Kinases ; Receptor, Fibroblast Growth Factor, Type 3 ; Receptors, Fibroblast Growth Factor ; genetics

OBJECTIVETo clarify the patients' pathogenic mechanism in an achondroplasia family not according with the genetic law of autosomal dominant inheritance disease at gene level.

METHODSGenomic DNA from peripheral blood of all members in this family was used for amplification of the exon 10 of fibroblast growth factor receptor 3(FGFR3) gene by PCR; mutation was detected by DNA sequencing and identified by restriction endonuclease MaeIII.

RESULTSA new mutation of A to T at nucleotide 1180 was found in patients but not in unaffected members.

CONCLUSIONCombined with pedigree analysis, it was summarized that achondroplasia patients in this family might result from this new mutation.

Achondroplasia ; genetics ; pathology ; Base Sequence ; DNA ; chemistry ; genetics ; DNA Mutational Analysis ; Family Health ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Protein-Tyrosine Kinases ; Receptor, Fibroblast Growth Factor, Type 3 ; Receptors, Fibroblast Growth Factor ; genetics