1,756 results on '"brachydactyly"'
Search Results
152. DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies
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Michael V. Zaragoza, Cecilia H. H. Nguyen, Halida P. Widyastuti, Julien L. P. Morival, and Timothy L. Downing
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Cardiomyopathy, Dilated ,Cardiomyopathy ,Clinical Sciences ,Dilated cardiomyopathy ,Laminopathy ,Biology ,Cardiovascular ,LMNA ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,0302 clinical medicine ,Rare Diseases ,Dilated ,medicine ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Epigenetics ,Aetiology ,Molecular Biology ,Gene ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Lamin A/C ,DNA methylation ,Research ,Laminopathies ,Brachydactyly ,Human Genome ,medicine.disease ,Lamin Type A ,Stem Cell Research ,Chromatin ,Differentially methylated regions ,Heart Disease ,Reduced representation bisulfite sequencing ,Lamin A ,030217 neurology & neurosurgery ,Developmental Biology ,Biotechnology - Abstract
Background Mutations in LMNA, encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly. Results Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA-related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development. Conclusions Our results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages.
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- 2021
153. Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome
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Shazia Maqbool, Patrick Sips, Piyanoot Tapaneeyaphan, Henry Houlden, Alper Gezdirici, Mohammad Al-Owain, Bert Callewaert, Monerah Alsaleh, Mais Hashem, Phil L. Salmon, Stephanie Efthymiou, William G. Newman, Fowzan S. Alkuraya, Fatima Rahman, Riet De Rycke, Adelbert De Clercq, Sawsan Mohamed Abdullah, Lore Pottie, Kay Metcalfe, Gerhard Sengle, Steffen Lütke, Elif Yilmaz Gulec, Reza Maroofian, Ikhlass Altweijri, Jill E. Urquhart, Aude Beyens, Najwa Anwar, Christin S. Adamo, and Naz Khan
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0301 basic medicine ,Male ,Adolescent ,Connective tissue ,030105 genetics & heredity ,Article ,Cutis Laxa ,Extracellular matrix ,03 medical and health sciences ,TGF beta signaling pathway ,Genetics ,medicine ,Animals ,Humans ,Child ,Zebrafish ,Genetics (clinical) ,Alleles ,Cells, Cultured ,Skin ,biology ,Brachydactyly ,Correction ,Genetic Variation ,Infant ,Fibrillogenesis ,Fibroblasts ,biology.organism_classification ,medicine.disease ,Cell biology ,Extracellular Matrix ,Pedigree ,030104 developmental biology ,medicine.anatomical_structure ,Latent TGF-beta Binding Proteins ,Child, Preschool ,Female ,Collagen ,Transforming growth factor ,Cutis laxa - Abstract
Summary Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFβ in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. In this study, we report homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families. Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). In vitro studies on proband-derived dermal fibroblasts indicate distinct molecular mechanisms depending on the position of the variant in LTBP1. C-terminal variants lead to an altered LTBP1 loosely anchored in the microfibrillar network and cause increased ECM deposition in cultured fibroblasts associated with excessive TGFβ growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGFβ levels or ECM assembly. In vivo validation with two independent zebrafish lines carrying mutations in ltbp1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. In addition, one of the mutant zebrafish lines shows voluminous and hypo-mineralized vertebrae. Overall, our findings in humans and zebrafish show that LTBP1 function is crucial for skin and bone ECM assembly and homeostasis.
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- 2021
154. Weill-Marchesani Syndrome, a Rare Presentation of Severe Short Stature with Review of the Literature
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Amnah A M Al Agnam, Majed J Al Buali, Manal S S Al Shehri, and Mossa N A Al Motawa
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Male ,Pediatrics ,medicine.medical_specialty ,genetic structures ,Glaucoma ,Dwarfism ,030204 cardiovascular system & hematology ,Short stature ,Ectopia Lentis ,03 medical and health sciences ,0302 clinical medicine ,ADAMTS Proteins ,medicine ,Humans ,Ectopia lentis ,Child ,Genetic heterogeneity ,business.industry ,Brachydactyly ,Homozygote ,General Medicine ,Articles ,medicine.disease ,Weill–Marchesani syndrome ,eye diseases ,Weill-Marchesani Syndrome ,ADAM Proteins ,Microspherophakia ,Latent TGF-beta Binding Proteins ,030220 oncology & carcinogenesis ,Child, Preschool ,medicine.symptom ,business - Abstract
Patient: Male, 9-year-old Final Diagnosis: Weill-Marchesani syndrome Symptoms: Joint stiffnes • myopia • short stature Medication: — Clinical Procedure: — Specialty: Endocrinology and Metabolic • Genetics Objective: Rare disease Background: Short stature is the second most common reason for referral to a pediatric endocrinology clinic. Numerous genetic causes have been identified. Weill-Marchesani syndrome (WMS) is one of the rare genetic disorders that cause short stature. It is caused by homozygous mutations in the FBN1 gene, ADAMTS10 gene, ADAMTS17 gene, or LTBP2 gene. Despite genetic heterogeneity, WMS is clinically homogeneous. It is characterized by short stature, brachydactyly, joint stiffness, ocular abnormalities, mainly microspherophakia and glaucoma, and occasionally cardiac defects. Case Report: A 9-year-old boy had bilateral narrow-angle glaucoma with lens subluxation, elevated intraocular pressure, and severe myopia since early childhood. He had phenotypic dysmorphic features and radiological findings consistent with WMS. He underwent lensectomy and scleral-fixated intraocular lens implantation as well as drug treatment to control the intraocular pressure. He was a slow grower, and his growth parameters showed disproportionate short stature with brachydactyly and joint stiffness. Growth hormone provocation tests were subnormal with a peak value of 7.89 ng/mL. Conclusions: The constellation of clinical presentation, radiological findings, and the molecular examination confirmed a homozygous familial variant of the ADAMTS10 gene identified by carrier gene testing. This known familial variant creates a premature termination codon classified as a likely pathogenic cause of WMS. In this syndrome, glaucoma treatment is considered the greatest challenge. The disease-causing mechanism in WMS is not known but thought to be due to abnormal actin distribution and organization in fibroblasts as a result of impaired connections between extracellular matrix components and the cytoskeleton.
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- 2021
155. Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease
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Sang-Yoon Shin, Camila Simoes, Lucía Spangenberg, Alejandra Tapié, Gabriel González, Víctor Raggio, Margarita Halty, Gonzalo Greif, Hugo Naya, Changhoon Kim, Jong-Yeon Shin, Nicolás Dell’Oca, Virgina Gonzalez, Estefania Garrone, Martín Graña, María Laura Rovella, Conrado Medici, Jeong-Sun Seo, Gonzalo Costa, and Soledad Rodríguez
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Heart Defects, Congenital ,genomica ,Bioinformatics ,Arterial Occlusive Diseases ,Cell Cycle Proteins ,Disease ,QH426-470 ,variantes estructurales ,Compound heterozygosity ,Frameshift mutation ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Ciencias Naturales y Exactas ,Drug Discovery ,Genetics ,Humans ,Medicine ,Child ,Frameshift Mutation ,Molecular Biology ,Exome sequencing ,030304 developmental biology ,Whole genome sequencing ,0303 health sciences ,Whole Genome Sequencing ,business.industry ,Homozygote ,Brachydactyly ,Grange syndrome ,Arteries ,medicine.disease ,Pedigree ,Neurology ,Ciencias de la Computación e Información ,Molecular Medicine ,Female ,Primary Research ,business ,Medical genomics ,Ciencias de la Información y Bioinformática ,030217 neurology & neurosurgery ,Transcription Factors ,Rare disease - Abstract
Background Rare diseases are pathologies that affect less than 1 in 2000 people. They are difficult to diagnose due to their low frequency and their often highly heterogeneous symptoms. Rare diseases have in general a high impact on the quality of life and life expectancy of patients, which are in general children or young people. The advent of high-throughput sequencing techniques has improved diagnosis in several different areas, from pediatrics, achieving a diagnostic rate of 41% with whole genome sequencing (WGS) and 36% with whole exome sequencing, to neurology, achieving a diagnostic rate between 47 and 48.5% with WGS. This evidence has encouraged our group to pursue a molecular diagnosis using WGS for this and several other patients with rare diseases. Results We used whole genome sequencing to achieve a molecular diagnosis of a 7-year-old girl with a severe panvascular artery disease that remained for several years undiagnosed. We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. Bioinformatic analyses propose these mutations as the most likely cause of the disease, according to its frequency, in silico predictors, conservation analyses, and effect on the protein product. Additionally, we confirmed one mutation in each parent, supporting a compound heterozygous status in the child. Conclusions In general, we think that this finding can contribute to the use of whole genome sequencing as a diagnosis tool of rare diseases, and in particular, it can enhance the set of known mutations associated with different diseases.
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- 2021
156. Metacarpophalangeal profile pattern analysis in a further patient with a novel ARID1B variant
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Giulia Pascolini
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Proband ,Embryology ,Pathology ,medicine.medical_specialty ,Adolescent ,Limb defects ,Radiography ,Micrognathism ,Pattern analysis ,Intellectual Disability ,Medicine ,Humans ,In patient ,Abnormalities, Multiple ,Coffin–Siris syndrome ,business.industry ,Brachydactyly ,General Medicine ,medicine.disease ,Clinical Practice ,DNA-Binding Proteins ,Face ,Pediatrics, Perinatology and Child Health ,Female ,business ,Hand Deformities, Congenital ,Neck ,Developmental Biology ,Transcription Factors - Abstract
Acral clinical and radiographic characteristics of a further patient with Coffin-Siris syndrome (CSS), which is caused by mutations in the ARID1B gene, encoding a subunit of the BAF-complex, are here described. Metacarpophalangeal profile pattern analysis (MCPPPA) of the present proband and other two known ARID1B mutated individuals has been performed for the first time, demonstrating hands brachydactyly. In this novel study, the utility of an accurate appendicular radiographic examination and MCPPPA in this congenital condition is highlighted. The MCPPPA could be considered in the clinical practice, to better study the hand skeletal morphology in patients with a syndrome characterized by limb defects, including CSS. This article is protected by copyright. All rights reserved.
