176 results on '"Marfanoid"'
Search Results
2. Marfan Syndrome
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Davis, Trent, Richardson, Randy Ray, and Richardson, MD, Randy Ray
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- 2017
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3. Truncating variants of the <italic>DLG4</italic> gene are responsible for intellectual disability with marfanoid features.
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Moutton, S., Bruel, A.‐L., Assoum, M., Chevarin, M., Sarrazin, E., Goizet, C., Guerrot, A.‐M., Charollais, A., Charles, P., Heron, D., Faudet, A., Houcinat, N., Vitobello, A., Tran‐Mau‐Them, F., Philippe, C., Duffourd, Y., Thauvin‐Robinet, C., and Faivre, L.
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INTELLECTUAL disabilities , *NUCLEOTIDE sequence , *SINGLE nucleotide polymorphisms , *NUCLEOTIDE sequencing , *CHROMOSOMES , *GENETICS - Abstract
Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH‐ID. After the search for variants in known disease‐causing genes and non‐disease‐causing genes with classical approaches, we searched for variants in non‐disease‐causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only
DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID.DLG4 encodes post‐synaptic density protein 95 (PSD‐95), a protein expressed in various tissues, including the brain. In neurons, PSD‐95 is located at the post‐synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD‐95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss‐of‐function. Patients exhibited mild‐to‐moderate ID, similar marfanoid features, including a long face, high‐arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role ofDLG4 as a novel post‐synaptic‐associated gene involved in syndromic ID associated with MH. [ABSTRACT FROM AUTHOR]- Published
- 2018
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4. A comprehensive review on MEN2B.
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Castinetti, Frederic, Moley, Jeffrey, Mulligan, Lois, and Waguespack, Steven G.
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MULTIPLE endocrine neoplasia , *PHEOCHROMOCYTOMA , *THYROIDECTOMY , *CANCER diagnosis , *PHYSICIANS - Abstract
MEN2B is a very rare autosomal dominant hereditary tumor syndrome associated with medullary thyroid carcinoma (MTC) in 100% cases, pheochromocytoma in 50% cases and multiple extra-endocrine features, many of which can be quite disabling. Only few data are available in the literature. The aim of this review is to try to give further insights into the natural history of the disease and to point out the missing evidence that would help clinicians optimize the management of such patients. MEN2B is mainly characterized by the early occurrence of MTC, which led the American Thyroid Association to recommend preventive thyroidectomy before the age of 1 year. However, as the majority of mutations are de novo, improved knowledge of the nonendocrine signs would help to lower the age of diagnosis and improve long-term outcomes. Future large-scale studies will be aimed at characterizing more in detail the main characteristics and outcomes of MEN2B. [ABSTRACT FROM AUTHOR]
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- 2018
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5. Multiple Endocrine Neoplasia Type 2
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Gagel, Robert F., Shefelbine, Sarah, Hayashi, Hironori, Cote, Gilbert, Runge, Marschall S., editor, and Patterson, Cam, editor
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- 2006
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6. Mutation in the ADAMTSL4 gene in a patient with a Marfan-like phenotype (Marfanoid appearance) without Ectopia lentis with uterine scar failure after cesarean section
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Chursin V.V. Chursin, Chuprynin V.D. Chuprynin, Smolnova T.Yu. Smolnova, and Trofimov D.Yu. Trofimov
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Pathology ,medicine.medical_specialty ,business.industry ,Mutation (genetic algorithm) ,Section (typography) ,Marfanoid ,Medicine ,business ,medicine.disease ,Ectopia lentis ,Gene ,Phenotype - Published
- 2020
7. To the point about etiopathogenetic causes of Marfan-like phenotype (marfanoid appearance) formation
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Trofimov D.Yu. Trofimov, Nechaeva G.I. Nechaeva, Smolnova T.Yu. Smolnova, and Chuprynin V.D. Chuprynin
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business.industry ,Marfanoid ,Medicine ,Anatomy ,business ,medicine.disease ,Phenotype - Published
- 2020
8. MEN2B syndrome – paediatric case report
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Gabriela Bis, Ewa Barg, Iga Zendran, Katarzyna Sondaj, and Wojciech Szlasa
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medicine.medical_specialty ,endocrine system diseases ,business.industry ,Marfanoid ,Medullary thyroid cancer ,General Medicine ,Disease ,medicine.disease ,Short stature ,Dermatology ,Thyroid carcinoma ,Pheochromocytoma ,medicine ,Family history ,medicine.symptom ,Multiple endocrine neoplasia ,business - Abstract
Multiple endocrine neoplasia 2B (MEN 2B) is a rare syndrome caused by mutation of the RET proto-oncogene. Early-onset medullary thyroid carcinoma (MTC), marfanoid habitus, and mucosal neuromas occur in most cases, and some patients develop pheochromocytoma in later life. We present a case of a 16-year-old girl diagnosed with MEN 2B syndrome with an atypical course of the disease. Our patient had no family history of MTC and presented short stature instead of marfanoid features. Rare ophthalmological manifestations also occurred. The example of this patient proves that rare endocrinological syndromes should be taken into consideration when diagnosing unclear symptoms, even if not all of the typical manifestations are present.
