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Achondroplasia (ACH; MIM #100800) is an autosomal dominant genetic disease caused by gain-of-function mutations in FGFR3 gene and results in short-limb dwarfism. Here, we generated an induced pluripotent stem cell line GZHMCi004-A derived from umbilical cord blood mononuclear cells (UCBMCs) of a fetus with heterozygous G380R mutation in FGFR3 gene. This iPSC line is a valuable in vitro model to study the pathological mechanism and the treatment of ACH.

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.

e15072 Background: Oncogenic FGFR3 (fibroblast growth factor receptor 3) gene fusions have been identified as driver mutations that lead to the activation of FGFR3 in many solid tumor types and serve as a novel therapeutic target for FGFR inhibitors in clinical development. TACC3 (transforming acid coiled coil 3) is the most common partner of these FGFR3 fusions. Methods: The study enrolled over ten thousand cases of Chinese patients with different types of solid tumors. We performed targeted sequencing assay with our 605 gene panel that covered all the exon and intron regions of the FGFR3 gene, so that we could identify nearly all the FGFR3 translocation events. Results: The prevalence and form of FGFR3 fusions in different tumor types were shown in Table. We identified seven patients harboring FGFR3 fusion events, with six cases of FGFR3-TACC3 and one case of FGFR3-UBE2K. In the seven patients, three of them were also harbored concomitant TP53 gene mutations, and six of them were microsatellite stability (MSS), and one was microsatellite instability-low (MSI-L). Conclusions: FGFR3 gene rearrangements were identified in different solid tumor types in our study, and they were relatively rare compared to other novel mutations. However, clinical testing for the identification of FGFR3 fusions should be prioritized in bladder cancer patients. Consistent with other studies, the most common FGFR3 fusion form was FGFR3-TACC3. Co-occurring genetic alterations in FGFR3 gene fusions cases were also common. From our limited number of cases, most of FGFR3 gene fusions patients were MSS.[Table: see text]

Thanatophoric dysplasia is one of thenewborn’s dwarfism syndromes usually resulting in death during perinatal periodand manifesting as short extremities. It is characterized by macrocephaly,prominent forehead, narrow thorax, short extremities, flattened vertebralbodies, curved femurs. This is caused by mutations in the fibroblast growthfactor receptor 3 (FGFR3) gene andshows autosomal dominant inheritance model. In this report, we presented a casewith abnormal USG findings during perinatal period and detected to carry ap.R248C mutation in FGFR3 gene inamniosynthesis fluid., Tanatoforik displazi, genelde perinataldönemde ölümle sonuçlanan ve kısa ekstremiteler ile kendini gösterenyenidoğanın cücelik sendromlarından biridir. Makrosefali, belirgin alın, dartoraks, vertebralarda düzleşme, ekstremitelerde kısalık, femurda eğrilme ilekarakterizedir. Fibroblast büyüme faktörü reseptörü 3 (FGFR3) genindeki mutasyonlardan kaynaklanır ve otozomal dominantkalıtım modeli gösterir. Bu makalede, prenatal dönemde anormal USG bulgularıolan, amniyosentez materyalinden yapılan FGFR3gen analizi ile p.R248C mutasyonu saptanan bir olgu anlatılmıştır.

SUMMARY Polymerase chain reaction (PCR) is a key technology of genetic testing, but the long thermal cycling time has been a problem in achieving rapid diagnosis of pathogenic organisms and cancer. We describe a simple, portable, and rapid genetic testing system based on ultrafast segment flow and fluorescent detection. In particular, we improved the flow-through PCR to accelerate the thermal cycling time and simplify the operation for practical use. The PCR solution was injected in a small volume of about several microliters by an air syringe, and flowed as segment flow. The segment of PCR solution was moved in a serpentine microchannel on a microfluidic device over two temperature zones for denaturation and annealing/extension reactions. The base plate formed upon the serpentine microchannel pattern was made of cyclo-olefin polymer (COP) and covered with a thin transparent film. Furthermore, a specialized portable system was developed for the microfluidic device of a segment-flow PCR. Heater units, a syringe pump, a fluorescence detector, and PC were integrated in a suitcase for portable use. Using this portable system, a microorganism modeling anthrax and a point mutation of FGFR3 gene were successfully detected within 6.5 min.