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- 2021
157. Sequence variants in <italic>GDF5</italic> and <italic>TRPS1</italic> underlie brachydactyly and tricho‐rhino‐phalangeal syndrome type III.
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Ullah, Asmat, Umair, Muhammad, Hussain, Shabir, Jan, Abid, and Ahmad, Wasim
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MUSCULOSKELETAL system abnormalities , *GENES , *TRANSCRIPTION factors , *MULTIPLE epiphyseal dysplasia , *SEQUENCE analysis , *GENETICS - Abstract
The article discusses the symptoms of Brachydactyly (BD) including shortening of fingers and toes caused due to hypoplasia or aplasia of bones. According to the author Brachydactyly is classified into non-syndromic which include BDA-E, brachymetatarsus IV and syndromic which include Tricho-rhino-phalangeal syndrome (TRPS).
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- 2018
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158. Brachydactyly‐anonychia with congenital absent phalanges of the hand
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Raman Sharma, Ramesh Kumar Sharma, and Jerry R. John
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business.industry ,Brachydactyly ,Nails, Malformed ,General Medicine ,Anatomy ,Phalanx ,Hand ,medicine.disease ,Fingers ,Finger Phalanges ,Anonychia ,Humans ,Medicine ,Surgery ,business - Published
- 2020
159. Grange syndrome due to homozygous YY1AP1 missense rare variants
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Sandhya Parkash, Dianna M. Milewicz, Dongchuan Guo, Callie S. Kwartler, Isabella Ciuffetelli Alamo, Rana O. Afifi, Ellen Regalado, and Andrea Rideout
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Heart Defects, Congenital ,Male ,Pathology ,medicine.medical_specialty ,Computed Tomography Angiography ,Mutation, Missense ,Arterial Occlusive Diseases ,Cell Cycle Proteins ,Compound heterozygosity ,Bone and Bones ,Cell Line ,Consanguinity ,Genetics ,Humans ,Medicine ,Missense mutation ,Genetic Predisposition to Disease ,Syndactyly ,Genetic Association Studies ,Genetics (clinical) ,business.industry ,Vascular disease ,Brachydactyly ,Homozygote ,Grange syndrome ,medicine.disease ,Penetrance ,Stenosis ,Hypertension ,Female ,Tomography, X-Ray Computed ,business ,Transcription Factors - Abstract
Grange syndrome (OMIM 602531) is an autosomal recessive condition characterized by severe early onset vascular occlusive disease and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Grange syndrome is caused by homozygous or compound heterozygous loss-of-function variants in the YYA1P1 gene. We report on the case of a 53-year old female with novel homozygous missense variants in YYA1P1 (c.1079C>T, p.Pro360Leu), presenting with a history of brachysyndactyly, hypertension, and ischemic stroke. Imaging studies revealed stenosis of the bilateral internal carotid with extensive collateralization of cerebral vessels in a moyamoya-like pattern, along with stenosis in the splenic, common hepatic, celiac, left renal, and superior mesenteric arteries. Functional studies conducted with the patient's dermal fibroblasts suggest that the p.Pro360Leu variant decreases the stability of the YY1AP1 protein. This is the first report of a missense variant associated with Grange syndrome characterized by later onset of vascular disease and a lack of developmental delay and bone fragility.
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- 2019
160. An Orofaciodigital Syndrome 1 Patient and Her Mother Carry the Same OFD1 Mutation but Have Different X Chromosome Inactivation Patterns
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Kazumoto Iijima, Kandai Nozu, Kenmei Takaichi, Naoya Morisada, Junichi Hoshino, Naoki Sawa, Takashi Iijima, Yoshifumi Ubara, and Noriko Hayami
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Mutation ,Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Brachydactyly ,General Medicine ,030204 cardiovascular system & hematology ,medicine.disease_cause ,medicine.disease ,Phenotype ,X-inactivation ,Orofaciodigital syndrome 1 ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Internal Medicine ,Enlarged polycystic kidneys ,Medicine ,030211 gastroenterology & hepatology ,Hemodialysis ,business - Abstract
Orofaciodigital syndrome 1 (OFD-1) is a rare, X-linked, dominantly inherited disorder caused by an OFD1 mutation that can cause polycystic kidneys. A 37-year-old woman on hemodialysis therapy was admitted to our hospital for trans-catheter arterial embolization therapy for enlarged polycystic kidneys. Lobulated tongue and brachydactyly were noticed, prompting an OFD1 sequencing analysis. Sequencing revealed a causal four-base-pair deletion in exon 13, both in the patient and in her mother, whose renal function had been retained. The peripheral leukocyte X chromosome inactivation pattern was skewed in the patient but not in her mother, suggesting some role in their phenotypic difference.
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- 2019
161. Novel de novo interstitial deletion in 2q36.1q36.3 causes syndromic hearing loss and further delineation of the 2q36 deletion syndrome
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Qiuju Wang, Jing Guan, Guohui Chen, Linwei Yin, Dayong Wang, Hongyang Wang, and Cui Zhao
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Genetics ,business.industry ,Hearing loss ,Brachydactyly ,General Medicine ,medicine.disease ,Phenotype ,03 medical and health sciences ,0302 clinical medicine ,Otorhinolaryngology ,030220 oncology & carcinogenesis ,Medicine ,Deletion syndrome ,medicine.symptom ,030223 otorhinolaryngology ,business - Abstract
Background: Deletions of the interstitial 2q36 are uncommon and associated with varying phenotypes. However, the list of currently known phenotypes is still far complete for an understanding of the...
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- 2019
162. A 3.06-Mb interstitial deletion on 12p11.22-12.1 caused brachydactyly type E combined with pectus carinatum
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Jia Huang, Hong-Yan Liu, Rong-Rong Wang, Hai Xiao, Dong Wu, Tao Li, Ying-Hai Jiang, Xue Zhang, and Peng Lyu
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Male ,DNA Copy Number Variations ,lcsh:Medicine ,Brachydactyly type E ,Biology ,Short stature ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Asian People ,medicine ,Humans ,Copy-number variation ,Sequence Deletion ,Homeodomain Proteins ,Genetics ,Sanger sequencing ,Comparative Genomic Hybridization ,Pectus carinatum ,Copy number variation ,lcsh:R ,Brachydactyly ,Parathyroid Hormone-Related Protein ,Original Articles ,General Medicine ,medicine.disease ,Pedigree ,Parathyroid-hormone-like hormone ,HOXD13 ,030220 oncology & carcinogenesis ,Mutation ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,symbols ,Female ,medicine.symptom ,Haploinsufficiency ,030217 neurology & neurosurgery ,Transcription Factors ,Comparative genomic hybridization - Abstract
Supplemental Digital Content is available in the text, Background Brachydactyly, a developmental disorder, refers to shortening of hands/feet due to small or missing metacarpals/metatarsals and/or phalanges. Isolated brachydactyly type E (BDE), characterized by shortened metacarpals and/or metatarsals, consists in a small proportion of patients with Homeobox D13 (HOXD13) or parathyroid-hormone-like hormone (PTHLH) mutations. BDE is often accompanied by other anomalies that are parts of many congenital syndromes. In this study, we investigated a Chinese family presented with BDE combined with pectus carinatum and short stature. Methods A four-generation Chinese family was recruited in June 2016. After informed consent was obtained, venous blood was collected, and genomic DNA was extracted by standard procedures. Whole-exome sequencing was performed to screen pathogenic mutation, array comparative genomic hybridization (Array-CGH) analysis was used to analyze copy number variations, and quantitative real-time polymerase chain reaction (PCR), stride over breakpoint PCR (gap-PCR), and Sanger sequencing were performed to confirm the candidate variation. Results A 3.06-Mb deletion (chr12:25473650–28536747) was identified and segregated with the phenotype in this family. The deletion region encompasses 23 annotated genes, one of which is PTHLH which has been reported to be causative to the BDE. PTHLH is an important regulator of endochondral bone development. The affected individuals showed bilateral, severe, and generalized brachydactyly with short stature, pectus carinatum, and prematurely fusion of epiphyses. The feature of pectus carinatum has not been described in the PTHLH-related BDE patients previously. Conclusions The haploinsufficiency of PTHLH might be responsible for the disease in this family. This study has expanded the knowledge on the phenotypic presentation of PTHLH variation.
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- 2019
163. A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability
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Weihao Zhao, Weiju Han, Yongyi Yuan, Song Gao, Pu Dai, Shi-Wei Qiu, Dongyang Kang, Bo Gao, Xue Gao, and Xin Zhang
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Adult ,Male ,0301 basic medicine ,Vacuolar Proton-Translocating ATPases ,Research paper ,Cognitive defects ,Mice, Transgenic ,Deafness ,Biology ,Hippocampal formation ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Intellectual Disability ,Intellectual disability ,medicine ,Animals ,Humans ,V-ATPases ,Zebrafish ,Cochlea ,ATP6V1B2 ,Gene knockdown ,Brachydactyly ,Genetic disorder ,Infant ,General Medicine ,medicine.disease ,biology.organism_classification ,Pedigree ,Disease Models, Animal ,Phenotype ,030104 developmental biology ,Auditory brainstem response ,Dominant deafness-onychodystrophy (DDOD) syndrome ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Female ,Neuroscience - Abstract
Background Dominant deafness-onychodystrophy (DDOD) syndrome is a rare disorder mainly characterized by severe deafness, onychodystrophy and brachydactyly. We previously identified c.1516C > T (p.Arg506X) in ATP6V1B2 as cause of DDOD syndrome, accounting for all cases of this genetic disorder. Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients. However, the underlying mechanisms were unknown. Methods atp6v1b2 knockdown zebrafish and Atp6v1b2 c.1516C > T knockin mice were constructed to explore the phenotypes and related mechanism. In mutant mice, auditory brainstem response test and cochlear morphology analysis were performed to evaluate the auditory function. Behavioral tests were used to investigate various behavioral and cognitive domains. Resting-state functional magnetic resonance imaging was used to evaluate functional connectivity in the mouse brain. Immunofluorescence, Western blot, and co-immunoprecipitation were performed to examine the expression and interactions between the subunits of V-ATPases. Findings atp6v1b2 knockdown zebrafish showed developmental defects in multiple organs and systems. However, Atp6v1b2 c.1516C > T knockin mice displayed obvious cognitive defects but normal hearing and cochlear morphology. Impaired hippocampal CA1 region and weaker interaction between the V1E and B2 subunits in Atp6v1b2Arg506X//Arg506X mice were observed. Interpretation Our study extends the phenotypic range of DDOD syndrome. The impaired hippocampal CA1 region may be the pathological basis of the behavioral defects in mutant mice. The molecular mechanism underlying V-ATPases dysfunction involves a weak interaction between subunits, although the assembly of V-ATPases can still take place.