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- 2020
9. Cooperative Mechanism of ADAMTS/ ADAMTSL and Fibrillin-1 in the Marfan Syndrome and Acromelic Dysplasias
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Pauline Arnaud, Zakaria Mougin, Catherine Boileau, and Carine Le Goff
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musculoskeletal diseases ,Genetics ,Marfan syndrome ,congenital, hereditary, and neonatal diseases and abnormalities ,extracellular matrix ,ADAMTS ,Marfanoid ,Review ,QH426-470 ,Biology ,medicine.disease ,Phenotype ,Short stature ,Knockout mouse ,medicine ,Molecular Medicine ,medicine.symptom ,fibrillin-1 ,Gene ,Fibrillin ,Genetics (clinical) ,acromelic dysplasias - Abstract
The term “fibrillinopathies” gathers various diseases with a wide spectrum of clinical features and severity but all share mutations in the fibrillin genes. The first described fibrillinopathy, Marfan syndrome (MFS), is a multisystem disease with a unique combination of skeletal, thoracic aortic aneurysm (TAA) and ocular features. The numerous FBN1 mutations identified in MFS are located all along the gene, leading to the same pathogenic mechanism. The geleophysic/acromicric dysplasias (GD/AD), characterized by short stature, short extremities, and joint limitation are described as “the mirror image” of MFS. Previously, in GD/AD patients, we identified heterozygous FBN1 mutations all affecting TGFβ-binding protein-like domain 5 (TB5). ADAMTS10, ADAMTS17 and, ADAMTSL2 are also involved in the pathogenic mechanism of acromelic dysplasia. More recently, in TAA patients, we identified mutations in THSD4, encoding ADAMTSL6, a protein belonging to the ADAMTSL family suggesting that ADAMTSL proteins are also involved in the Marfanoid spectrum. Together with human genetic data and generated knockout mouse models targeting the involved genes, we provide herein an overview of the role of fibrillin-1 in opposite phenotypes. Finally, we will decipher the potential biological cooperation of ADAMTS-fibrillin-1 involved in these opposite phenotypes.
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- 2021
10. Atlantooccipital Assimilation and Basilar Invagination Treated Successfully in a Young Male With Marfanoid Features: A Stich in Time
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Sandeep Iratwar, Dhruv Talwar, Sunil Kumar, Sourya Acharya, SN Mahajan, and Akhilesh Annadatha
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basilar invagination ,business.industry ,craniocervical abnormalities ,General Engineering ,Marfanoid ,Assimilation (biology) ,Basilar invagination ,Anatomy ,medicine.disease ,atlantooccipital assimilation ,decompression surgery ,Internal Medicine ,medicine ,marfanoid features ,business ,Young male - Abstract
Marfan syndrome is a spectrum of disorders caused by a genetic defect involving connective tissue and is heritable by the autosomal dominant mode of inheritance. Atlantooccipital assimilation is a partial or complete fusion of the atlas and the occiput base congenitally. Although primarily asymptomatic, some patients with atlantooccipital assimilation may present with neurological issues, including myelopathy. Here, we are discussing a case of an 18-year-old male who presented with bilateral paraesthesia, tingling and neck pain which, upon investigations, turned out to be a case of atlantooccipital assimilation along with basilar invagination with spinal cord compression. The patient also had marfanoid features like tall stature, reduced upper to lower segment ratio, and increased arm span to height with positive wrist and thumb signs. As myelopathy had already developed, the patient was treated surgically rather than with medical management with a favorable outcome.
