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Abstract Background Achondroplasia is a congenital skeletal system malformation caused by missense variant of FGFR3 gene with an incidence of 1 per 20,000–30,000 newborns, which is an autosomal dominant inheritance disease. Despite similar imaging features, the homozygous achondroplasia is absolutely lethal due to thoracic stenosis, whereas heterozygous achondroplasia does not lead to fetal death. Case presentation A fetus with progressive rhizomelic short limbs and overt narrow chest was detected by prenatal ultrasound in the second trimester. Gene sequencing results of amniotic fluid sample indicated a rare missense variant NM_000142.4: c.1123G > T(p.Gly375Cys), leading to a glycine to cysteine substitution. Re-sequencing confirmed that it was a heterozygous variant, and thoracic stenosis was then confirmed in the corpse by radiological examination. Conclusions We identified a heterozygous variant of the FGFR3 gene as the rare pathogenic variant of severe achondroplasia in a fetus. Heterozygous variants of p.Gly375Cys may have a severe phenotype similar to homozygote. It’s crucial to combine prenatal ultrasound with genetic examination to differentiate heterozygous from homozygous achondroplasia. The p.Gly375Cys variant of FGFR3 gene may serve as a vital target for the diagnosis of severe achondroplasia.

Background: Achondroplasia is a congenital skeletal system malformation caused by missense variant of FGFR3 gene with an incidence of 1 per 20,000–30,000 newborns, which is an autosomal dominant inheritance disease. Despite similar imaging features, the homozygous achondroplasia is absolutely lethal due to thoracic stenosis, whereas heterozygous achondroplasia does not lead to fetal death. Case presentation: A fetus with progressive rhizomelic short limbs and overt narrow chest was detected by prenatal ultrasound in the second trimester. Gene sequencing results of amniotic fluid sample indicated a rare missense variant NM_000142.4: c.1123G > T(p.Gly375Cys), leading to a glycine to cysteine substitution. Re-sequencing confirmed that it was a heterozygous variant, and thoracic stenosis was then confirmed in the corpse by radiological examination. Conclusions: We identified a heterozygous variant of the FGFR3 gene as the rare pathogenic variant of severe achondroplasia in a fetus. Heterozygous variants of p.Gly375Cys may have a severe phenotype similar to homozygote. It's crucial to combine prenatal ultrasound with genetic examination to differentiate heterozygous from homozygous achondroplasia. The p.Gly375Cys variant of FGFR3 gene may serve as a vital target for the diagnosis of severe achondroplasia. [ABSTRACT FROM AUTHOR]

Objective: To analyze the fibroblast growth factor receptor 3 gene (FGFR3) mutations in fetuses with thanatophoric dysplasia type I (TD1) and to provide additional data for genotype-phenotype analyses. Materials and Methods: Eight cases of severe fetal short-limb dwarfism detected by antenatal ultrasonography were referred to this center. Before the termination of pregnancy, cordocentesis was performed for FGFR3 gene-sequencing analysis. Postmortem radiographic examination was performed in each instance for definitive diagnosis. Results: By FGFR3 gene sequencing, the authors identified six cases with missense mutations and two cases with stop codon mutations in the FGFR3 gene. Among the 6 FGFR3 missense mutations, four cases revealed a heterozygous p.Arg248Cys mutation, one case had a heterozygous p. Tyr373Cys mutation, and one case had a heterozygous p.Ser348Cys mutation. Discussion: The present data confirm the existence of hotspot FGFR3 mutations of TD1 and suggest that considerable overlap may occur between genotypes and phenotypes among FGFR3-related skeletal dysplasias.