The authors present clinical and angiographic findings in a 12-year-old girl with achondroplasia who presented with bilateral retinal peripheral nonperfusion and unilateral rhegmatogenous retinal detachment, which has not been previously described in achondroplasia. This report contributes incremental knowledge regarding aberrant retinal vascular phenomena observed in pediatric disease states and implicates the possible role of mutations in the FGFR3 gene in peripheral vascular abnormalities. [ Ophthalmic Surg Lasers Imaging Retina. 2017;48:272–274. ]

Background and Objective: Muscle-invasive bladder cancer (MIBC) is a complex disease for which perioperative chemotherapy followed by radical cystectomy is a standard treatment. In recent years new therapy options for advanced urothelial tumors have emerged, representing a personalized medicine approach for patients. For example, targeting fibroblast growth factor receptors (FGFR) as well as restoring antitumor activity using PD-1/PD-L1 inhibitors are currently being evaluated in clinical trials and show promising results. Our present goal in this study was to assess the relationship of FGFR3-gene alterations, immune cell types, gene expression of checkpoint inhibitors like PD-L1/PD-1, and immune-related genes in MIBC to gain insight into significant differential expression. Materials and Methods: We analyzed the TCGA cohort (n=407). Tumors were identified with activating FGFR3-gene alterations (FGFR3-altered: mutation, amplification, fusion, gain). A comparison was performed between tumors with FGFR3-altered or wild-type tumors and tumor mutational burden (TMB), neoantigen load, immune checkpoint, and immune-related gene expression as well as specific immune cell populations using the CIBERSORT-algorithm. Results: Activating FGFR3-altered tumors showed significantly less TMB and neoantigen load compared to wild-type cases (p=0.037 and p=0.04). Tumors with high expression of PD-1, PD-L1, CTLA4, and IDO1 were predominately not FGFR3-altered (p Conclusion: Strikingly, our analysis demonstrates that activating FGFR3 gene alterations in MIBC show low immune checkpoint and immune-related gene expression as well as low amounts of immune cells, demonstrating association with an uninflamed tumor microenvironment. Therefore, combination therapies targeting FGFR3 and, e.g., PD-1/PD-L1 might not be effective. It will be essential to validate these results in another MIBC cohort as well as unravel the role of aberrant signaling of FGFR3. Citation Format: Veronika Weyerer, Robert Stoehr, Pamela Strissel, Reiner Strick, Christian Bolenz, Arndt Hartmann, Philipp Erben, Markus Eckstein. Uninflamed immunologic microenvironment of muscle-invasive bladder cancer associates with activating FGFR3 gene alterations [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A15.

Проведено проспективное исследование по оценке прогностического значения мутационного статуса гена FGFR 3 у пациентов с раком мочевого пузыря без мышечной инвазии (РМПБМИ). В исследование включено 265 пациентов, у 168 (63,4%) обнаружены мутации гена FGFR 3 . Установлено, что частота мутаций гена FGFR 3 была статистически значимо выше в высокодифференцированных опухолях (р=0,00004). При медиане наблюдения 34 мес. не выявлено статистически значимого показателя относительного риска прогрессирования РМПБМИ при наличии мутации гена FGFR 3 по сравнению с ее отсутствием (0,50; 95%ДИ 0,17-1,49; P = 0,21). При анализе прогностического значения мутационной изменчивости гена FGFR 3 в различных подгруппах было обнаружено, что у пациентов с опухолями T1 high grade (n=41) мутации гена FGFR 3 были связаны со статистически значимо лучшим прогнозом: 3-летняя выживаемость до прогрессирования при наличии мутации (n=17) составила 100% по сравнению с 71,2% (95%ДИ 42,8-99,6%) при отсутствии мутации (n=24). При остальных категориях опухолей (Ta, T1 low grade) статистически значимых различий в выживаемости до прогрессирования в зависимости от мутационного статуса FGFR 3 выявлено не было.