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- 2021
11. Children with multiple endocrine neoplasia type 2B: Not tall and marfanoid, but short with normal body proportions
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Annemarie A. Verrijn Stuart, Medard F M van den Broek, Gerlof D. Valk, and Hanneke M van Santen
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Adult ,medicine.medical_specialty ,Pediatrics ,Endocrinology, Diabetes and Metabolism ,growth ,Adrenal Gland Neoplasms ,Multiple Endocrine Neoplasia Type 2a ,Short stature ,Endocrinology ,Pediatric Endocrinology ,Internal medicine ,medicine ,Humans ,Thyroid Neoplasms ,marfanoid body habitus ,Multiple endocrine neoplasia ,Child ,Retrospective Studies ,Body proportions ,business.industry ,Marfanoid ,multiple endocrine neoplasia type 2B ,Tall Stature ,medicine.disease ,Carcinoma, Neuroendocrine ,short stature ,Arm span ,Original Article ,final height ,medicine.symptom ,ORIGINAL ARTICLES ,business ,Body mass index ,Multiple endocrine neoplasia type 2b - Abstract
Objective Multiple endocrine neoplasia 2B (MEN2B) is characterised by early-onset medullary thyroid carcinoma (MTC), pheochromocytoma and several nonendocrine manifestations. Unfortunately, MEN2B is often diagnosed late, after the development of clinically significant MTC. Marfanoid habitus is considered an important related feature, which may lead to the assumption that patients with MEN2B have tall stature. Here, we describe the longitudinal growth and body proportions of eight MEN2B patients during childhood. Design It is a retrospective case series. Methods Patients were under the care of a Dutch MEN expertise centre. Growth patterns were assessed and interpreted in relation to body mass index (BMI), age at diagnosis and at thyroidectomy, extensiveness of disease manifestations and parental height. Results Seven patients were short during childhood, of whom four showed growth below target height range (THR) and three at the lowest margin of THR. Only one patient grew well within THR. All patients who attained final height (n = 4) ended within THR, despite short stature during childhood. Arm span/height ratio was not increased and upper segment/lower segment ratio was not reduced in any patient. Short stature in childhood in this study did not seem to be associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, endocrine deficiencies or BMI. Conclusions This study shows that children with MEN2B may well present with short rather than tall stature. Thereafter, final height within THR was attained in those who already reached adulthood, but none had tall stature. Finally, body proportions were normal in all children and adults in this case series, not underlining a 'marfanoid' body habitus.