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- 2019
164. An emerging ribosomopathy affecting the skeleton due to biallelic variations in NEPRO
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Gandham SriLakshmi Bhavani, Neethukrishna Kausthubham, Anju Shukla, Geert Mortier, Katta M. Girisha, Hitesh Shah, and Dhanya Lakshmi Narayanan
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Proband ,Glycoside Hydrolases ,Ribosomopathy ,Primary Immunodeficiency Diseases ,Endoribonuclease complex ,Dwarfism ,Nerve Tissue Proteins ,Biology ,Osteochondrodysplasias ,Genetics ,medicine ,Cartilage–hair hypoplasia ,Humans ,Missense mutation ,Hirschsprung Disease ,Child ,Alleles ,Skeleton ,Genetics (clinical) ,Brachydactyly ,medicine.disease ,Metaphyseal dysplasia ,Pedigree ,Repressor Proteins ,Phenotype ,Ribonucleoproteins ,Dysplasia ,Multiprotein Complexes ,Mutation ,Female ,RNA, Long Noncoding ,Human medicine ,Apoptosis Regulatory Proteins ,Ribosomes ,Hair - Abstract
Cartilage hair hypoplasia (CHH), anauxetic dysplasia 1, and anauxetic dysplasia 2 are rare metaphyseal dysplasias caused by biallelic pathogenic variants in RMRP and POP1, which encode the components of RNAse-MRP endoribonuclease complex (RMRP) in ribosomal biogenesis pathway. Nucleolus and neural progenitor protein (NEPRO), encoded by NEPRO (C3orf17), is known to interact with multiple protein subunits of RMRP. We ascertained a 6-year-old girl with skeletal dysplasia and some features of CHH. RMRP and POP1 did not harbor any causative variant in the proband. Parents-child trio exomes revealed a candidate biallelic variant, c.435G>C, p.(Leu145Phe) in NEPRO. Two families with four affected individuals with skeletal dysplasia and a homozygous missense variant, c.280C>T, p.(Arg94Cys) in NEPRO, were identified from literature and their published phenotype was compared in detail to the phenotype of the child we described. All the five affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. Protein modeling and stability prediction showed that the mutant protein has decreased stability. Both the reported variants are in the same domain of the protein. Our report delineates the clinical and radiological characteristics of an emerging ribosomopathy caused by biallelic variants in NEPRO.
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- 2019
165. Delineating the expanding phenotype associated with SCAPER gene mutation
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Anthony G. Robson, Claire G. Salter, James Fasham, Gaurav V. Harlalka, Olivia Wenger, Amelia Lane, F. Lucy Raymond, Sarah Hull, Rui Chen, Emma L. Baple, Lynn Schema, Gavin Arno, Mingchu Xu, Anthony T. Moore, Andrew R. Webster, Siying Lin, Michael E. Cheetham, Timothy J. Moss, Keren J. Carss, Jay E. Self, and Andrew H. Crosby
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0303 health sciences ,Philosophy ,Brachydactyly ,030305 genetics & heredity ,Intellectual disability ,Gene mutation ,Research Letters ,3. Good health ,Retinitis pigmentosa ,03 medical and health sciences ,Research Letter ,Genetics ,Theology ,SCAPER ,CCNA2–CDK2 ,Genetics (clinical) ,030304 developmental biology - Abstract
Author(s): Fasham, James; Arno, Gavin; Lin, Siying; Xu, Mingchu; Carss, Keren J; Hull, Sarah; Lane, Amelia; Robson, Anthony G; Wenger, Olivia; Self, Jay E; Harlalka, Gaurav V; Salter, Claire G; Schema, Lynn; Moss, Timothy J; Cheetham, Michael E; Moore, Anthony T; Raymond, F Lucy; Chen, Rui; Baple, Emma L; Webster, Andrew R; Crosby, Andrew H; NIHR Bioresource Rare Diseases Consortium
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- 2019
166. KBG syndrome presenting with brachydactyly type E
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Sophie Devery, Renata Libianto, Kathy H C Wu, and John A. Eisman
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Karyotype ,Acrodysostosis ,030209 endocrinology & metabolism ,Short stature ,03 medical and health sciences ,0302 clinical medicine ,Skeletal disorder ,Intellectual Disability ,Humans ,Medicine ,Abnormalities, Multiple ,Bone Diseases, Developmental ,Whole Genome Sequencing ,Tooth Abnormalities ,business.industry ,Brachydactyly ,Facies ,KBG SYNDROME ,Microdeletion syndrome ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,Mutation ,Female ,Pseudopseudohypoparathyroidism ,medicine.symptom ,business - Abstract
We report the case of a young woman who presented at age 10 years with height on the tenth centile, brachydactyly type E and mild developmental delay. Biochemistry and hormonal profiles were normal. Differential diagnoses considered included Albright hereditary osteodystrophy without hormone resistance (a.k.a pseudopseudohypoparathyroidism), 2q37 microdeletion syndrome and acrodysostosis. She had a normal karyotype and normal FISH of 2q37. Whole genome sequencing (WGS) identified a mutation in the ANKRD11 gene associated with KBG syndrome. We review the clinical features of the genetic syndromes considered, and suggest KBG syndrome be considered in patients presenting with syndromic brachydactyly type E, especially if short stature and developmental delay are also present.
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- 2019
167. A novel mutation in COL1A2 leads to osteogenesis imperfecta/Ehlers-Danlos overlap syndrome with brachydactyly
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Narin Intarak, Thanakorn Theerapanon, Thantrira Porntaveetus, Thunyaporn Budsamongkol, Vorasuk Shotelersuk, and Somchai Yodsanga
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,lcsh:QH426-470 ,Dentinogenesis imperfecta ,Connective tissue ,macromolecular substances ,030105 genetics & heredity ,Collagen defect ,Biochemistry ,Article ,03 medical and health sciences ,Exon ,stomatognathic system ,Dentin ,medicine ,Skeletal fragility ,Molecular Biology ,Genetics (clinical) ,Exome sequencing ,lcsh:R5-920 ,business.industry ,Brachydactyly ,Overlap syndrome ,Skin hypermobility ,Cell Biology ,medicine.disease ,Joint laxity ,lcsh:Genetics ,stomatognathic diseases ,Bone-like dentin ,030104 developmental biology ,medicine.anatomical_structure ,Osteogenesis imperfecta ,lcsh:Medicine (General) ,business - Abstract
Osteogenesis imperfecta (OI) is mainly characterized by bone fragility and Ehlers-Danlos syndrome (EDS) by connective tissue defects. Mutations in COL1A1 or COL1A2 can lead to both syndromes. OI/EDS overlap syndrome is mostly caused by helical mutations near the amino-proteinase cleavage site of type I procollagen. In this study, we identified a Thai patient having OI type III, EDS, brachydactyly, and dentinogenesis imperfecta. His dentition showed delayed eruption, early exfoliation, and severe malocclusion. For the first time, ultrastructural analysis of the tooth affected with OI/EDS showed that the tooth had enamel inversion, bone-like dentin, loss of dentinal tubules, and reduction in hardness and elasticity, suggesting severe developmental disturbance. These severe dental defects have never been reported in OI or EDS. Exome sequencing identified a novel de novo heterozygous glycine substitution, c.3296G > A, p.Gly1099Glu, in exon 49 of COL1A2. Three patients with mutations in the exon 49 of COL1A2 were previously reported to have OI with brachydactyly and intracranial hemorrhage. Notably, two of these three patients did not show hyperextensible joints and hypermobile skin, while our patient at the age of 5 years had not developed intracranial hemorrhage. Here, we demonstrate that the novel glycine substitution in the carboxyl region of alpha2(I) collagen triple helix leads to OI/EDS with brachydactyly and severe tooth defects, expanding the genotypic and phenotypic spectra of OI/EDS overlap syndrome. Keywords: Bone-like dentin, Collagen defect, Dentinogenesis imperfecta, Joint laxity, Skeletal fragility, Skin hypermobility
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- 2019
168. Severe brachydactyly and short stature resulting from a novel pathogenic TRPS1 variant within the GATA DNA-binding domain
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Nese Ersoz Gulcelik, Lauren T Shumate, Monica Reyes, Isilay Taskaldiran, Tülay Omma, Anara Karaca, and Murat Bastepe
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Adult ,0301 basic medicine ,Candidate gene ,Histology ,Adolescent ,Physiology ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Nonsense ,Parathyroid hormone ,Dwarfism ,030209 endocrinology & metabolism ,Biology ,GATA Transcription Factors ,Severity of Illness Index ,Short stature ,Article ,03 medical and health sciences ,Exon ,0302 clinical medicine ,medicine ,Humans ,Missense mutation ,Gene ,media_common ,Genetics ,Brachydactyly ,Genetic Variation ,medicine.disease ,Pedigree ,DNA-Binding Proteins ,Repressor Proteins ,030104 developmental biology ,Female ,medicine.symptom - Abstract
Brachydactyly type E, which can be an isolated finding or part of a syndrome in combination with other clinical anomalies, involves metacarpals and metatarsals with or without short phalanges. Herein we report two unrelated Turkish females who presented with brachydactyly type E and vitamin D deficiency in the absence of marked alterations in serum calcium, phosphate, and parathyroid hormone. After excluding disease-causing variants in two candidate genes, PTHLH and PDE4D, we identified different pathogenic variants in TRPS1, the gene mutated in patients with tricho-rhino-phalangeal syndrome (TRPS). In one of the patients, who displayed severe brachydactyly and short stature, we identified a novel heterozygous missense pathogenic variant in exon 6 (c.2783A>G, p.Tyr928Cys), located within the GATA DNA-binding domain. The second patient, who had relatively milder brachydactyly and was of normal height, carried a heterozygous nonsense pathogenic variant in exon 4 (c. 1870C>T, p.Arg624Ter), which has been previously described. Both pathogenic variants segregated in affected family members. The patients additionally showed sparse hair and a bulbous nose, consistent with the clinical features of TRPS. Our findings, in addition to identifying the genetic cause of brachydactyly in two unrelated kindreds, emphasize the role of pathogenic TRPS1 variants in the development of brachydactyly type E and highlight the GATA DNA-binding region of TRPS1 protein with respect to phenotype-genotype correlation.
