Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome

2019 ◽  
Vol 158 (4) ◽  
pp. 184-191 ◽  
Author(s):  
Naye Choi ◽  
Jung Min Ko ◽  
Seung Han Shin ◽  
Ee Kyung Kim ◽  
Han Suk Kim ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Left Ventricular ◽  
Mitogen Activated Protein Kinase ◽  
Alveolar Type ◽  
Costello Syndrome ◽  
De Novo Mutations ◽  
Genetic Characteristics ◽  
Korean Patients ◽  
Skeletal Defects

Costello syndrome (CS) is a rare genetic disorder characterized by distinctive facial appearance, cardiopulmonary complications, severe growth retardation, skin and skeletal defects, developmental delay, and tumor predisposition. CS is caused by heterozygous de novo mutations in the proto-oncogene HRAS, which is a component of the RAS/mitogen-activated protein kinase pathway. Herein, we reviewed the phenotypic and genetic features of 5 Korean patients who were genetically diagnosed with CS. Atrial tachycardia and polyhydramnios, which are important prenatal features for CS, were observed in 4 and 5 patients, respectively. The distinctive coarse facial appearances of the patients and presence of deep palmoplantar creases supported the clinical diagnosis of CS, which was confirmed by HRAS sequence analysis. Extremely poor postnatal growth was observed in all 5 patients. Further, all patients exhibited cardiac abnormalities; left ventricular hypertrophy and hypertrophic cardiomyopathy were observed in 3 patients. All 5 patients suffered from airway problems; 3 of them required intubation right after birth, and 2 of them received tracheostomy. One patient with a p.Gly12Ser mutation was diagnosed with retroperitoneal rhabdomyosarcoma alveolar type at the age of 5 years. Consistent with previous reports, both patients with p.Gly12Cys mutations died within the first year of life due to cardiopulmonary failure. Our study summarizes the characteristics of these 5 Korean patients with CS and, along with previous studies, provides clues for genotype-phenotype correlation in patients with CS.

Review of treatment and therapeutic targets in brain arteriovenous malformation

2021 ◽  
pp. 0271678X2110267
Author(s):  
Peipei Pan ◽  
Shantel Weinsheimer ◽  
Daniel Cooke ◽  
Ethan Winkler ◽  
Adib Abla ◽  
...  
Keyword(s):  
Animal Models ◽  
De Novo ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Current Treatment ◽  
Mitogen Activated Protein Kinase ◽  
De Novo Mutations ◽  
Genetic Syndromes ◽  
Mitogen Activated Protein

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase ( MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.

scholarly journals Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice

2015 ◽  
Vol 73 (11) ◽  
pp. 946-958 ◽  
Author(s):  
Marina C. Gonsales ◽  
Maria Augusta Montenegro ◽  
Camila V. Soler ◽  
Ana Carolina Coan ◽  
Marilisa M. Guerreiro ◽  
...  
Keyword(s):  
Clinical Practice ◽  
De Novo ◽  
Current Knowledge ◽  
Molecular Testing ◽  
De Novo Mutations ◽  
Genetic Characteristics ◽  
Epileptic Encephalopathies ◽  
New Findings ◽  
Recent Developments ◽  
The Impact

Recent advances in molecular genetics led to the discovery of several genes for childhood epileptic encephalopathies (CEEs). As the knowledge about the genes associated with this group of disorders develops, it becomes evident that CEEs present a number of specific genetic characteristics, which will influence the use of molecular testing for clinical purposes. Among these, there are the presence of marked genetic heterogeneity and the high frequency of de novo mutations. Therefore, the main objectives of this review paper are to present and discuss current knowledge regarding i) new genetic findings in CEEs, ii) phenotype-genotype correlations in different forms of CEEs; and, most importantly, iii) the impact of these new findings in clinical practice. Accompanying this text we have included a comprehensive table, containing the list of genes currently known to be involved in the etiology of CEEs.

Multimodal Imaging and Genetic Characteristics of Chinese Patients with USH2A-Associated Nonsyndromic Retinitis Pigmentosa

2020 ◽  
Author(s):  
Chong Chen ◽  
Qiao Sun ◽  
Mingmin Gu ◽  
Tianwei Qian ◽  
Dawei Luo ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
De Novo ◽  
Molecular Genetic ◽  
In Silico Analysis ◽  
Chinese Patients ◽  
Insertion Mutation ◽  
Missense Mutations ◽  
De Novo Mutations ◽  
Cross Sectional ◽  
Genetic Characteristics

Abstract Background To determine the clinical characteristics and molecular genetic background responsible for USH2A mutations associated with nonsyndromic retinitis pigmentosa (RP) in five Chinese families, a retrospective cross-sectional study was performed. Data of detailed history and comprehensive ophthalmological examinations were extracted from medical charts. Genomic DNA was sequenced by whole-exome sequencing. The pathogenicity predictions were evaluated by in silico analysis. The structural modeling of the wide-type and mutant USH2A proteins was displayed based on I-Tasser software.Results The ultrawide-field fundus imaging showed a distinctive pattern of hyperautofluorescence in the parafoveal ring with macular sparing. Ten USH2A variants were detected, including seven missense mutations, two splicing mutations and one insertion mutation. Six of these variants have already been reported, and the remaining four were novel. Of the de novo mutations, the p.C931Y and p.G4489S mutations were predicted to be deleterious or probably damaging; the p.M4853V mutation was predicted to be neutral or benign; and the IVS22+3A>G mutation was a splicing mutation that could influence mRNA splicing and affect the formation of the hairpin structure of the USH2A protein.Conclusions Our data further confirm that USH2A plays a pivotal role in the maintenance of photoreceptors and expand the spectrum of USH2A mutations that are associated with nonsyndromic RP in Chinese patients.