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- 2021
12. Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement
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Zoltán Szabolcs, Bálint Fekete, Tamás Radovits, Bence Ágg, Gabor Matyas, Béla Merkely, Kálmán Benke, Mária Judit Molnár, Miklós Pólos, András Bors, Dóra Csabán, Roland Stengl, and Hajnalka Andrikovics
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musculoskeletal diseases ,Aortic involvement ,0301 basic medicine ,Marfan syndrome ,Gene panel ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Genetic testing ,Genotype ,Fibrillin-1 ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Fibrillins ,Gastroenterology ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Pharmacology (medical) ,FBN1 ,Multiplex ligation-dependent probe amplification ,Aorta ,Risk stratification ,Genetics (clinical) ,Aortic dissection ,Sanger sequencing ,Loeys-Dietz Syndrome ,medicine.diagnostic_test ,business.industry ,Research ,lcsh:R ,Marfanoid ,General Medicine ,Cardiac surgery ,medicine.disease ,MLPA ,030104 developmental biology ,Mutation ,Next-generation sequencing ,symbols ,business ,Haploinsufficiency - Abstract
BackgroundMarfan syndrome (MFS) is a systemic connective tissue disorder with life-threatening manifestations affecting the ascending aorta. MFS is caused by dominant negative (DN) and haploinsufficient (HI) mutations of theFBN1gene. Our aim was to identify mutations of MFS patients with high detection rate and to investigate the use of a gene panel for patients with Marfanoid habitus. We also aimed to examine correlations between genotype and cardiovascular manifestations to predict “malignant” mutations.Methods136 individuals were enrolled. In the first phase, next-generation sequencing (NGS) and Sanger sequencing were performed for 57 patients to screen theFBN1gene, followed by multiplex ligation-dependent probe amplification (MLPA) in negative cases. For repeated negative results, NGS gene panel involving 9 genes was used. In the second phase, 79 patients were tested primarily with the same gene panel, negative samples were tested by MLPA.Results84 pathogenic mutations were detected, out of which 78 affectedFBN1, 6 non-FBN1mutations (2TGFB2, 1TGFBR2, 2TGFBR1, 1SMAD3) are associated with Loeys-Dietz syndrome (LDS). LDS patients had lower systemic score and they were younger, but their aortic involvement did not differ. MLPA detected 4 multi-exon deletions ofFBN1gene, which could not be identified by our first-step screening method. Aortic involvement (aortic dissection and/or dilation) did not differ significantly among HI and DN mutations (p = 0.061). Combined group of HI and DN mutations eliminating a disulphide-bonding cysteine (DN Cys) had significantly higher aortic involvement rate than DN mutations not eliminating a disulphide-bonding cysteine (DN non-Cys) (p p = 0.042 andp = 0.015, respectively).ConclusionsDue to the relevant number of mutations affecting genes other thanFBN1, preferred approach for testing individuals with Marfanoid habitus is using a gene panel rather than single-gene analysis, followed by MLPA for negative samples. DN Cys and HI mutations should be considered as risk factors for aortic involvement. Genetic testing for patients with Marfanoid features and a systemic score under 7 is recommended, as LDS patients may have lower scores, but they may have severe cardiovascular manifestations.
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- 2020
13. Lujan-Fryns Syndrome Phenotype with Autism-Like Behavior and Atypical Psychotic Symptoms: Case Report
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Ferit Şahin, Bahadır Geniş, and Behçet Coşar
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Gene mutation ,MED12 ,Marfan Syndrome ,Craniofacial Abnormalities ,Diagnosis, Differential ,Lujan–Fryns syndrome ,Medicine ,Humans ,Craniofacial ,Autistic Disorder ,Exome sequencing ,business.industry ,Marfanoid ,General Medicine ,medicine.disease ,Hypotonia ,Psychiatry and Mental health ,Psychotic Disorders ,Mental Retardation, X-Linked ,Autism ,medicine.symptom ,business - Abstract
Lujan-Fryns Syndrome (LFS) is defined as a set of symptoms including mild-moderate mental retardation, marfanoid appearance, hypotonia at birth, hypernasal speech, characteristic craniofacial appearance and normal testis size. The frequency of the syndrome is not known thus the information obtained is solely based on case reports. Hereby, we present a patient with LFS diagnosis. The 29-year old male patient had mental retardation, aggression, and persecutory delusions, characteristic craniofacial and marfanoid features. During his speech pronominal reversal was observed ('the hurt him, he is so upset' when talking abour himself). After examination and genetic analysis, fragile X, Klinefelter, Marfan and Down syndromes and homocystinuria were eliminated as causes of mental retardation. A preliminary diagnoses of LFS done. No mutation was detected in exon 22 of the MED12 gene; but. Whole Exome Sequencing (WES) is ongoing. The patient was started on risperidone (4 mg/day) for psychotic symptoms and carbamazepine (200 mg/day) for impulse control and as an antiepileptic. After a follow up of 8 months, impulse control, psychotic symptoms and aggression improved significantly. Since the specific gene mutation of LFS was not determined in our case, we solely had to depend on clinical evaluation and genetic analysis. Although it is not easy to fully define or classify these syndromes, we believe every reported case will be a step in overcoming these difficulties.