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- 2019
169. Genetic interactions between Ror2 and Wnt9a, Ror1 and Wnt9a and Ror2 and Ror1: Phenotypic analysis of the limb skeleton and palate in compound mutants
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Hsin-Yi Henry Ho, Martina Weissenböck, Yasuhiro Minami, Michiru Nishita, Richard Latham, Christine Hartmann, and Lena I. Wolff
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Mutant ,Limb Deformities, Congenital ,Biology ,Receptor Tyrosine Kinase-like Orphan Receptors ,Article ,Mice ,03 medical and health sciences ,Osteogenesis ,Genetics ,medicine ,Animals ,Allele ,030304 developmental biology ,0303 health sciences ,Brachydactyly ,Wnt signaling pathway ,Epistasis, Genetic ,ROR2 ,Cell Biology ,medicine.disease ,Phenotype ,Molecular biology ,Cleft Palate ,Mice, Inbred C57BL ,Wnt Proteins ,body regions ,Mutation ,ROR1 ,Secondary palate - Abstract
Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2(−/−) mutant mice. In contrast, Ror1(−/−) mutant mice are viable and show no limb phenotype. Ror1(−/−);Ror2(−/−) double mutants are embryonic lethal, whereas double mutants containing a hypomorphic Ror1 allele (Ror1(hyp)) survive up to birth and display a more severe shortened limb phenotype. Both orphan receptors have been shown to act as possible Wnt coreceptors and to mediate the Wnt5a signal. Here, we analyzed genetic interactions between the Wnt ligand, Wnt9a, and Ror2 or Ror1, as Wnt9a has also been implicated in skeletal development. Wnt9a(−/−) single mutants display a mild shortening of the long bones, whereas these are severely shortened in Ror2(−/−) mutants. Ror2(−/−);Wnt9a(−/−) double mutants displayed even more severely shortened long bones, and intermediate phenotypes were observed in compound Ror2;Wnt9a mutants. Long bones were also shorter in Ror1(hyp/hyp);Wnt9a(−/−) double mutants. In addition, Ror1(hyp/hyp);Wnt9a(−/−) double mutants displayed a secondary palate cleft phenotype, which was not present in the respective single mutants. Interestingly, 50% of compound mutant pups heterozygous for Ror2 and homozygous mutant for Ror1 also developed a secondary palate cleft phenotype.
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- 2019
170. Further delineation of the phenotype caused by loss of function mutations in PRMT7
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Eduardo F. Tizzano, Teresa Vendrell, Maria Segura-Puimedon, Paula Fernández-Álvarez, Lluís Armengol, Irene Valenzuela, and Benjamín Rodríguez-Santiago
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Male ,Biallelic Mutation ,Protein-Arginine N-Methyltransferases ,Genetic counseling ,Dwarfism ,Short stature ,Loss of Function Mutation ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Loss function ,Exome sequencing ,Phenocopy ,business.industry ,Brachydactyly ,Infant ,Syndrome ,General Medicine ,medicine.disease ,Phenotype ,medicine.symptom ,business - Abstract
PRMT7 encodes for an arginine methyltransferase that methylates arginine residues on various protein substrates and has been shown to play a role in various developmental processes. Mutations in PRMT7 have been recently shown to be implicated in a phenotype with intellectual disability, short stature and brachydactyly, and considered to be a phenocopy of pseudohypoparathyroidism. We report a patient with short stature, psychomotor delay, hearing loss and brachydactyly, for whom whole exome sequencing detected two mutations in PRMT7 and parental segregation studies detected biallelic mutation inheritance. Few patients with biallelic PRMT7 mutations have been reported so far in the literature. We report a new patient and review all reported cases to date to delineate the clinical manifestations that may help in diagnosis this disorder, known as Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures syndrome, allowing appropriate management and genetic counselling.
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- 2019
171. A Chinese Family with Pseudoachondroplasia Caused by COMP Gene Mutation
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Qing Jiang, Wenjin Yan, Jin Dai, Yinhe Wang, and Xiao Han
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musculoskeletal diseases ,Genetics ,Sanger sequencing ,Brachydactyly ,General Medicine ,Biology ,Gene mutation ,medicine.disease ,Short stature ,Osteochondrodysplasia ,Pseudoachondroplasia ,symbols.namesake ,medicine ,symbols ,medicine.symptom ,Achondroplasia ,Exome sequencing - Abstract
Pseudoachondroplasia (PSACH; MIM 177170) is a rare disease which was characterized by disproportionate short stature, deformity of the lower limbs, brachydactyly, loose joints, and ligamentous laxity. It is an autosomal dominant osteochondrodysplasia presented in childhood, and usually resolved with age, but osteoarthritis is progressive and severe. Genetic testing using the whole exome sequencing and Sanger sequencing was performed for the patients, a 30-year-old woman and her affected son, who is only 8 years old. A heterozygous mutationin exon 15 of COMP (c.1675G > A, p.Glu559Lys, NM 000095.2) was identified. The Polyphen-2 predicted that the mutation may damage the COMP protein function. This study suggested that the heterozygous mutations in COMP were responsible for PSACH and demonstrated the genotype-phenotype relationship between mutations in COMP and clinical characteristics of PSACH.
- Published
- 2019
172. A Case with XXXX Syndrome Who Was Incidentally Diagnosed during Examination for Suspected Post-Human Papillomavirus Vaccination Syndrome
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Tomoki Kosho, Shu-ichi Ikeda, Akiyo Hineno, Yoshiki Sekijima, and Hiroyuki Kato
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Pediatrics ,medicine.medical_specialty ,business.industry ,Brachydactyly ,General Medicine ,medicine.disease ,Hypoplasia ,body regions ,Vaccination ,Orthostatic vital signs ,Complex regional pain syndrome ,Cubitus varus ,Deformity ,medicine ,medicine.symptom ,Hypertelorism ,business - Abstract
A 19-year-old Japanese woman was referred to us with the complaints of arthralgia and meralgia following human papillomavirus (HPV) vaccination. She received HPV vaccination at the age of 15 years and three years later, she developed intermittent arthralgia, meralgia, and numbness in limbs. There were no orthostatic dysregulation symptoms. She had hypertelorism, and brachydactyly in both the hands, and revealed mild cubitus varus deformity with lateral instability. X-ray examination disclosed hypoplasia of the humeral capitellum and trochlea in elbow joints. G-banded chromosomes were shown to be composed of 48, XXXX. She was, therefore, diagnosed with XXXX syndrome, which explained the reason for her limb symptoms. Although some girls with HPV vaccination complain of various symptoms including limb pain and numbness, exact underlying cause of these symptoms needs to be ascertained carefully for reaching a final diagnosis.
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- 2019
173. Trichorhinophalangeal syndrome as a diagnostic and therapeutic challenge for paediatric endocrinologists
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Elżbieta Foryś-Dworniczak, Barbara Kalina-Faska, Olimpia Zajdel-Cwynar, Ewa Małecka-Tendera, and Pawel Matusik
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Male ,medicine.medical_specialty ,Adolescent ,Langer-Giedion Syndrome ,Genetic counseling ,Nose ,Short stature ,Growth hormone deficiency ,Fingers ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,030212 general & internal medicine ,Child ,business.industry ,Brachydactyly ,Genetic disorder ,General Medicine ,Phalanx ,medicine.disease ,Dermatology ,Repressor Proteins ,Phenotype ,medicine.anatomical_structure ,Child, Preschool ,030220 oncology & carcinogenesis ,Mutation ,Pectus carinatum ,Female ,Poland ,medicine.symptom ,Hair Diseases ,business - Abstract
Trichorhinophalangeal syndrome (TRPS) is rare genetic disorder with autosomal dominant inheritance. The TRPS1 gene is located on the long arm of the eighth chromosome (8q24.12). The phenotype is variable and presents a wide clinical spectrum. Most cases are characterised by thin, sparse scalp hair, distinctive facial dysmorphism, and various skeletal abnormalities, especially of the hands and feet. Characteristic facial features may include a "pear-shaped" nose, micrognathia, dental anomalies, prominent ears, elongated philtrum, and thin upper vermillion border. In most cases, affected individuals exhibit skeletal abnormalities including brachydactyly and clinodac-tyly, short metacarpals phalanges, short feet and metatarsals, and pectus carinatum and hip joint malformations. Additionally, patients may exhibit short stature. This report presents four cases of TRPS (three sporadic and one familial). Clinical presentation included typical facial features and vari-ous skeletal abnormalities. Some TRPS symptoms may mimic growth hormone deficiency and other endocrine disturbances. The aim of this article is to deliver TRPS symptomatology. The treatment of TRPS is symptomatic and supportive and requires the coordination of several specialists, including paediatricians, endocrinologists, orthopaedic surgeons, dermatologists, and medical rehabilitation and den-tal specialists. In some cases, recombinant growth hormone therapy may be necessary. Genetic counselling may be of benefit for affect-ed individuals and their families.Zespół włosowo-nosowo-paliczkowy jest rzadką chorobą uwarunkowaną genetycznie, w większości przypadków o autosomalnie do-minującym sposobie dziedziczenia. Gen TRPS1 jest zlokalizowany na długim ramieniu chromosomu 8 – 8q24(8q24.12). Fenotyp jest zróżnicowany i prezentuje szerokie spektrum objawów klinicznych. Do charakterystycznych cech fenotypowych zalicza się rzadkie włosy, dysmorfię twarzoczaszki oraz zaburzenia kostno-szkieletowe, zwłaszcza w obrębie dłoni i stóp. Do typowych cech dysmorficz-nych twarzy należą: "gruszkowaty nos", mikrognacja, anomalie zębowe, wydatne uszy, wydłużona rynienka nosowa i wąska czerwień wargowa. W większości przypadków występują anomalie szkieletowe, takie jak klino- i brachydaktylia, skrócenie paliczków śródręcza i śródstopia, kurza klatka piersiowa oraz malformacje stawu biodrowego. Część pacjentów ma niedobór wzrostu. Artykuł przygotowano na podstawie serii czterech przypadków klinicznych (trzy sporadyczne i jeden rodzinny). Wszystkie dzieci pre-zentowały typowe dla TRPS cechy dysmorfii twarzoczaszki oraz różne anomalie układu kostno-szkieletowego. Przyczyną skierowania na Oddział Endokrynologii Dziecięcej było podejrzenie różnych endokrynopatii, w tym niedobór hormonu wzrostu, zaburzeń gospo-darki wapniowo-fosforanowej czy zespołu Turnera. Celem pracy jest przybliżenie symptomatologii TRPS. Leczenie jest objawowe i wymaga skoordynowanej współpracy wielu specjalistów, w tym lekarza pediatry, endokrynologa, ortopedy, dermatologa, specjalisty rehabilitacji medycznej czy chirurga szczękowego. Część pacjentów z niskorosłością i niedoborem GH może wymagać terapii substytu-cyjnej rGH. Doradztwo genetyczne może przynieść korzyści dotkniętym TRPS osobom i ich rodzinom.