Muenke syndrome is caused by a specific pathogenic variant in the FGFR3 gene (c.749C>G - p.Pro250Arg). It is characterized by the presence of craniosynostosis as well as other phenotypic features, which may vary greatly. We present a 6 month old child with hypoplasia of corpus callosum, facial dysmorphism and craniostenosis. This led to targeted sequencing of 11 genes, responsible for the phenotype that we discovered. A specific pathogenic variant in FGFR3 (c.749C>G - p.Pro250Arg) was found which established the correct diagnosis. No specific variants in FGFR3 were found in the parents. Muenke syndrome is a rare genetic condition which causes craniostenosis among other dysmorphic features. Neurosurgical correction (if necessary) is most beneficial when the diagnosis is established early in life. As soon as Muenke syndrome is genetically verified, the patient‘s parents should be investigated for possible carrier status. All of the affected individuals should be followed up by a multidisciplinary team in terms of craniostenosis, vit.D and calcium metabolism. [ABSTRACT FROM AUTHOR]

Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype. [ABSTRACT FROM AUTHOR]

Achondroplasia is one of the commonest causes of dwarfism, inherited as autosomal dominant trait. Majority of the cases are due to mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3). The mutation results in gain of FGFR3 function, which affects cartilaginous growth plate in the growing bone causing the skeletal changes. At birth it manifest as short limbs, large head with midfacial hypoplasia and narrow trunk. Diagnosis is mainly based on clinical features and skeletal radiography. Complications are hypotonia, delayed development, hydrocephalus, recurrent ear infections and dental malocclusion.

Thanatophoric dysplasia (TD) is a lethal form of skeletal dysplasia with shortlimb dwarfism. Two types distinguished with their radiological characteristics have been defined clinically. The femur is curved in type 1, while it is straight in type 2. TD is known to be due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. We report a male patient who showed clinical findings congruent with TD type 2 and a new mutation in the FGFR3 gene, a finding which has not been reported previously. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hypochondroplasia is a rare skeletal dysplasia characterized by disproportionately short stature, lumbar lordosis, and limited extension of the elbow caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene that plays a role in controlling nervous system development. Hypochondroplasia with FGFR3 mutation associated with bilateral medial temporal lobe anomalies and focal epilepsy was previously reported in several patients. Patient: We report clinical, electroclinical, and neuroradiological findings of one patient affected by hypochondroplasia. Results: Clinical diagnosis was confirmed by molecular analysis of the FGFR3 gene, which showed a N540 K mutation. The patient had normal psychomotor development and showed early-onset focal seizures with left temporal localization on interictal and ictal electroencephalograph. The seizures were well controlled, and the patient has been seizure-free since infancy. Magnetic resonance imaging showed abnormal anteriorly posteriorly infolding in the hippocampus and abnormally oriented parahippocampus sulci, and additional cortical rim dysplasia with gray-white matter junction blurring in the hippocampus. Conclusions: The present case of hypochondroplasia and FGFR3 mutation in Asn540Lys associated with characteristic abnormalities involving bilaterally medial temporal lobe structures, probable hippocampal cortex focal dysplasia, and early onset of focal epilepsy underscores the possibility of a rare syndrome. [Copyright &y& Elsevier]

Abstract: Background: Hypochondroplasia (HCH) is a mild, autosomal dominant human skeletal dysplasias characterized by short extremities, short stature and lumbar lordosis. There are three other kinds of dwarfism (Pseudoachondroplasia, Achondroplasia and Thanatophoric Syndromes) with similar clinical features, which makes it difficult to give a precise diagnosis. Molecular genetic analysis of related genes should be employed. Methods: In this study, we reported a Chinese family diagnosed as a type of skeletal dysplasia based on clinical and radiologic findings. To make an accurate diagnosis quickly and economically, we performed microarray-based next-generation sequencing (NGS) to detect the variants in the disease-related genes (FGFR3 and COMP). Results: The mother presents short limbed stature, short iliac bones, short femoral necks, short stubby tibia and mildly increased fibular length and genu varum. Her fetus demonstrated abnormally short femur at 23 and 28week's gestation by ultrasound scan, and was highly suspected with dwarfism. Eventually, a novel missense mutation (c.1024G>T) in FGFR3 was identified by next-generation sequencing. The substitution is found in both the mother and her fetus. The mutation was further confirmed by Sanger sequencing. Conclusions: This is the first report of missense mutation identified in the IgIII domain of the FGFR3 gene using NGS. Our results extended the mutational spectrum of FGFR3 and proved that applications of NGS and bioinformatics are effective methods for skeletal dysplasia diagnosis in clinical practices. [Copyright &y& Elsevier]