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- 2020
14. A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis
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Dominique Bonneau, Bruno Delobel, Catherine Boileau, Guillaume Jondeau, Christine Coubes, Jean-Luc Alessandri, Laurence Faivre, V. Carmignac, Sylvie Odent, Pauline Arnaud, Christel Thauvin-Robinet, Nadine Hanna, Caroline Racine, Carine Le Goff, Julien Thevenon, Laurent Gouya, Jill Clayton-Smith, Sophie Dupuis-Girod, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Université de Paris, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Grenoble, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Manchester [Manchester], Hôpital Lapeyronie [Montpellier] (CHU), Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Hospices Civils de Lyon (HCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Burgundy Regional Council through the Plan d'Actions Regional pour l'Innovation (PARI 2015), European Union through the PO FEDER-FSE Bourgogne 2014/2020 programs, Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
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Adult ,Male ,Proband ,Marfan syndrome ,Connective Tissue Disorder ,Adolescent ,[SDV]Life Sciences [q-bio] ,Context (language use) ,Biology ,Marfan Syndrome ,Craniosynostoses ,03 medical and health sciences ,Proto-Oncogene Proteins ,Intellectual disability ,Genetics ,medicine ,Humans ,Pathology, Molecular ,Craniofacial ,Child ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,030305 genetics & heredity ,Marfanoid ,Middle Aged ,medicine.disease ,Human genetics ,3. Good health ,DNA-Binding Proteins ,Arachnodactyly ,Child, Preschool ,Mutation ,Female - Abstract
International audience; SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.
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- 2020
15. Recessive marfanoid syndrome with herniation associated with a homozygous mutation in Fibulin-3
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Stephany El-Hayek, Sami Bizzari, Valérie Delague, Lara El-Bazzal, Pratibha Nair, Antoine Younan, Cybel Mehawej, Samantha Stora, André Mégarbané, delague, valérie, Centre for Arab Genomic Studies (CAGS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bellevue, Institut Jérôme Lejeune, Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
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Male ,Connective Tissue Disorder ,Hernia ,Hernia, Inguinal ,Telecanthus ,Arachnodactyly ,0302 clinical medicine ,Ptosis ,Missense mutation ,Diaphragmatic hernia ,Connective Tissue Diseases ,Genetics (clinical) ,Exome sequencing ,Extracellular Matrix Proteins ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Homozygote ,Marfanoid ,Syndrome ,General Medicine ,3. Good health ,VCPKMT ,Female ,medicine.symptom ,MYO3A ,medicine.medical_specialty ,Adolescent ,Mutation, Missense ,Genes, Recessive ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Young Adult ,03 medical and health sciences ,Genetics ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Humans ,Recessive ,Myosin Type III ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,030304 developmental biology ,Myosin Heavy Chains ,EFEMP1 ,business.industry ,Siblings ,Methyltransferases ,medicine.disease ,Dermatology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Marfanoid habitus ,Mutation ,business ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; We have previously reported on a consanguineous family where 2 siblings, a girl and a boy, presented with tall stature, long and triangular faces, prominent forehead, telecanthus, ptosis, everted lower eyelids, downslanting palpebral fissures, large ears, high arched palate, long arm span, arachnodactyly, advanced bone age, joint laxity, pectus excavatum, inguinal hernia, and myopia, suggestive of a new subtype of connective tissue disorder (Megarbane et al. AJMG, 2012; 158(A)5: 1185-1189). On clinical follow-up, both patients had multiple inguinal, crural, and abdominal herniae, intestinal occlusions, several huge diverticula throughout the gut and the bladder, and rectal prolapse. In addition, the girl had a mild hearing impairment, and the boy a left diaphragmatic hernia. Here we describe the molecular characterization of this disorder using Whole Exome Sequencing, revealing, in both siblings, a novel homozygous missense variant in the EFEMP1 gene, c.163T > C; p.(Cys55Arg) whose homozygous by descent, autosomal recessive transmission was confirmed through segregation analysis by Sanger sequencing. In addition, the girl exhibited a homozygous mutation in the MYO3A gene, c.1370_1371delGA; p.(Arg457Asnfs*25), associated with non-syndromic deafness. The siblings were also found to harbor a homozygous nonsense variant in the VCPKMT gene. We review the literature and discuss our updated clinical and molecular findings that suggest EFEMP1 to be the probable candidate gene implicated in this novel connective tissue disease.