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- 2019
174. Hypoplastic nails and brachydactyly in a girl with moderate acne and hirsutism.
- Author
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Di Bartolomeo, Luca, Di Benedetto, Antonino, Giunta, Loretta, Guarneri, Fabrizio, and Vaccaro, Mario
- Subjects
- *
HYPERTRICHOSIS , *ACNE , *CHORIONIC villus sampling - Abstract
Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients. Keywords: brachydactyly; chondroectodermal dysplasia; Ellis Van Creveld Syndrome; growth hormone; polycystic ovary syndrome EN brachydactyly chondroectodermal dysplasia Ellis Van Creveld Syndrome growth hormone polycystic ovary syndrome 1322 1323 2 11/11/21 20210901 NES 210901 CASE PRESENTATION A 17-year-old girl presented to our dermatology department with moderate acne and mild hirsutism on her chin and arms. Diagnosis: Ellis-Van Creveld syndrome DISCUSSION Chondroectodermal dysplasia, also called Ellis-Van Creveld syndrome (EVCS) after the authors who first described it in 1940, is a rare congenital disorder with autosomal recessive inheritance. [Extracted from the article]
- Published
- 2021
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175. Albright Hereditary Osteodystrophy: A Case Report
- Author
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Deepa Hugar, Sangameshwar Sajjanshetty, Santosh Hugar, and Megha Kadani
- Subjects
albright hereditary osteodystrophy (aho) ,brachydactyly ,pseudohypoparathyroidism ,Medicine - Abstract
A dental practitioner with an eagle’s eye can diagnose many hidden disease through careful examination of the oral cavity. One such hereditary metabolic disorder is Albright hereditary osteodystrophy (AHO). Characteristic presentations in an individual affected by AHO were short stature, obesity and brachydactyly especially of 4th and 5th digits, which are the phenotypic features of genetic mutation. Pseudohypoparathyroidism (PHP) is characterized by inability of the body to respond appropriately to parathormone, mainly characterized by hypocalcemia, increased serum parathormone concentration, insensitivity to the biological activity of parathormone and hyperphosphatemia. AHO when seen in association with resistance to parathormone (PTH), it is called PHP. Here is, a case report of 32-year-old male patient with AHO with distinctive physical characteristics and oral manifestations.
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- 2014
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- View/download PDF
176. Prenatal and postnatal presentation of PRMT7 related syndrome: Expanding the phenotypic manifestations
- Author
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Naama Yosha-Orpaz, Tally Lerman-Sagie, Keren Yosovich, Miri Yanoov-Sharav, Dvora Kidron, Hila Gur, R. Birnbaum, Gustavo Malinger, and Dorit Lev
- Subjects
Male ,0301 basic medicine ,Protein-Arginine N-Methyltransferases ,Pathology ,medicine.medical_specialty ,Developmental Disabilities ,Intrauterine growth restriction ,Astrocytoma ,Arginine ,Compound heterozygosity ,Methylation ,Short stature ,03 medical and health sciences ,Frontal Bossing ,0302 clinical medicine ,Pregnancy ,Intellectual Disability ,Genetics ,medicine ,Humans ,Global developmental delay ,Genetics (clinical) ,Fetal Growth Retardation ,business.industry ,Brachydactyly ,Infant, Newborn ,Infant ,medicine.disease ,Hypotonia ,030104 developmental biology ,Mutation ,Muscle Hypotonia ,Orbital Neoplasms ,Female ,Sensorineural hearing loss ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor.
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- 2018
177. Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing
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Matthias Rath, Tim M. Strom, Ute Felbor, Johannes Trenkler, Peter M. Kroisel, and Stefanie Spiegler
- Subjects
0301 basic medicine ,Adult ,Heart Defects, Congenital ,Male ,Adolescent ,splice variant ,Arterial Occlusive Diseases ,Cell Cycle Proteins ,030105 genetics & heredity ,Biology ,Grange Syndrome ,Splice Variant ,Vascular Disease ,Whole Exome Sequencing ,Clinical Reports ,Bone and Bones ,whole exome sequencing ,03 medical and health sciences ,Exon ,symbols.namesake ,Exome Sequencing ,Genetics ,medicine ,Humans ,Protein Isoforms ,Genetic Predisposition to Disease ,Syndactyly ,Allele ,Child ,Genetics (clinical) ,Exome sequencing ,Sanger sequencing ,Clinical Report ,Brachydactyly ,Intron ,Grange syndrome ,vascular disease ,Middle Aged ,medicine.disease ,ddc ,Pedigree ,030104 developmental biology ,Hypertension ,symbols ,Female ,Transcription Factors - Abstract
Grange syndrome is an autosomal recessive condition characterized by arterial occlusions and hypertension. Syndactyly, brachydactyly, bone fragility, heart defects, and learning disabilities have also been reported. Loss-of-function variants in YY1AP1 have only recently been associated with Grange syndrome. YY1AP1 encodes for the transcription coactivator yin yang 1-associated protein 1 which regulates smooth muscle cell proliferation and differentiation. We here report on three siblings with steno-occlusive arterial disorder and syndactyly in two of them. Whole exome sequencing including near-splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing. Sanger sequencing demonstrated compound-heterozygosity in all affected siblings. RT-PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other. This is the first report of biallelic YY1AP1 variants in noncoding regions and just the second family with multiple affected siblings. Therefore, our report further delineates the phenotypic spectrum of Grange syndrome.
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- 2018
178. Clinical spectrum of male patients with OFD1 mutations
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Tomoko Horinouchi, Junya Shimizu, Takuzo Wada, China Nagano, Yuko Shima, Akemi Shono, Toshiyuki Ohta, Shogo Minamikawa, Tomohiko Yamamura, Koichi Nakanishi, Junya Fujimura, Ming Juan Ye, Yoshimi Nozu, Naoya Morisada, Koji Nagatani, Kazumoto Iijima, Nana Sakakibara, and Kandai Nozu
- Subjects
0301 basic medicine ,Adult ,Male ,Pediatrics ,medicine.medical_specialty ,030105 genetics & heredity ,03 medical and health sciences ,Genetics ,medicine ,Missense mutation ,Humans ,Global developmental delay ,Child ,male patients ,Genetics (clinical) ,Cystic kidney ,business.industry ,Brachydactyly ,Proteins ,Micropenis ,Orofaciodigital Syndromes ,medicine.disease ,Prognosis ,Pedigree ,Ciliopathy ,030104 developmental biology ,ciliopathy ,Child, Preschool ,Speech delay ,Mutation ,Female ,Oral-facial-digital syndrome ,medicine.symptom ,OFD1 ,business ,Kidney disease - Abstract
Oral-facial-digital syndrome type 1 (OFD1) is a ciliopathy characterized by oral, facial, and digital malformations that are often accompanied by polycystic lesion of the kidney and central nervous involvement. OFD1 shows an X-linked recessive inheritance caused by mutation in the OFD1 gene (Xp22.2). The disease is generally considered embryonic lethal for hemizygous males. However, males with OFD1 mutations were recently reported. Here, we report four additional Japanese male patients with OFD1 variants and describe the variable clinical manifestation and disease severity among the four patients. Patient 1 with pathogenic indels including a 19-bp deletion and 4-bp insertion (c.2600–18_2600delinsACCT) had end-stage renal disease (ESRD) with bilateral cystic kidneys and sensory hearing loss. He showed neither intellectual disability nor facial or digital dysmorphism. Patient 2 with a missense variant in exon 7 (c.539 A > T, p.Asp180Val) presented head circumference enlargement, brachydactyly, high-arched palate, micropenis, severe global developmental delay, and ESRD. Patient 3 had a single base substitution at the splice donor site of intron 16 (c.2260 + 2 T > G) causing a 513-bp deletion at the transcript level. The patient had chronic kidney disease and speech delay, but no oral, facial, or digital dysmorphism. His uncle (patient 4) carried the same OFD1 variant and showed ESRD with extra-renal malformations including obesity and micropenis, which was previously diagnosed as Bardet-Biedl syndrome. The OFD1 mutations were not lethal in these four male patients, likely because the three mutations were in-frame or missense. This report provided insights into the onset mechanism and phenotype-genotype association in patients with OFD1 mutations.