Purpose Prenatal diagnosis with ultrasound findings compatible with skeletal dysplasia due to FGFR3 mutations over a 9 year period in pregnancies and abortuses. Methods 54 samples were studied. Aneuploidy studies were carried out on all samples. By sequencing analysis, we determined mutations for achondroplasia (ACH), hypochondroplasia (HCH), and type I and type II tanathophoric dysplasia (TD). Results 2 chorionic villi samples had a G380R mutation due to a mother with ACH; 4 amniotic fluid samples with TDs in which the foetuses had micromelia plus hypoplastic thoraces; 5 samples from abortuses with TDs. Neither ACH nor HCH occurred in sporadic cases. Conclusions Molecular studies in ongoing pregnancies are indicated in cases with an affected parent, a family history with positive molecular studies (maternal anxiety), and when the US finding demonstrates micromelia with a hypoplastic thorax. A protocol for tissues of abortuses should include an X-ray, pathologic anatomy, and genetic studies. [ABSTRACT FROM AUTHOR]

The aim of this study was to perform a morphometric analysis of untreated adult skulls displaying syndromic and nonsyndromic craniosynostosis. We analyzed, in detail, 42 adult craniosynostoses (18 scaphocephaly, 11 anterior plagiocephaly, 2 trigonocephaly, 9 oxycephaly, and 2 brachycephaly) from archeological (three skulls) and pathoanatomical samples (39 skulls). The univariate and bivariate measurements from the pathological skulls were compared with 40 anatomical skulls with normal cranial vault morphology. Bony signs of chronic elevated intracranial pressure (ICP) are (1) diffuse beaten copper pattern, (2) dorsum sellae erosion, (3) suture diastasis, and (4) abnormalities of venous drainage that particularly affect the sigmoid–jugular sinus complex. The mean cranial length was significantly greater in scaphocephaly than in anatomical skulls (20.3 vs 18.0 cm), and the sagittal suture was also longer (14.3 vs 11.8 cm). There were three types of suture course in the bregma region in scaphocephaly: anterior spur (28%), normal configuration (61%), and posterior spur (11%). The plagiocephaly measurements showed nonsignificant differences, and there was no correlation between the length of the anterior and middle skull base (ipsilateral anterior–posterior shortening of the skull) and incomplete or complete suture synostosis. Bony signs of chronic elevated ICP were found in 82% of cases of oxycephaly and brachycephaly. In three such cases of oxycephaly, we found a marked (1.8–2.1 cm) elevation of bregma region. One skull (Saethre–Chotzen syndrome) yielded human DNA sufficient for polymerase chain reaction (PCR)-based amplification procedures. Mutation analyses in the FGFR3 gene revealed nucleotide alterations located in the mutational hot spot at amino acid residue 250 (g.C749). The mean cranial length in adult scaphocephaly was 12% greater than anatomical skulls. A unilateral complete or incomplete coronal synostosis can be found with or without plagiocephalic deformation. Elevation of the bregma region is a bony sign of chronic elevated ICP. These data on adult craniosynostosis could be of interest for physicians dealing with craniosynostotic children. [ABSTRACT FROM AUTHOR]