Familial CNS Tumor Syndromes

2017 ◽  
Author(s):  
Jennie W Taylor ◽  
Scott R Plotkin
Keyword(s):  
Standard Treatment ◽  
Retrospective Studies ◽  
De Novo ◽  
Genetic Disorder ◽  
Neurofibromatosis Type ◽  
Suppressor Gene ◽  
Vestibular Schwannomas ◽  
De Novo Mutations ◽  
Genetic Features

Neurofibromatosis type 2 (NF2) is a genetic disorder caused by constitutional mutations in the NF2 tumor-suppressor gene. Bilateral vestibular schwannomas are the hallmark of the syndrome, though meningiomas, ependymomas, and other peripheral schwannomas are common. Inheritance is autosomal dominant and de novo mutations are found in about 50% of patients. Standard treatment for symptomatic tumors is surgery. Radiation therapy may be considered for progressive tumors that are not surgically accessible, but secondary cancers after radiation have been reported. Retrospective studies suggest that bevacizumab may be active for progressive vestibular schwannomas and trials of chemotherapy for NF2-related tumors are in progress. This chapter reviews the epidemiology, genetic features, clinical characteristics, and current treatments for patients with NF2.

Clinical and Genetic Characteristics of 23 Korean Patients with Haploinsufficiency of the Short-stature Homeobox-containing Gene

2020 ◽  
Author(s):  
Jeong-Seon Lee ◽  
Hwa Young Kim ◽  
Young-Ah Lee ◽  
Seong-Young Lee ◽  
Tae-Joon Cho ◽  
...  
Keyword(s):  
Short Stature ◽  
De Novo ◽  
Standard Deviation Score ◽  
Hormone Treatment ◽  
Chromosomal Microarray ◽  
Tibia Vara ◽  
Genetic Characteristics ◽  
Korean Patients ◽  
Madelung Deformity ◽  
High Index Of Suspicion

Abstract Background The short-stature homeobox-containing gene (SHOX) is one of the major growth genes in humans. The clinical spectrum of SHOX haploinsufficiency ranges from Léri–Weill dyschondrosteosis to idiopathic short stature. Herein, we describe the clinical and genetic characteristics of 23 Korean patients with SHOX deficiency disorders. Methods Medical records of 23 patients (19 females and 4 males) from 15 unrelated families who were genetically confirmed to have SHOX deficiency were retrospectively reviewed. SHOX gene deletions or mutations were determined by sequence analyses using multiplex ligation-dependent probe amplification, chromosomal microarray, and/or Sanger sequencing methods. Results In the 15 families, 9 probands were de novo cases. All 23 patients showed mesomelia. Madelung deformity and tibia vara were observed in 13 (56.5%) and 3 (13.1%) patients, respectively. Genetically, 11 (73.3%) of the 15 families showed SHOX deletions of various sizes, and the other 4 families harboured SHOX sequence variants. Four patients had undergone orthopaedic surgeries (3 for tibia vara and 1 for Madelung deformity). Among 7 patients who had received growth hormone treatment for ≥1 year, 5 showed good responses, with a median first-year change-in-height standard deviation score of +0.6. There were no significant differences in the clinical characteristics of the deletion and point mutation groups. Conclusions A high index of suspicion and the genetic confirmation of SHOX deficiency are helpful for the timely management of the condition and are needed to provide genetic counselling to the family members of the patients.

scholarly journals A complex of distal appendage–associated kinases linked to human disease regulates ciliary trafficking and stability

2021 ◽  
Vol 118 (16) ◽  
pp. e2018740118
Author(s):  
Abdelhalim Loukil ◽  
Chloe Barrington ◽  
Sarah C. Goetz
Keyword(s):  
Human Disease ◽  
Cellular Response ◽  
De Novo ◽  
Genetic Disorder ◽  
Structural Defects ◽  
De Novo Mutations ◽  
Superresolution Microscopy ◽  
Mother Centriole ◽  
Multistep Process ◽  
Human Genetic Disorder

Cilia biogenesis is a complex, multistep process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified Tau tubulin kinase 2 (TTBK2) as a key regulator of ciliogenesis. Here, using CRISPR kinome and biotin identification screening, we identify the CK2 catalytic subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Superresolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages. Csnk2a1 mutant cilia are longer than those of control cells, showing instability at the tip associated with ciliary actin cytoskeleton changes. These cilia also abnormally accumulate key cilia assembly and SHH-related proteins. De novo mutations of Csnk2a1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells causes ciliary structural defects. Our findings provide insights into mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance of cilia instability in human disease.