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- 2018
179. Bone morphogenetic protein receptor signal transduction in human disease
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Gomez‐Puerto, Maria Catalina, Iyengar, Prasanna Vasudevan, García de Vinuesa, Amaya, ten Dijke, Peter, and Sanchez‐Duffhues, Gonzalo
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Ligands ,bone ,hemorrhagic telangiectasia ,pulmonary arterial hypertension ,fibrodysplasia ossificans progressiva ,Neoplasms ,BMP ,cancer ,Animals ,Humans ,Musculoskeletal Diseases ,Phosphorylation ,TGF‐β ,Invited Review ,cardiovascular ,brachydactyly ,activin ,acromesomelic dysplasia ,Bone Morphogenetic Protein Receptors ,Smad Proteins, Receptor-Regulated ,hematopoiesis ,juvenile polyposis syndrome ,heterotopic ossification ,Cardiovascular Diseases ,Bone Morphogenetic Proteins ,Signal Transduction - Abstract
Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physiopathological processes. There are about 15 BMP family members, which signal via three transmembrane type II receptors and four transmembrane type I receptors. Mechanistically, BMP binding leads to phosphorylation of the type I receptor by the type II receptor. This activated heteromeric complex triggers intracellular signaling that is initiated by phosphorylation of receptor‐regulated SMAD1, 5, and 8 (also termed R‐SMADs). Activated R‐SMADs form heteromeric complexes with SMAD4, which engage in specific transcriptional responses. There is convergence along the signaling pathway and, besides the canonical SMAD pathway, BMP‐receptor activation can also induce non‐SMAD signaling. Each step in the pathway is fine‐tuned by positive and negative regulation and crosstalk with other signaling pathways. For example, ligand bioavailability for the receptor can be regulated by ligand‐binding proteins that sequester the ligand from interacting with receptors. Accessory co‐receptors, also known as BMP type III receptors, lack intrinsic enzymatic activity but enhance BMP signaling by presenting ligands to receptors. In this review, we discuss the role of BMP receptor signaling and how corruption of this pathway contributes to cardiovascular and musculoskeletal diseases and cancer. We describe pharmacological tools to interrogate the function of BMP receptor signaling in specific biological processes and focus on how these agents can be used as drugs to inhibit or activate the function of the receptor, thereby normalizing dysregulated BMP signaling. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
- Published
- 2018
180. Comprehensive analysis of clinical spectrum and genotype associations in Chinese and literature reported KBG syndrome
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Lin Yang, Feihong Luo, Qiuyue Li, Chengjun Sun, and Wei Lu
- Subjects
Sanger sequencing ,business.industry ,Brachydactyly ,Gene mutation ,Bioinformatics ,medicine.disease ,Short stature ,Frontal Bossing ,symbols.namesake ,Macrodontia (tooth) ,Pediatrics, Perinatology and Child Health ,Genotype ,medicine ,symbols ,Original Article ,medicine.symptom ,business ,Exome sequencing - Abstract
BACKGROUND: Patients with KBG Syndrome due to ANKRD11 mutations and 16q24.3 microdeletions including ANKRD11 were identified. Classical and most frequent phenotypes include various degrees of intelligence disability (ID), short stature (SS), delayed bone age, macrodontia, distinctive facial features and skeletal anomalies. The variable expressivity of KBG syndrome makes it challenging to establish genotype-phenotype correlations, which also affects further studies for this novel syndrome. We aim to report three unrelated patients with KBG syndrome caused by ANKRD11 gene pathological variants and to evaluate potential associations among ANKRD11 gene variant types, the 16q24.3 microdeletion, and the clinical spectrum of KBG syndrome. METHODS: The genetic etiology of three unreported KBG patients was identified by whole exome sequencing and confirmed via Sanger sequencing. Literature review was conducted to summarize the phenotype-genotype relationship based on three unreported Chinese cases and 186 reported cases. RESULTS: Two pathological variants (c.7407dupC, p.P2530Rfs*61; c.G3046A, p.D1016N) and one reported variant (c.6792dupC, p. P2271Pfs*8) were detected in our patients. Compared with the 16q24.3 microdeletion, patients harboring ANKRD11 gene mutations showed significantly higher frequency of malformations including macrodontia, long philtrum, abnormal eyebrows, widely spaced eyes, anteverted nares, eyelid ptosis, brachydactyly, brachycephaly (P
- Published
- 2021
181. Pseudohypoparathyroidism: application of the Italian common healthcare-pathway for a homogeneous clinical approach and a shared follow up
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Marco Pitea, Giuseppe Scirè, Danilo Fintini, Malgorzata Wasniewska, M. Caruso-Nicoletti, Luisa de Sanctis, Daniele Tessaris, Giovanna Weber, Domenico Corica, and Elisa Bonino
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Male ,0301 basic medicine ,Delayed puberty ,Pediatrics ,medicine.medical_specialty ,Consensus ,Pediatric endocrinology ,030209 endocrinology & metabolism ,Practice Patterns ,PHP ,Short stature ,03 medical and health sciences ,0302 clinical medicine ,iPPSDs ,Surveys and Questionnaires ,Health care ,medicine ,GNAS complex locus ,Humans ,Practice Patterns, Physicians' ,Child ,Pseudohypoparathyroidism ,GNAS locus ,Healthcare pathway ,Physicians' ,Data collection ,biology ,business.industry ,Research ,Brachydactyly ,lcsh:RJ1-570 ,lcsh:Pediatrics ,medicine.disease ,030104 developmental biology ,Italy ,Critical Pathways ,biology.protein ,Female ,medicine.symptom ,business ,Follow-Up Studies - Abstract
Background Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies. Methods Through a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice. Results In addition to the proposing Center, 4 Centers joined the study, thus obtaining a large collection of data on 48 PHP patients. Highest rates in the completion of data were obtained for diagnostic history, auxological measurements and subcutaneous ossifications evaluation. As expected, the availability of data for the other investigated fields was lower, coming from recent research studies. More information has been obtained on hormonal resistance classically involved in PHP (PTH, TSH, GHRH and GnRH) and on cognitive impairment, while a few data has been collected on bone mineral status, calcitonin levels and glucolipid metabolism. Conclusions The presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.
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- 2021
182. A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia
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Bing-Bing Guo, Lei Zeng, Jie-Yuan Jin, Zhuang-Zhuang Yuan, and Rong Xiang
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Male ,0301 basic medicine ,musculoskeletal diseases ,Adolescent ,Article Subject ,Mutation, Missense ,Cartilage Oligomeric Matrix Protein ,030105 genetics & heredity ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Achondroplasia ,03 medical and health sciences ,Pseudoachondroplasia ,Mutant protein ,Exome Sequencing ,medicine ,Humans ,Missense mutation ,Family ,Allele ,Alleles ,Exome sequencing ,Genetics ,Cartilage oligomeric matrix protein ,Mutation ,General Immunology and Microbiology ,biology ,Brachydactyly ,General Medicine ,medicine.disease ,musculoskeletal system ,030104 developmental biology ,Amino Acid Substitution ,biology.protein ,Medicine ,Female ,Research Article - Abstract
Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.
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- 2021
183. BMPR1B gene in brachydactyly type 2–A family with de novo R486W mutation and a disease phenotype
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Ewelina Użarowska-Gąska, Izabela Górzyńska, Mateusz Koziej, Anna Kubiak-Dydo, Katarzyna Serwan, Pawel Gaj, Marta Kotlarek-Łysakowska, Krystian Jazdzewski, Anna Wojcicka, Julia Staręga-Rosłan, Michał Świerniak, Monika Kolanowska, Adam Kot, Marcin Bednarek, Beata Kieć-Wilk, Artur Dobosz, and Marek Trybus
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0301 basic medicine ,Proband ,Adult ,Male ,Mutation, Missense ,human genetics ,030105 genetics & heredity ,Biology ,QH426-470 ,medicine.disease_cause ,DNA sequencing ,03 medical and health sciences ,medicine ,Genetics ,Humans ,Molecular Biology ,Gene ,Genetics (clinical) ,Bone Morphogenetic Protein Receptors, Type I ,BMPR1B ,Mutation ,Brachydactyly ,brachydactyly ,Original Articles ,medicine.disease ,Phenotype ,Human genetics ,Pedigree ,030104 developmental biology ,Child, Preschool ,Original Article ,mutation - Abstract
Background Brachydactylies are a group of inherited conditions, characterized mainly by the presence of shortened fingers and toes. Based on the patients’ phenotypes, brachydactylies have been subdivided into 10 subtypes. In this study, we have identified a family with two members affected by brachydactyly type A2 (BDA2). BDA2 is caused by mutations in three genes: BMPR1B, BMP2 or GDF5. So far only two studies have reported the BDA2 cases caused by mutations in the BMPR1B gene. Methods We employed next‐generation sequencing to identify mutations in culpable genes. Results and Conclusion In this paper, we report a case of BDA2 resulting from the presence of a heterozygous c.1456C>T, p.Arg486Trp variant in BMPR1B, which was previously associated with BDA2. The next generation sequencing analysis of the patients’ family revealed that the mutation occurred de novo in the proband and was transmitted to his 26‐month‐old son. Although the same variant was confirmed in both patients, their phenotypes were different with more severe manifestation of the disease in the adult., In this study, we have identified a family with two members affected by brachydactyly type A2 caused by BMPR1B mutation.
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- 2021
184. ERI1: A case report of an autosomal recessive syndrome associated with developmental delay and distal limb abnormalities.
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Hoxha V and Aliu E
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- Humans, Female, Syndrome, Exoribonucleases genetics, Limb Deformities, Congenital diagnosis, Limb Deformities, Congenital genetics, Syndactyly diagnosis, Syndactyly genetics, Brachydactyly, Intellectual Disability diagnosis, Intellectual Disability genetics
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ERI1 is an evolutionary conserved 3'-5' exonuclease with an important function in multiple RNA processing pathways. Although the molecular mechanisms in which ERI1 is involved have been studied extensively in model organisms, the pathology associated with ERI1 variants in humans has remained elusive because no case has been reported so far. Here, we present a case of a female patient with a homozygous nonsense variant in ERI1 gene. The patient exhibits mild intellectual disability, eyelid ptosis, and anomalies in her hands and feet (brachydactyly, clinodactyly, dysplastic/short nail of halluces, brachytelephalangy, short metacarpals, and toe syndactyly). This case report is the first of its kind and is invaluable for understanding ERI1 pathology in humans., (© 2022 Wiley Periodicals LLC.)
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- 2023
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185. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.