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- 2020
16. Multiple Endocrine Neoplasia Type 2b (MEN2B) in a 9-Year-Old Female
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Rafik A. Abdelsayed, Christopher J. Capua, and Solon T. Kao
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medicine.medical_specialty ,Biopsy ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Multiple Endocrine Neoplasia Type 2b ,Diagnosis, Differential ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Biomarkers, Tumor ,medicine ,Humans ,Child ,Multiple endocrine neoplasia ,Neoplasm Staging ,medicine.diagnostic_test ,business.industry ,Thyroidectomy ,Marfanoid ,Neck dissection ,Hyperplasia ,medicine.disease ,Dermatology ,Otorhinolaryngology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Neck Dissection ,Female ,Surgery ,Oral Surgery ,medicine.symptom ,business ,Multiple endocrine neoplasia type 2b - Abstract
Multiple endocrine neoplasia (MEN) is an uncommon genetic syndrome transmitted as an autosomal dominant condition characterized by multiple tumors or hyperplasia of neuroendocrine tissues. MEN type 2b (MEN2B) often has clinical signs of marfanoid facial appearance and mucosal neuromas of the head. This report describes the diagnosis of MEN2B in a previously undiagnosed 9 year old who presented for biopsy of an oral lesion.
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- 2018
17. Psychopathology in a Patient with Lujan-Fryns Syndrome: A Case Report
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Arghavan Fariborzifar, Forouzan Elyasi, and Zahra Kashi
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0301 basic medicine ,Psychosis ,Pediatrics ,medicine.medical_specialty ,business.industry ,Neuropsychology ,Marfanoid ,Disease ,030105 genetics & heredity ,medicine.disease ,MED12 ,03 medical and health sciences ,0302 clinical medicine ,Lujan–Fryns syndrome ,medicine ,Craniofacial ,business ,030217 neurology & neurosurgery ,Psychopathology - Abstract
Introduction: Lujan-Fryns syndrome (LFS) is an X-linked disorder characterized by varying degrees of symptoms, including mental retardation, Marfanoid habitus, facial deformities, hyper nasal speech, and psychopathology and related behavioral abnormalities. The prevalence and full spectrum of LFS’s clinical symptoms remain unknown, but the disease is reportedly caused by at least one mutation in the mediator complex subunit 12 (MED12) gene. Case Presentation: This study reports the case of an 18-year-old male with moderate mental disability, a height exceeding the 97th percentile, marfanoid characteristics, obvious craniofacial appearance, and psychiatric and behavioral disorders. Adults with LFS are usually tall, but their heights still fall within the normal range. Conclusions: The higher-than-normal mean height of the young man and psychosis led us to conclude that patients with LFS may be those taller than the normal range. The results provided insights into clinical and therapeutic remedies and highlighted the need to carefully examine the psychological and neuropsychological symptoms of LFS.
