Achondroplasia: Clinical, Radiological and Molecular Profile from Rare Disease Centre, India

AbstractAchondroplasia is the most common autosomal dominant form of skeletal dysplasia and is caused by heterozygous mutations of the fibroblast growth factor receptor 3 (FGFR3) gene at region 4p16.3. This study highlights the data of achondroplasia cases, clinical spectrum, and their outcome from small cities and the region around Rajasthan. The data for analysis were collected retrospectively from genetic records of rare disease clinic in Rajasthan. Clinical profile, radiographic features, molecular test results, and outcome were collected. There were 15 cases, including eight males and seven females, in this cohort. All had facial hypoplasia, depressed nasal bridge, prominent forehead, and characteristic radiographic features. A total of 14 cases were sporadic and one case was inherited from the mother. Mutation analysis showed 13 out of 15 cases with the p.Gly380Arg mutation in the FGFR3 gene. Hydrocephalus was developed in three cases, required shunting in two cases.

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Identification of the FGFR3G380R Mutant As a Likely Cause of Psychomotor Delay in an Achondroplastic Child: A Combined Clinical Exome Sequencing and Biomolecular Modeling Approach

Proceedings ◽

10.3390/proceedings2251551 ◽

2018 ◽

Vol 2 (25) ◽

pp. 1551

Author(s):

Kerem Teralı ◽

Şehime Gülsün Temel ◽

Erdal Eren

Keyword(s):

Exome Sequencing ◽

Autosomal Dominant ◽

Transmembrane Domain ◽

Growth Factor Receptor ◽

Dominant Form ◽

Psychomotor Delay ◽

Clinical Exome Sequencing ◽

Autosomal Dominant Form ◽

Biomolecular Modeling ◽

Predicted Model

Mutations in the gene for fibroblast growth factor receptor 3 (FGFR3) are implicated in achondroplasia, an autosomal-dominant form of short-limbed dwarfism. The present study involves a combination of clinical exome sequencing, targeted resequencing and protein modeling methods to decipher the pathobiology of achondroplasia with psychomotor delay in a two-year-old child. Accordingly, the resulting genetic information establishes the frequent FGFR3 c.1138G > A (p.G380R) mutation as the single hit causing pediatric achondroplasia with psychomotor delay, while the predicted model stresses the importance of a phenylalanyl residue (F384) in enhancing the dimerization potential of the receptor’s transmembrane domain via a cation‒π interaction with the newly introduced arginyl residue. Overall, the likely involvement of FGFR3G380R in psychomotor delay calls for comprehensive clinical assessment in achondroplastic children, although the precise mechanism by which the mutant receptor results in the development of neurological manifestations awaits further investigation.

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Thanatophoric dysplasia type 1 as seen in a tertiary institution in South-East Nigeria: A case report

Nigerian Journal of Paediatrics ◽

10.4314/njp.v47i3.14 ◽

2020 ◽

Vol 47 (3) ◽

pp. 277-279

Author(s):

O.W. Daniyan ◽

O.B. Ezeanosike ◽

C. Ogbonna-Nwosu ◽

U.C. Iloduba

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Lower Limbs ◽

Fibroblast Growth ◽

Thanatophoric Dysplasia ◽

Tertiary Institution ◽

Nasal Bridge ◽

Fgfr3 Gene

Thanatophoric dysplasia is a lethal form of skeletal dysplasia seen in neonates. The word ‘thanatophoric’ is derived from the Greek word thanatophorus meaning death bringing. Thanatophoric dysplasia results from mutations within the Fibroblast Growth Factor Receptor 3 (FGFR3) gene which is located on chromosome 4p16.3. A female neonate with dysmorphic features such as macrocephaly, frontal bossing, periorbital swelling and depressed nasal bridge was delivered to a 35year old woman. The upper and lower limbs were short with excessive skin folds. A case of female neonate with thanatophoric dysplasia is hereby reported to raise awareness of this condition and to describe the features of thanatophoric dysplasia seen in this patient . Key words: Thanatophoric Dysplasia (TD), Fibroblast Growth Factor Receptor 3 Gene (FGFR3), dysmorphic, macrocephaly

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FGFR3 overexpression is a useful detection tool for FGFR3 fusions and sequence variations in glioma

Neuro-Oncology Practice ◽

10.1093/nop/npaa075 ◽

2020 ◽

Author(s):

Jens Schittenhelm ◽

Lukas Ziegler ◽

Jan Sperveslage ◽

Michel Mittelbronn ◽

David Capper ◽

...