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Cali E, Suri M, Scala M, Ferla MP, Alavi S, Faqeih EA, Bijlsma EK, Wigby KM, Baralle D, Mehrjardi MYV, Schwab J, Platzer K, Steindl K, Hashem M, Jones M, Niyazov DM, Jacober J, Littlejohn RO, Weis D, Zadeh N, Rodan L, Goldenberg A, Lecoquierre F, Dutra-Clarke M, Horvath G, Young D, Orenstein N, Bawazeer S, Vulto-van Silfhout AT, Herenger Y, Dehghani M, Seyedhassani SM, Bahreini A, Nasab ME, Ercan-Sencicek AG, Firoozfar Z, Movahedinia M, Efthymiou S, Striano P, Karimiani EG, Salpietro V, Taylor JC, Redman M, Stegmann APA, Laner A, Abdel-Salam G, Li M, Bengala M, Müller AJ, Digilio MC, Rauch A, Gunel M, Titheradge H, Schweitzer DN, Kraus A, Valenzuela I, McLean SD, Phornphutkul C, Salih M, Begtrup A, Schnur RE, Torti E, Haack TB, Prada CE, Alkuraya FS, Houlden H, and Maroofian R
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- Humans, Obesity genetics, Phenotype, Protein-Arginine N-Methyltransferases genetics, Brachydactyly, Neurodevelopmental Disorders genetics, Intellectual Disability genetics, Dwarfism genetics, Musculoskeletal Abnormalities
- Abstract
Purpose: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder., Methods: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature., Results: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss., Conclusion: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities., Competing Interests: Conflict of Interest Megan Li is an employee of Invitae. Erin Torti, Amber Begtrup, and Rhonda E Schnur are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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186. Clinical Effects of Phosphodiesterase 3A Mutations in Inherited Hypertension With Brachydactyly.
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Toka, Okan, Tank, Jens, Schächterle, Carolin, Aydin, Atakan, Maass, Philipp G., Elitok, Saban, Bartels-Klein, Eireen, Hollfinger, Irene, Lindschau, Carsten, Mai, Knut, Boschmann, Michael, Rahn, Gabriele, Movsesian, Matthew A., Müller, Thomas, Doescher, Andrea, Gnoth, Simone, Mühl, Astrid, Toka, Hakan R., Wefeld-Neuenfeld, Yvette, and Utz, Wolfgang
- Abstract
Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A- mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormonerelated peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population. [ABSTRACT FROM AUTHOR]
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- 2015
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187. 2q37.3 Deletion Syndrome: Two Cases with Highly Distinctive Facial Phenotype, Discordant Association with Schizophrenic Psychosis, and Shared Deletion Breakpoint Region on 2q37.3.
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Mehraein, Yasmin, Pfob, Martina, Steinlein, Ortrud, aichinger, Eric, Eggert, Marlene, Bubendorff, Valerie, Mannhart, adelina, and Müller, Stefan
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PSEUDO-pseudohypoparathyroidism , *BRACHYDACTYLY , *PSYCHOSES , *SCHIZOPHRENIA , *PARATHYROID hormone , *PSEUDOHYPOPARATHYROIDISM , *METAPLASTIC ossification - Abstract
2q37.3 deletion syndrome belongs to the chromosomal 2q37 deletion spectrum which clinically resembles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachydactyly type E, intellectual disability, behavioral problems, and variable intellectual deficits. Different from classical AHO syndrome, patients with 2q37 deletion syndrome lack renal parathyroid hormone resistance (pseudohypoparathyroidism) and soft tissue ossification. So far, deletion mapping or molecular breakpoint analyses of 2q37 have been performed in only few patients. Here, we report on 2 patients with 2q37.3 deletion syndrome. In both patients the breakpoint of the 5.5-Mb terminal microdeletion could be narrowed down to the same ∼200-kb interval on 2q37.3 by BAC-FISH and/or array-CGH. Flanking low-copy repeats may indicate a classical microdeletion syndrome genesis for the 2q37.3 microdeletion subgroup. Clinical evaluation revealed intellectual deficits and type E brachydactyly typical for classical AHO syndrome together with distinctive facial dysmorphisms not present in the former. Furthermore, one patient presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an association between schizophrenia susceptibility and an unknown gene within the chromosomal region 2q37. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2015
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188. Mini External Fixator Assisted Metacarpal Lengthening With The Distraction Method.
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Kilinc, Bekir Eray, Kara, Adnan, Ertürer, Ramazan Erden, and Oc, Yunus
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BRACHYDACTYLY , *CONGENITAL disorders , *PHALANGES , *ELONGATION factors (Biochemistry) , *OSTEOTOMY , *DISEASES - Abstract
Phalangeal brachydactyly, which is caused by the abnormal development of the metacarpal, is characterized by shortness that can be seen in a single finger or in all fingers of the hands. Although brachydactyly is usually thought of as congenital, it can occur due to metabolic disorders or trauma. A twelve-year-old girl was admitted to our clinic with complaints of shortness in the fourth finger of the left hand. Osteotomy was applied with the drilling-osteotomy technique. The screws holding the upper and lower segments were adapted to the external fixator. Lengthening began one week after the osteotomy. The lengthening rate was organized as 0.25×2 mm/day. The amount of elongation was planned not to exceed 40% of the original bone length. Distraction was terminated after the planned elongation amount was reached, and the bone was allowed to heal. In patients under twenty years of age, the results from progressive distraction without bone grafting are close to perfect. Although the technique of successfully lengthening metacarpal fractures in children is simple, strict rules should not be ignored. Primarily, the external fixator and the distraction system should be sufficiently stable, lightweight, and should be appropriate for the size of a child's hand. [ABSTRACT FROM AUTHOR]
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- 2015
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189. Brachydactyly Type C patient with compound heterozygosity for p.Gly319Val and p.Ile358Thr variants in the GDF5 proregion: benign variants or mutations?
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Stange, Katja, Ott, Claus-Eric, Schmidt-von Kegler, Mareen, Gillesen-Kaesbach, Gabriele, Mundlos, Stefan, Dathe, Katarina, and Seemann, Petra
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- *
BRACHYDACTYLY , *HETEROZYGOSITY , *GENETIC mutation , *CONGENITAL disorders , *LUCIFERASES , *PATIENTS - Abstract
We report on a Brachydactyly Type C (BDC) patient with clinically inconspicuous parents. Molecular genetic analyses revealed compound heterozygosity for two GDF5 variants. The variant c.956G>T (p.Gly319Val) was inherited from her mother and has been reported in exome sequencing projects, whereas c.1073T>C (p.Ile358Thr) has never been reported so far. In silico, both variants were predicted to be 'disease-causing', but the fact that p.Ile358Thr was predicted by SIFT to be 'tolerated' raised our suspicion. Therefore, we performed in vitro assays. To our surprise, GDF5G319V showed pronounced loss of function in luciferase reporter assays and in vitro chondrogenesis, whereas GDF5I358T and GDF5WT had comparable biological activities. Western blot analyses revealed decreased protein levels after overexpression of GDF5G319V. In absence of linkage or de novo mutation, several scenarios could explain the underlying mechanism of the patient's phenotype. Owing to reduced activity of GDF5G319V in our functional assays, p.Gly319Val might be causative for BDC, but typically evoke an unrecognizably mild phenotype or even nonpenetrance. Another possibility is that our assays failed to pinpoint the disease-causing mechanism of the p.Ile358Thr allele. A final possibility is that compound heterozygosity for p.Ile358Thr and p.Gly319Val is more deleterious to GDF5 activity than either variant alone. Until all possible explanations can be rigorously tested experimentally, a precise recurrence risk counseling for the parents and the affected child is not possible. [ABSTRACT FROM AUTHOR]
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- 2015
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190. FGFR2 mutation in a patient without typical features of Pfeiffer syndrome – The emerging role of combined NGS and phenotype based strategies.
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Flöttmann, Ricarda, Knaus, Alexej, Zemojtel, Tomasz, Robinson, Peter N., Mundlos, Stefan, Horn, Denise, and Spielmann, Malte
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- *
FIBROBLAST growth factor receptors , *GENETIC mutation , *APERT syndrome , *NUCLEOTIDE sequencing , *CRANIOFACIAL abnormalities , *BRACHYDACTYLY , *CRANIOSYNOSTOSES , *PATIENTS - Abstract
Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 ( FGFR1 and FGFR2 ). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term “FGFR2 associated phenotypes” for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses. [ABSTRACT FROM AUTHOR]
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- 2015
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191. Two novel homozygous missense mutations in the GDF5 gene cause brachydactyly type C.
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Al‐Qattan, Mohammad M., Al‐Motairi, Muhammed I., and Al Balwi, Mohammed A.
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Mutations of the GDF5 gene cause a variable phenotype including brachydactyly type C. A review of the literature showed that it is caused either by heterozygous frameshift mutations within the prodomain or heterozygous missense/nonsense mutations within the active domain. Only a single patient with a homozygous mutation (c.517A > G, which predicts p. Met173Val) has been reported in this disorder. In this paper, we report two children with novel homozygous missense mutations in the GDF5 gene associated with brachydactyly type C: one mutation was within the region coding for the prodomain (c.608C > A, which predicts p.Thr203Asn) and the other was within the region coding for the active domain (c.1456 G > A, which predicts p.Val486Met). The genotype-phenotype correlations in the mutational spectrum of the GDF5 gene are discussed. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2015
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192. Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature.
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Wang, Jian, Wang, Zhigang, An, Yu, Wu, Chunxing, Xu, Yunlan, Fu, Qihua, Shen, Yiping, and Zhang, Qinghua
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PARATHYROID hormone-related protein gene , *GENETIC mutation , *BRACHYDACTYLY , *SHORT stature , *PHALANGES , *DYSOSTOSIS , *N-terminal residues - Abstract
Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone ( PTHLH ) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated. [ABSTRACT FROM AUTHOR]
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- 2015
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193. PDE3A mutations cause autosomal dominant hypertension with brachydactyly.