Resume Introduction Le syndrome de Crouzon avec acanthosis nigricans est une forme rare de syndrome de Crouzon, qui associe une craniostenose et une dysmorphie faciale a un acanthosis nigricans. Observation Un enfant de 9 ans souffrant de craniostenose bicoronale presentait a l�examen cutane un acanthosis nigricans des regions cervicales, axillaires, inguinales et poplitees apparu vers l�âge de 2 ans. Son visage etait dysmorphique avec un front large, un hypertelorisme, une hypoplasie du massif facial superieur, une inversion de l�articule dentaire et des oreilles bas-implantees. Ces anomalies cliniques nous orientaient vers un syndrome de Crouzon avec acanthosis nigricans, qui fut confirme par la mise en evidence d�une mutation du gene FGFR3. Discussion L�acanthosis nigricans chez l�enfant est frequemment un marqueur d�insulinoresistance. Cependant, il peut etre inclus egalement dans diverses pathologies, notamment genetiques. L�association d�une craniostenose et d�un acanthosis nigricans permet d�emblee d�incriminer le gene FGFR3 et de faire le diagnostic de syndrome de Crouzon avec acanthosis nigricans. L�examen dermatologique a permis ici de poser l�etiologie d�une craniostenose. Summary Background Crouzon syndrome with acanthosis nigricans is a rare form of Crouzon syndrome in which craniosynostosis and facial dysmorphism are associated with acanthosis nigricans. Patients and methods Cutaneous examination of a 9-year-old child presenting bicoronal craniosynostosis revealed acanthosis nigricans of the cervical, axillar, inguinal and popliteal regions which appeared at the age of two. He had a dysmorphic face including a large forehead, hypertelorism, mid-face hypoplasia, prognathism and low-set ears. These clinical anomalies suggested a case of Crouzon syndrome with acanthosis nigricans, which was later confirmed by the finding of a mutation in the FGFR3 gene. Discussion Acanthosis nigricans in children is often a cutaneous marker of insulin resistance. However, it may also form part of diverse diseases, notably those of genetic origin. The association of craniosynostosis and acanthosis nigricans allows incrimination of the FGFR3 gene from the outset and diagnosis of Crouzon syndrome with acanthosis nigricans. In the present case, dermatological examination allowed an aetiology of craniosynostosis to be determined. Mots cles Acanthosis nigricans; Crouzon (syndrome de); FGFR3; Craniostenose Keywords Acanthosis nigricans; Crouzon syndrome; FGFR3; Craniosynostosis

Throughout the last four centuries, many anatomical museums across the world have collected teratological specimens that became precious objects. These can be regarded as spirits of the past which have captured the morphology of diseases through time. These valuable and irreplaceable specimens can be perfectly used in contemporary dysmorphological or genetic research. Unfortunately, due to the historical nature of these specimens and the regularly used aggressive preservation fluids, DNA degradation is often present. Furthermore, the use of material for DNA extraction is restricted to preserve the appearance of these valuable museological specimens. Thus, the most challenging part in this perspective is to harvest sufficient DNA of good quality for further testing without damaging the specimens. Besides fixated specimens, most teratological collections contain dried skeletal and teeth materials which are an excellent source to extract DNA. We here present a DNA-based method that enables genetic identification of the G1138A mutation of the FGFR3 gene in a 180-year-old achondroplastic skeleton, confirming the previously morphologically determined disease. Nuclear DNA was extracted from a premolar tooth and the mutation was found using Sanger sequencing of a small region of the FGFR3 gene.