Keyword(s):

Coiled Coil ◽

Growth Factor Receptor ◽

Gene Mutations ◽

Diagnostic Tools ◽

Wild Type ◽

Rt Pcr ◽

Fgfr3 Gene ◽

Detection Tool ◽

Sequence Variations ◽

Gene Panel Sequencing

Abstract Background Fibroblast growth factor receptor (FGFR) inhibitors are currently used in clinical development. A subset of glioblastomas carries gene fusion of FGFR3 and transforming acidic coiled-coil protein 3. The prevalence of other FGFR3 alterations in glioma is currently unclear. Methods We performed RT-PCR in 101 glioblastoma samples to detect FGFR3-TACC3 fusions (“RT-PCR cohort”) and correlated results with FGFR3 immunohistochemistry (IHC). Further, we applied FGFR3 IHC in 552 tissue microarray glioma samples (“TMA cohort”) and validated these results in two external cohorts with 319 patients. Gene panel sequencing was carried out in 88 samples (“NGS cohort”) to identify other possible FGFR3 alterations. Molecular modeling was performed on newly detected mutations. Results In the “RT-PCR cohort,” we identified FGFR3-TACC3 fusions in 2/101 glioblastomas. Positive IHC staining was observed in 73/1024 tumor samples of which 10 were strongly positive. In the “NGS cohort,” we identified FGFR3 fusions in 9/88 cases, FGFR3 amplification in 2/88 cases, and FGFR3 gene mutations in 7/88 cases in targeted sequencing. All FGFR3 fusions and amplifications and a novel FGFR3 K649R missense mutation were associated with FGFR3 overexpression (sensitivity and specificity of 93% and 95%, respectively, at cutoff IHC score > 7). Modeling of these data indicated that Tyr647, a residue phosphorylated as a part of FGFR3 activation, is affected by the K649R mutation. Conclusions FGFR3 IHC is a useful screening tool for the detection of FGFR3 alterations and could be included in the workflow for isocitrate dehydrogenase (IDH) wild-type glioma diagnostics. Samples with positive FGFR3 staining could then be selected for NGS-based diagnostic tools.

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An unusual radiological finding in thanatophoric dysplasia type 1 with common mutation of the fibroblast growth factor receptor-3 (FGFR3) gene (Arg248Cys)

American Journal of Medical Genetics ◽

10.1002/(sici)1096-8628(19970711)71:1<122::aid-ajmg22>3.0.co;2-n ◽

1997 ◽

Vol 71 (1) ◽

pp. 122-123 ◽

Cited By ~ 5

Author(s):

Gianni Camera ◽

Maurizia Baldi ◽

Maria Baffico ◽

Silvano Pozzolo

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor Receptor ◽

Radiological Finding ◽

Growth Factor Receptor ◽

Common Mutation ◽

Fibroblast Growth ◽

Thanatophoric Dysplasia ◽

Fgfr3 Gene

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CADASIL Syndrome: A Genetic Form of Vascular Dementia

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/089198879801100205 ◽

1998 ◽

Vol 11 (2) ◽

pp. 71-77 ◽

Cited By ~ 14

Author(s):

Stephen Salloway ◽

Joseph Hong

Keyword(s):

Vascular Dementia ◽

Autosomal Dominant ◽

Microvascular Disease ◽

The Elderly ◽

Dominant Form ◽

Genetic Features ◽

Autosomal Dominant Form ◽

Family Gene ◽

Cerebral Arteriopathy ◽

Genetic Form

Mental disorders due to cerebral microvascular disease have been known for over 100 years. Recently, an autosomal dominant form of cerebral arteriopathy (CADASIL) has been described in association with a Notch3 family gene on the short arm of chromosome 19. CADASIL causes subcortical lacunar infarction and dementia in over 80% of cases and depression in a large proportion of patients. Clinically, CADASIL may appear to be very similar to hypertensive microvascular disease (Binswanger's disease), a condition that is seen in the elderly. This article reviews the clinical, pathologic, and genetic features of CADASIL. CADASIL is of interest to neurologists and psychiatrists because it is the first syndrome of vascular dementia and depression with an identified gene. How the gene causes the widespread arteriopathy is not yet known. Insights gained from the study of CADASIL should help us better understand its etiology, as well as the options for treatment of the more common forms of microvascular disease seen in the elderly.

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Craniometaphyseal dysplasia (CMD), autosomal dominant form.

Journal of Medical Genetics ◽

10.1136/jmg.32.5.370 ◽

1995 ◽

Vol 32 (5) ◽

pp. 370-374 ◽

Cited By ~ 44

Author(s):

P Beighton

Keyword(s):

Autosomal Dominant ◽

Dominant Form ◽

Autosomal Dominant Form ◽

Craniometaphyseal Dysplasia

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Chronic Mild Hyperglycemia in GCK-MODY Patients Does Not Increase Carotid Intima-Media Thickness

International Journal of Endocrinology ◽

10.1155/2013/718254 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Stepanka Pruhova ◽

Petra Dusatkova ◽

Pavel J. Kraml ◽

Michal Kulich ◽

Zdena Prochazkova ◽

...