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Maass, Philipp G, Aydin, Atakan, Qadri, Fatimunnisa, Gong, Maolian, Bähring, Sylvia, Krawitz, Peter M, Parkhomchuk, Dmitri, Mundlos, Stefan, Hecht, Jochen, Kann, Martin, Schuster, Herbert, Chitayat, David, Bialer, Martin G, Wienker, Thomas F, Ott, Jürg, Jordan, Jens, Tank, Jens, Plessis, Ghislaine, Luft, Friedrich C, and Mai, Knut
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CARDIOVASCULAR diseases , *HYPERTENSION , *BRACHYDACTYLY , *REGULATION of blood pressure , *PHOSPHORYLATION - Abstract
Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension. [ABSTRACT FROM AUTHOR]
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- 2015
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194. Refinement of genotype-phenotype correlation in 18 patients carrying a 1q24q25 deletion.
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Chatron, Nicolas, Haddad, Véronique, Andrieux, Joris, Désir, Julie, Boute, Odile, Dieux, Anne, Baumann, Clarisse, Drunat, Séverine, Gérard, Marion, Bonnet, Céline, Leheup, Bruno, Till, Marianne, Rossi, Massimiliano, Flori, Elisabeth, Alembik, Yves, Stewart, Helen, McParland, Joanna, Bernardini, Laura, Castelluccio, Pia, and Roos, Laura
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Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2015
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195. Case Report of GNAS Epigenetic Defect Revealed by a Congenital Hypothyroidism.
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Romanet, Pauline, Osei, Lindsay, Netchine, Irène, Pertuit, Morgane, Enjalbert, Alain, Reynaud, Rachel, and Barlier, Anne
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BRACHYDACTYLY , *GENETIC disorder diagnosis , *CHROMOSOMES , *MEDICAL screening , *CONGENITAL hypothyroidism , *METHYLATION , *GENETIC mutation , *PARATHYROID hormone , *THYROTROPIN , *THYROXINE , *PHENOTYPES , *EPIGENOMICS , *SYMPTOMS , *GENETICS , *DIAGNOSIS - Abstract
Pseudohypoparathyroidism (PHP) is a group of disorders characterized by end-organ resistance to the parathyroid hormone (PTH). PHP type 1A includes multihormone resistance syndrome, Albright's hereditary osteodystrophy and obesity and is caused by mutations in GNAS exon 1 through 13. PHP type 1B (PHP1B), caused by epigenetic changes in the GNAS locus, was initially described as an isolated resistance to PTH. Epigenetic changes in GNAS have also been reported in patients who display mild Albright's hereditary osteodystrophy or mild thyroid-stimulating hormone (TSH) resistance without mutation of GNAS. Here we report a case of PHP caused by epigenetic changes in GNAS in a patient with congenital hypothyroidism. The patient was referred for a positive newborn screening for hypothyroidism (TSH 50 mIU/L). She exhibited severe clinical features of congenital hypothyroidism. The thyroid was in place, and etiologic explorations were negative. TSH was normalized under L-thyroxin, and the symptoms disappeared, except for a macroglossia. In childhood, PHP was suspected in addition to elevated PTH, obesity, brachydactyly and a rounded face. Sequencing, methylation analysis, and large deletion research were performed in GNAS. No genetic mutations were found. Methylation analysis revealed a broad epigenetic defect without deletion in GNAS consistent with sporadic PHP1B. The multilocus methylation analysis were negative. This finding expands the known onsets of PHP1B and emphasizes the need for a new PHP classification system. This case report has important consequences for the etiologic diagnosis of congenital hypothyroidism because it adds a new cause of the disease. [ABSTRACT FROM AUTHOR]
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- 2015
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196. Kabuki syndrome: clinical and molecular diagnosis in the first year of life.
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Dentici, Maria Lisa, Di Pede, Alessandra, Lepri, Francesca Romana, Gnazzo, Maria, Lombardi, Mary Haywood, Auriti, Cinzia, Petrocchi, Stefano, Pisaneschi, Elisa, Bellacchio, Emanuele, Capolino, Rossella, Braguglia, Annabella, Angioni, Adriano, Dotta, Andrea, Digilio, Maria Cristina, and Dallapiccola, Bruno
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KABUKI syndrome , *MOLECULAR genetics , *GENETIC counseling , *GENETIC mutation , *FACIAL abnormalities , *NUCLEOTIDE sequencing , *BRACHYDACTYLY , *DIAGNOSIS ,NEWBORN infant health - Abstract
Objective To review the clinical and molecular genetic characteristics of 16 patients presenting a suspected diagnosis of Kabuki syndrome (KS) in the first year of life, to evaluate the clinical handles leading to a prompt diagnosis of KS in newborns. Clinical diagnosis of KS can be challenging during the first year of life, as many diagnostic features become evident only in subsequent years. Methods All patients were clinically investigated by trained clinical geneticists. A literature review was performed using the Pubmed online database and diagnostic criteria suggested by DYSCERNE--Kabuki Syndrome Guidelines (2010) were used (a European Network of Centres of Expertise for Dysmorphology, funded by the European Commission Executive Agency for Health and Consumers (DG Sanco), Project 2006122). Molecular analysis of the known causative genes of KS, KMT2D/MLL2 and KDM6A, was performed through MiSeq-targeted sequencing platform. All mutations identified were validated by Sanger sequencing protocols. Results Mutations in KMT2D gene were identified in 10/16 (62%) of the patients, whereas none of the patients had KDM6A mutations. Facial dysmorphisms (94%), feeding difficulties (100%) and hypotonia (100%) suggested the clinical diagnosis of KS. No significative differences in terms of facial features were noticed between mutation positive and negative patients of the cohort. Brachydactyly, joint laxity and nail dysplasia were present in about 80% of the patients. Other congenital anomalies were most commonly present in the mutated group of patients, including leftsided cardiac abnormalities, skeletal, renal and anorectal malformations and hypertricosis. Conclusions We present an overview of patients with KS diagnosed during the first year of life. Early diagnosis is serviceable in terms of clinical management and for targeted genetic counselling. [ABSTRACT FROM AUTHOR]
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- 2015
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197. Morphological abnormalities in a population of Pleurodeles waltl (Caudata: Salamandridae) from southwestern Spain
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Ministerio de Economía y Competitividad (España), Zamora-Camacho, Francisco J., Ministerio de Economía y Competitividad (España), and Zamora-Camacho, Francisco J.
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Prevalence of morphological abnormalities usually is less than 5% in most amphibian populations (Ouellet et al. 1997, Vandenlangenberg et al. 2003, Mester et al. 2015). Morphology is closely related to whole-organism performance in amphibians (Zamora-Camacho 2018, Zamora- Camacho and Aragón 2019a), and thus, is under strong selection (Watkins 1996). Therefore, this low frequency likely reflects the negative effects of abnormalities on whole-organism performance (Zamora-Camacho and Aragón 2019b). However, amphibian populations are experiencing an alarming increase in morphological abnormality rates worldwide (Lanoo 2008, Johnson and Bowerman 2010, Laurentino et al. 2016). Amongst these, the most common are limb malformations, such as misshapen or fused limbs, and missing, or presence of extra limbs and toes (Harris et al. 2008, Johnson and Bowerman 2010, Reeves et al. 2013).
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- 2020
198. Síndrome tricorrinofalangiana - relato de um caso.
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de Oliveira Cardoso, Maria Teresinha, da Silva, Marina Sousa, Brito Pogue, Huri, Araújo Benicio, Rosenelle, and Pogue, Robert
- Abstract
Copyright of Revista de Medicina e Saúde de Brasília is the property of Revista de Medicina e Saude de Brasilia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2015
199. The first familial case of inherited 2q37.3 interstitial deletion with isolated skeletal abnormalities including brachydactyly type E and short stature.
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Jean‐Marçais, Nolwenn, Decamp, Matthieu, Gérard, Marion, Ribault, Virginie, Andrieux, Joris, Kottler, Marie‐Laure, and Plessis, Ghislaine
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Albright hereditary osteodystrophy (AHO)-like syndrome is also known as brachydactyly-mental retardation syndrome (BDMR; OMIM 60040). This disorder includes intellectual disability in all patients, skeletal abnormalities, including brachydactyly E (BDE) in approximately half, obesity, and facial dysmorphism. Patients with 2q37 microdeletion or HDAC4 mutation are defined as having an AHO-like phenotype with normal stimulatory G (Gs) function. HDAC4 is involved in neurological, cardiac, and skeletal function. This paper reports the first familial case of 2q37.3 interstitial deletion affecting two genes, HDAC4 and TWIST2. Patients presented with BDE and short stature without intellectual disability, showing that haploinsufficiency of the HDAC4 critical region may lead to a spectrum of phenotypes, ranging from isolated brachydactyly type E to BDMR. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2015
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200. Traumatic bone cyst of the mandible in Langer-Giedion syndrome: a case report.
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Nagori, Shakil Ahmed, Jose, Anson, Agarwal, Bhaskar, Bhatt, Krushna, Bhutia, Ongkila, and Roychoudhury, Ajoy
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BONE tumors , *CYSTS (Pathology) , *BONE abnormalities , *FACIAL abnormalities , *MEDICAL radiography , *MEDICAL screening , *BRACHYDACTYLY - Abstract
Introduction Langer-Giedion syndrome (trichorhinophalangeal syndrome type II) is an extremely rare disorder characterized by dysmorphic facial features, multiple exostoses, mental retardation and digit deformities. We report the first case of any maxillofacial pathology in such a syndromic patient. Case presentation A 22-year-old Indian woman with mild intellectual disability presented with malaligned teeth. Routine radiographic screening demonstrated a large multilocular lesion in her right mandible. She had peculiar features such as short stature, short limbs, brachydactyly, and dysmorphic facial characters, which prompted us to evaluate her further. After findings of multiple bony exostoses she was diagnosed with Langer-Giedion syndrome. On surgical exploration of her right mandibular lesion an empty cavity was found suggestive of traumatic bone cyst. The lesion healed completely after 1 year without loss of vitality of any teeth. Conclusions Although diagnosis and management of any maxillofacial pathology can be challenging in syndromic patients, our report suggests a possible correlation between traumatic bone cyst and Langer-Giedion syndrome. Clinicians should routinely screen these patients for any undetected maxillofacial pathology. In future cases of this syndrome, one should consider the possibility of traumatic bone cyst which may not require aggressive surgical management. [ABSTRACT FROM AUTHOR]
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- 2014
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