Rationale: Hypochondroplasia (HCH) is the mildest form of chondrodysplasia characterized by disproportionate short stature, short extremities, and variable lumbar lordosis. It is caused by mutations in fibroblast growth factor receptor 3 (FGFR3) gene. Up to date, at least thirty mutations of FGFR3 gene have been found to be related to HCH. However, mutational screening of the FGFR3 gene is still far from completeness. Identification of more mutations is particularly important in diagnosis of HCH and will gain more insights into the molecular basis for the pathogenesis of HCH. Patient concerns: A large Chinese family consisting of 53 affected individuals with HCH phenotypes was examined. Diagnoses: A novel missense mutation, c.1052C>T, in FGFR3 gene was identified in a large Chinese family with HCH. On the basis of this finding and clinical manifestations, the final diagnosis of HCH was made. Interventions: Next-generation sequencing (NGS) of DNA samples was performed to detect the mutation in the chondrodysplasia-related genes on the proband and her parents, which was confirmed by Sanger sequencing in the proband and most of other living affected family members. Outcomes: A novel missense mutation, c.1052C>T, in the extracellular, ligand-binding domain of FGFR3 was identified in a large Chinese family with HCH. This heterozygous mutation results in substitution of serine for phenylalanine at amino acid 351 (p.S351F) and co-segregates with the phenotype in this family. Molecular docking analysis reveals that this unique FGFR3 mutation results in an enhancement of ligand-binding affinity between FGFR3 and its main ligand, fibroblast growth factor 9. Lessons: This novel mutation is the first mutation displaying an increase in ligand-binding affinity, therefore it may serve as a model to investigate ligand-dependent activity of FGF-FGFR complex. Our data also expanded the mutation spectrum of FGFR3 gene and facilitated clinic diagnosis and genetic counseling for this family with HCH.

Thanatophoric dysplasia (TD) is a relatively common lethal skeletal dysplasia. These malformations result from the mutations in fibroblast growth factor receptor 3 (FGFR3) gene, which is located on the short arm of chromosome 4. Accurate diagnosis of fetal TD is important for patient counseling and to plan the management. A definite diagnosis can be established by molecular genetic analysis to find out the abnormal mutations in the FGFR3 gene. We reported on two cases of TD type I found by prenatal ultrasound and confirmed by molecular analysis of FGFR3 gene using high-resolution melting analysis.

Background: Thanatophoric dysplasia (TD) is the most lethal and most severe type of dysplasia. It has distinct features, the most important of which is short tubular bones and short ribs with platyspondyly, allowing a precise radiologic and prenatal ultrasonographic diagnosis. It has been reported to be caused by mutations in the FGFR3 gene, but exactly how cytogenetic abnormalities might lead to TD is unclear. Case Report: We report a case of TD with different prenatal sonographic features compatible with the classification of type I. In the result of cytogenetic examination, we found de novo CAs in 28% of cells analyzed from the affected infant; 75% of the abnormalities were numerical, and of those, 25% were structural aberrations; 21% of cells revealed predominantly numerical aberrations. Monosomy 18, 21 and 22 was observed in 4% of cells, monosomy 20 in 2%, and monosomy 7, 8, 14, 17 and 19 in 1%. Structural changes were observed in 7% of cells. Conclusions: It appears that these chromosomes may be preferentially involved in and important for TD development. © Am J Case Rep.

Hypochondroplasia (HCH) is a genetic skeletal dysplasia, inherited in an autosomal dominant fashion. About 50–70% of HCH patients have a mutation in FGFR3 gene and in the majority of cases it is a de novo mutation. Recent magnetic resonance imaging studies on relative large cohorts of HCH patients have showed a central nervous system involvement with a high incidence of characteristic temporal lobe and hippocampal abnormalities. To the best of our knowledge, this report shows the first magnetic resonance imaging prenatal detection of characteristic brain anomalies in a case of HCH, molecularly confirmed through postnatal FGFR3 analysis. © 2014 John Wiley & Sons, Ltd.