Achondroplasia, the most common form of dwarfism, is a candidate for preimplantation genetic diagnosis (PGD) because a single mutation accounts for almost all cases. Multiplex fluorescent assay including the common G380R mutation in the FGFR3 gene and eight close polymorphic markers was developed. First and second polar bodies (PB) were used for PGD analysis. An affected woman was treated with routine long-protocol ovarian stimulation and puncture. In the first PGD cycle, out of four fertilized oocytes, PB analysis revealed two mutant oocytes, one with total amplification failure of the maternal allele and one with inconclusive results. In the second PGD cycle, 14 oocytes were retrieved following a higher FSH dose and by performing oocyte retrieval and by placing the patient in the anti-Trendelenburg position using abdominal pressure to allow all follicles to be drained. Following PB analysis, two embryos containing the wild-type FGFR3 allele were transferred. This led to an uncomplicated pregnancy and delivery by Caesarean section at week 38 of a healthy boy, carrying the FGFR3 wild-type maternal allele. In conclusion, oocyte retrieval, while difficult in patients with achondroplasia, can be successfully performed. PB analysis is a reliable and sensitive method for PGD for maternal achondroplasia. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: : The fibroblast growth factor receptor 3 gene (FGFR3) plays a critical role in cartilage growth-plate differentiation and bony development. It has been shown that 97% of patients with achondroplasia have a G to A transition mutation at position 1138 (c.1138 G>A) of codon 380 of the FGFR3 gene. Design and methods: : Exon 8 of the FGFR3 gene was analyzed in 40 patients with achondroplasia, as well as in 50 control individuals for the presence of the c.1138G>A variant using melting curve analysis with a high-resolution melting instrument (HR-1). Results: : The high-resolution melting curve analysis successfully genotyped the c.1138G>A mutation in exon 8 of the FGFR3 gene in all 40 patients with achondroplasia without the need of further assays. The technique had a sensitivity and specificity of 100%. Conclusion: : High-resolution melting analysis is a simple, rapid, and sensitive one tube assay for genotyping the FGFR3 gene. The technique is a low cost high-throughput FGFR3 screening assay. [Copyright &y& Elsevier]

Type 1 thanatophoric dysplasia (TD) is typically a lethal dwarfism. It is not always possible to distinguish fetuses with TD from other skeletal dysplasia in utero by ultrasonography. A definite diagnosis should be established by molecular genetic analysis to find out the abnormal mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. Among the known mutations of this gene, the C742T (R248C) mutation is the most common one associated with type 1 TD. Exon 7 of the FGFR3 gene was analyzed in 10 prenatal samples with type 1 TD, as well as in 30 control individuals for the presence of the c.742 C > T variant using melting curve analysis with a high-resolution melting instrument. The high-resolution melting curve analysis successfully genotyped this mutation in all 10 samples with type 1 TD without the need of further assays. The technique had a sensitivity and specificity of 100%. This study suggest that high-resolution melting analysis is a simple, rapid, and sensitive one tube assay for genotyping the FGFR3 gene. [ABSTRACT FROM AUTHOR]

Objective: Thanatophoric dysplasia type 1 (TD 1) is typically a lethal dwarfism. We report our findings of fibroblast growth factor receptor 3 (FGFR3) mutations in Chinese cases of TD 1. Methods: Ten cases of TD 1 were identified prenatally by ultrasound. The FGFR3 gene was analyzed using direct DNA sequencing of the selected regions (exons 7, 10, 15, and 19) previously reported to contain mutations for TD 1. Results: A heterozygous C742T (R248C) mutation was found in 9 of the 10 cases. The remaining case was negative for mutations involved in exons 7, 10, 15 and 19. Conclusion: The results suggest that the R248C mutation may serve as the primarily targeted one of the FGFR3 gene for rapid molecular diagnosis of TD 1. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Mutation analysis in Indian children with achondroplasia. We studied 11 sporadic cases of achondroplasia. Mutation analysis was done by PCR/RFLP (Polymerase chain reaction/Restriction fragment length polymorphism) method. Nine of the 11 cases had mutation G→A at 1138 nucleotide position in transmembrane domain of fibroblast growth-factor receptor 3 ( FGFR3) gene. Substitution G→A is a common recurrent mutation reported worldwide. In two cases we could not detect any common mutation and also in entire region of transmembrane domain sequenced. There is possibility of mutation in the other regions of FGFR3 gene in these two cases. Further study of these two cases is needed in order to define other genotypes resulting in achondroplasia. Postnatal diagnosis of achondroplasia depends on clinical and radiological features. Mutation detection is mainly useful for prenatal diagnosis. [ABSTRACT FROM AUTHOR]