Keyword(s):

Fasting Blood Glucose ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Macrovascular Complications ◽

Family Status ◽

Dominant Form ◽

Media Thickness ◽

Mutation Carriers ◽

Mild Hyperglycemia ◽

Autosomal Dominant Form

Aim.GCK-MODY is an autosomal dominant form of diabetes caused by heterozygous mutations in the glucokinase gene leading to a lifelong mild hyperglycemia. The risk of macrovascular complications is considered low, but studies are limited. We, therefore, investigated the carotid intima-media thickness (CIMT) as an indicator of macrovascular complications in a group of patients with GCK-MODY.Methods.Twenty-seven GCK mutation carriers and 24 controls recruited among their first-degree relatives were compared, all aging over 35 years. The CIMT was tested using a high-resolution B-mode carotid ultrasonography. Medical history, anthropometry, and biochemical blood workup were obtained.Results.The mean CIMT was 0.707 ± 0.215 mm (mean ± SD) in GCK mutation carriers and 0.690 ± 0.180 mm in control individuals. When adjusted for age, gender, and family status, the estimated mean difference in CIMT between the two groups increased to 0.049 mm (P=0.19). No difference was detected for other characteristics, with the exception of fasting blood glucose (GCK-MODY 7.6 mmol/L ± 1.2 (136.4 mg/dL); controls 5.3 mmol/L ± 0.3 (95.4 mg/dL);P<0.0001) and glycated hemoglobin HbA1c(GCK-MODY 6.9% ± 1.0%, 52 mmol/mol ± 10; controls 5.7% ± 0.4%, 39 mmol/mol ± 3;P<0.0001). The frequency of myocardial infarction and ischemic stroke did not differ between groups.Conclusion.Our data indicate that the persistent hyperglycemia in GCK-MODY is associated with a low risk of developing diabetic macrovascular complications.

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Tripod-shaped Syndactyly in Apert Syndrome with FGFR2 p.P253R Mutation

Indian Journal of Plastic Surgery ◽

10.1055/s-0041-1733808 ◽

2021 ◽

Author(s):

Chandra Bhan Singh ◽

Biswajit Mishra ◽

Rashmi Patel ◽

Ashok Kumar ◽

Akhtar Ali

Keyword(s):

Autosomal Dominant ◽

Growth Factor Receptor ◽

Sporadic Case ◽

Apert Syndrome ◽

Nasal Bridge ◽

Craniofacial Dysmorphism ◽

Fgfr2 Gene ◽

Craniofacial Features ◽

Ocular Hypertelorism ◽

Hands And Feet

AbstractApert syndrome is a rare acrocephalosyndactyly (craniosynostosis) syndrome characterized by craniofacial dysmorphism and syndactyly of the hands and feet. It is caused by FGFR2 mutations and inherited in an autosomal dominant manner. This article describes a novel clinical variant of Apert syndrome having bilateral symmetrical tripod-shaped syndactyly in hands with milder craniofacial features in a sporadic case, along with a mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. The patient had shown craniosynostosis, dysmorphic face, ocular hypertelorism, marked depression of the nasal bridge, long philtrum, and low set ears. Direct resequencing of the FGFR2 gene through Sanger’s method identified a heterozygous missense mutation; FGFR2c.758C>G (FGFR2p.P253R) in the exon-7 of the gene.

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Copy number variation in MODY diabetes - Familial case presentation

Genetics & Applications ◽

10.31383/ga.vol2iss2pp73-77 ◽

2018 ◽

Vol 2 (2) ◽

pp. 73

Author(s):

Naida Lojo-Kadric ◽

Zelija Velija Asimi ◽

Jasmin Ramic ◽

Ksenija Radic ◽

Lejla Pojskic

Keyword(s):

Insulin Secretion ◽

Copy Number ◽

Autosomal Dominant ◽

Single Gene ◽

Maturity Onset Diabetes ◽

Dominant Form ◽

Case Presentation ◽

Monogenic Diseases ◽

Number Variation ◽

Autosomal Dominant Form

MODY (maturity-onset diabetes of the young) is an autosomal dominant form of diabetes that is usually manifested before the 25-year of life. This type of diabetes is caused by defects in the primary insulin secretion. There are several types of MODY, which are monogenic diseases, where mutations in a single gene are responsible for a particular type of MODY. Currently, there are eleven types of MODY, from which the most common types are MODY 2 and MODY 3 (with mutations on GCK and HNF1A genes, respectively). We identified very rare MODY 7 type of diabetes in three family members by MLPA analysis.

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