Muenke syndrome caused by point mutation (C749G) in the FGFR3 gene affects 1 in 30,000 newborns and accounts for 25% to 30% of genetic causes of craniosynostosis. Anomalies in patients with Muenke syndrome include craniosynostosis, hypertelorism, sensorineural hearing loss, and developmental delay, among others. Most craniosynostoses in patients with Muenke syndrome involve bicoronal suture fusion. This article reports, for the first time, the existence of squamosal craniosynostosis in patients with Muenke syndrome.

Thanatophoric dysplasia (TD) is the most frequent form of lethal skeletal dysplasia. Prenatal diagnosis is commonly accomplished in the second-trimester scan, but occasionally TD is found to be associated with increased nuchal translucency (NT) at first-trimester screening for aneuploidies. TD may not be clearly distinguished from the other skeletal dysplasias. A definite diagnosis can be established by molecular genetic analysis to find out the abnormal mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We reported a case of TD type 1 detected by first-trimester NT measurement, and confirmed by molecular analysis of FGFR3 gene using high-resolution melting analysis.

Hypochondroplasia (MIM 146000) is a skeletal dysplasia characterized by disproportional dwarfism with rhizomelic or mesomelic shortening of the upper and lower extremities, with variable severity. Patients often have macrocephaly with normal facial features. Hypochondroplasia is a disease with autosomal dominant inheritance. In some patients it is caused by germline mutations in the FGFR3 gene, in others the cause of the disease remains unknown . The FGFR3 gene encodes a tyrosine kinase receptor. This receptor negatively regulates the conversion of cartilage to bone. FGFR3 gene mutations that cause hypochondroplasia lead to constitutive activation of the receptor and inhibit the growth of long bones. In this study, we analysed selected regions (exons) of the FGFR3 gene in 98 patients with disproportional dwarfism and clinical diagnosis of hypochondroplasia. Eighteen patients from 12 families had familial and 80 patients had sporadic form of the disease. All patients were previously tested negative for frequent germline mutations in exon 13 (codon 540) and exon 15 (codon 650). Genomic DNA was isolated from patient's peripheral blood leukocytes. The examination was conducted with the informed consent of the patient or his legal representative. We performed mutational analysis by direct sequencing of...

Cherubism is a rare autosomal dominant fibro-osseous disorder that affects almost exclusively maxilla and mandible. Extracranial skeletal involvement is rare. We report on three affected males in three generations. The youngest affected relative was examined at age 4 months. He also had craniosynostosis. His affected father and grandfather had cherubism and clubbing of the fingers. Cherubism was mapped to region 4p16. Because of the associated cranio-synostosis, we excluded the FGFR3 gene as a candidate gene for cherubism.

“Bone dysplasia family”refers to a group of disorders which share qualitatively similar skeletal alterations and a conceivably common pathogenesis. This concept was first described by Spranger, and has provided a practical guide for the differential diagnosis of bone dysplasias. This idea has since become a pilotage for molecular investigation on this field; for instance, the discovery of heterozygous mutations of the FGFR3 gene in achondroplasia led to the elucidation of other heterozygous mutations of the FGFR3 gene in thanatophoric dysplasia and hypochondroplasia, which had been classed as allelic disorders in the“achondroplasia family”solely based on clinical and radiologic grounds. Understanding the bone dysplasia family concept can facilitate further nosologic and molecular investigations in this molecular era, which will ultimately provide information beneficial to the management of affected individuals. Common“bone dysplasia families”are outlined here, particularly from the radiological standpoint. The importance of phenotype-genotype correlation is discussed by exemplifying the radiologic findings in achondroplastic individuals with uncommon mutations of the FGFR3 gene and radiologic variabilities in a severe form of type II collagenopathy.

Muencke syndrome results from mutations in the FGFR3 gene, and although it is well recognized that the clinical presentation is variable, the important key finding includes coronal synostosis. We present a family where a mother with proven FGFR3 Pro250Arg mutation gave birth to identical twins both of whom had craniosynostosis but had coexisting bilateral cleft lip and palate. We believe that this is the first description of clefting occurring in conjunction with Muencke syndrome and so further extends the range of phenotypic variation that can occur in this syndrome.