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- 2019
18. Aortic Root Dilation: Do Patients With Marfan Syndrome Fare Worse Than Those With Marfanoid Features?
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Hartzell V. Schaff, David R. Deyle, Meghana R.K. Helder, Alberto Pochettino, Nandan S. Anavekar, Thomas A. Foley, and Heidi M. Connolly
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Adult ,Male ,musculoskeletal diseases ,0301 basic medicine ,Marfan syndrome ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,macromolecular substances ,030105 genetics & heredity ,Marfan Syndrome ,03 medical and health sciences ,Aneurysm ,Internal medicine ,Outcome Assessment, Health Care ,medicine ,Humans ,In patient ,Eye Abnormalities ,cardiovascular diseases ,skin and connective tissue diseases ,Aorta ,Retrospective Studies ,Aortic dissection ,Body surface area ,business.industry ,Marfanoid ,Retrospective cohort study ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Aortic Aneurysm ,Aortic Dissection ,Arachnodactyly ,030104 developmental biology ,Echocardiography ,Cardiology ,Female ,Tomography, X-Ray Computed ,business ,Vascular Surgical Procedures ,Aortic root dilation ,Dilatation, Pathologic - Abstract
Objective To discover whether patients with aortic root dilation and leptosomic features but without a diagnosis of Marfan syndrome (MFS) fare similarly to patients with MFS. Methods Of 124 patients with aortic root dilation identified from August 1, 1994, through October 31, 2012, 66 had MFS and 58 had leptosomic features but did not meet the Ghent criteria. Genetic testing was performed in 35% of patients (n=43). We compared z scores and aortic root diameters for patients who presented with aortic root dilation with and without an MFS diagnosis and with and without aortic root repair. Results No difference existed in initial aortic root diameters between groups ( P =.15); however, mean ± SD z scores for patients without MFS and with MFS were 3.1±2.3 vs 4.5±3.2 ( P =.005). Fourteen of 58 patients (24%) without MFS and 35 (53%) with MFS underwent aortic root operations ( P z scores remained similar at follow-up ( P =.20), as did 10-year survival: MFS, 100%; no MFS, 94.1% ( P =.98). No significant difference was found for mean ± SD root diameter (no MFS, 38.9±7.3 mm; MFS, 35±8.6 mm; P =.06) or z score (no MFS, 2.4±2.0; MFS, 2.1±2.0; P =.53) for patients who underwent surgery. Two patients in each group had aortic root dissections. Conclusion Similar rates of aortic dissection between the 2 groups warrant further study regarding patients with leptosomic features but no diagnosis of MFS. Aortic root dilation progressed similarly in patients who did not undergo surgery.
- Published
- 2018
19. The first patient with sporadic X-linked intellectual disability with de novo ZDHHC9 mutation identified by targeted next-generation sequencing
- Author
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Soyoung Shin, Ja Hyun Jang, Ji Yoon Han, Joonhong Park, In Goo Lee, and Myungshin Kim
- Subjects
Male ,0301 basic medicine ,Proband ,X-linked intellectual disability ,Mutation, Missense ,03 medical and health sciences ,symbols.namesake ,Intellectual disability ,Genetics ,medicine ,Humans ,Missense mutation ,Global developmental delay ,Genetics (clinical) ,Sanger sequencing ,business.industry ,Marfanoid ,General Medicine ,medicine.disease ,030104 developmental biology ,Child, Preschool ,Mutation (genetic algorithm) ,Mental Retardation, X-Linked ,symbols ,business ,Acyltransferases - Abstract
X-linked intellectual disability (XLID) is a genetically heterogeneous disorder involving more than 100 genes known to date. Here, we describe a Korean male infant with global developmental delay. He had neither facial dysmorphism nor skeletal abnormalities. Bayley scale of infant and toddler development third edition (Bayley-III) measured at age of 2 years revealed marked global developmental delays without Marfanoid habitus, structural brain abnormalities, or epilepsy. The patient's cognitive, motor, and language developmental ages were 8-9 months, 12 months, and 9 months, respectively. Targeted next-generation sequencing revealed a de novo mutation [NM_001008222.2(ZDHHC9): c.286C > T (p.(Arg96Trp))] in the affected patient. This mutation has been reported previously in a family XLID with Marfanoid features. Sanger sequencing analysis of the proband and his parents revealed that the missense mutation was present in the proband only (absent in his parents). This indicates that the mutation is de novo in origin. To the best of our knowledge, this is the first report describing sporadic XLID with de novo ZDHHC9 mutation identified by targeted next-generation sequencing.