Schinzel—Giedion Syndrome: First Czech Patients Confirmed by Molecular Genetic Analysis

2018 ◽  
Vol 17 (03) ◽  
pp. 125-127
Author(s):  
Jana Neupauerová ◽  
Katalin Štěrbová ◽  
Vladimír Komárek ◽  
Andrea Gřegořová ◽  
Markéta Vlčková ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Sanger Sequencing ◽  
De Novo ◽  
Genetic Disorder ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Facial Features ◽  
De Novo Mutations ◽  
Whole Exome ◽  
Exon 4

AbstractSchinzel–Giedion syndrome (SGS) is a very rare genetic disorder characterized by distinctive facial features, severe developmental delay, seizures, and skeletal abnormalities. Whole exome sequencing, Sanger sequencing, and correlation with already published variants and cases allowed us to identify two different de novo mutations in the SETBP1 gene: NM_015559.2 (SETBP1): c.2601C > G (p.Ser867Arg) and c. 2608 G > A (p.Gly870Ser) in two Czech patients presenting with SGS features. Both mutations are within exon 4 of SETBP1, supporting the notion that exon 4 represents the mutation hotspot of the gene in patients with SGS.

scholarly journals Six New Mutations of the Thyroglobulin Gene Discovered in Taiwanese Children Presenting with Thyroid Dyshormonogenesis

2009 ◽  
Vol 94 (12) ◽  
pp. 5045-5052 ◽  
Author(s):  
Dau-Ming Niu ◽  
Ju-Hui Hsu ◽  
Kah-Wai Chong ◽  
Cheng-Hung Huang ◽  
Yung-Hsiu Lu ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Amino Acid Residues ◽  
De Novo Mutations ◽  
Study Objective ◽  
Genetic Characteristics ◽  
Thyroid Dyshormonogenesis ◽  
Taiwan Chinese ◽  
Thyroglobulin Gene

Background: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis. Study Objective: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein. Patients and Results: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C>T), g.IVS3 + 2T>G, c.1712delT, p.Q1765X (c.5350C>T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T>G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T>G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues. Conclusions: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T4 withdrawal, plasma T4 ≦ 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.

scholarly journals Hepatic Tumor as Antenatal Presentation of Costello Syndrome

2020 ◽  
Author(s):  
Chusana Petpichetchian ◽  
Richard Brown ◽  
Gabriel Altit ◽  
Karl Muchantef ◽  
Isabelle De Bie
Keyword(s):  
De Novo ◽  
Left Ventricular ◽  
Left Ventricular Cavity ◽  
Costello Syndrome ◽  
Fetal Head ◽  
Tumor Embolization ◽  
Abnormal Posture ◽  
Ultrasound Findings ◽  
Complete Obliteration ◽  
Congenital Hemangioma

A large hepatic mixed echoic mass occupying the left fetal abdomen was identified at 266/7 weeks. The mass showed peripheral and internal vascularity. Other ultrasound findings included edema of the fetal head and face, macrosomia, shortened long bones, abnormal posture of hands, small stomach, polyhydramnios and biventricular hypertrophy. Fetal magnetic resonance imaging confirmed a hypervascular mass replacing the lateral left hepatic lobe, suggestive of a congenital hemangioma. The fetus was delivered by cesarean section at 282/7 weeks. The baby was stabilized at day 3 of life, and underwent successful selective tumor embolization. The baby remained stable for 3 days, then deteriorated with a progressive thickening of the myocardium. The child then passed away on day 11 from severe progressive hypertrophic cardiomyopathy, with almost complete obliteration of the left ventricular cavity; an autopsy was declined. Postnatal investigations reported a de novo heterozygous pathogenic HRAS variant (NM_005343.3(HRAS): c.35_36 delinsTT, p.Gly21Val), previously reported in 8 cases associated with the early, lethal form of Costello syndrome.

Obstructive hydrocephalus treated with endoscopic third ventriculostomy in a patient with Hajdu-Cheney syndrome: case report

2020 ◽  
Vol 26 (5) ◽  
pp. 513-516
Author(s):  
Ryan M. Johnson ◽  
Brent R. O’Neill
Keyword(s):  
Autosomal Dominant ◽  
Endoscopic Third Ventriculostomy ◽  
De Novo ◽  
Obstructive Hydrocephalus ◽  
Genetic Disorder ◽  
Aqueductal Stenosis ◽  
Third Ventriculostomy ◽  
De Novo Mutations ◽  
First Case ◽  
Complex Anatomy

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder with autosomal dominant inheritance, although most cases result from de novo mutations. Progressive platybasia and basilar impression (BI) can potentiate obstructive hydrocephalus due to aqueductal stenosis. Limited literature exists on the surgical intervention for hydrocephalus in patients with this condition. The authors present (to their knowledge) the first case of obstructive hydrocephalus due to aqueductal stenosis from BI treated with an endoscopic third ventriculostomy in a patient with the complex anatomy of HCS.

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