- Published
- 2017
20. Early onset ataxia with Marfanoid features a new varient of Friedreich s ataxia
- Author
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Shubhakaran Khichar
- Subjects
medicine.medical_specialty ,Ataxia ,business.industry ,Marfanoid ,medicine.disease ,medicine.anatomical_structure ,medicine ,Neurosurgery ,medicine.symptom ,Medical science ,Early onset ataxia ,business ,Neuroscience ,Neuroanatomy - Abstract
A young male with ataxia since early childhood with Marfanoid features, normal intellect and no biochemical abnormality is reported. The syndrome has partial resemblance with previously described syndrome of arachnodactyle, cerebellar ataxia and other features, what has been named as "Bhaskar Syndrome". The documentation of such rare entities is worth for future research.
- Published
- 2021
21. Molybdenum cofactor deficiency: Identification of a patient with homozygote mutation in the MOCS3 gene
- Author
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Frans W. Verheijen, Monique Williams, Grazia M.S. Mancini, Marinus Duran, Marjon van Slegtenhorst, J. G. M. Huijmans, René de Coo, Johannis B.C. de Klerk, Rachel Schot, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Clinical Genetics, Pediatrics, and Neurology
- Subjects
Male ,0301 basic medicine ,Adolescent ,Mutation, Missense ,Gene Expression ,Biology ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,Sulfite ,Intellectual Disability ,Genetics ,medicine ,Humans ,Missense mutation ,Autistic Disorder ,Exome ,Molybdenum cofactor deficiency ,Genetics (clinical) ,Metal Metabolism, Inborn Errors ,Mutation ,Homozygote ,Marfanoid ,medicine.disease ,Nucleotidyltransferases ,Phenotype ,030104 developmental biology ,chemistry ,Sulfurtransferases ,Molybdenum cofactor - Abstract
We describe the clinical presentation and 17 years follow up of a boy, born to consanguineous parents and presenting with intellectual disability (ID), autism, "marfanoid" dysmorphic features, and moderate abnormalities of sulfite metabolism compatible with molybdenum cofactor deficiency, but normal sulfite oxidase activity in cultured skin fibroblasts. Genomic exome analysis revealed a homozygous MOCS3 missense mutation, leading to a p.Ala257Thr substitution in the highly conserved ubiquitin-like-domain of the protein. MOCS3 is the third protein, besides MOCS1 and MOCS2, involved in the biosynthesis of the molybdenum cofactor and has a dual ubiquitin-like function in tRNA thiolation. It is plausible that the phenotype results from deficiency of this dual function, not only from defective synthesis of molybdenum cofactor, which would explain similarities and differences from the MOCS1 and MOCS2-related disorders. This observation should encourage testing of additional ID patients with mild abnormalities of sulfite metabolism for MOCS3 mutations.
- Published
- 2017
22. Síndrome de Loeys-Dietz, una mutación en el gen TGFBR2, primer reporte en el suroccidente colombiano
- Author
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María A. Acosta-Aragón and Marco Fidel Sierra-Zúñiga
- Subjects
Aortic arch ,Pathology ,medicine.medical_specialty ,Male patient ,business.industry ,medicine.artery ,Aortic root ,medicine ,Marfanoid ,Clinical case ,business ,medicine.disease - Abstract
El síndrome de Loeys-Dietz es una rara enfermedad genética, autosómica dominante, con hábito marfanoide, que pertenece a un subconjunto de enfermedades del tejido conectivo con afectación esquelética, ocular y cardiovascular, principalmente. El desarrollo de aneurismas es característico en esta patología. El síndrome de Loeys-Dietz es causado por mutaciones en los genes TGFBR1, TGFBR2, TGFB2, TGFB3 Y SMAD3. En este manuscrito se describe el caso clínico de un paciente masculino, de 22 meses de vida, con una dilatación importante de la raíz aórtica y arco aórtico elongado cuya prueba molecular confirma el diagnóstico de síndrome de Loeys-Dietz, asociado a una mutación en el gen TGFBR2. Este corresponde al primer caso reportado en el suroccidente colombiano.
- Published
- 2017
23. REGULAR GENETIC COUNSELING AND DNA-DIAGNOSTICS OF MARFAN SYNDROME IN THE WORK OF FEDERAL SURGERY INSTITUTION
- Author
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V. A. Rumyantseva, Yu. A. Rogozhina, A. A. Bukaeva, D. V. Bazarov, E. R. Charchyan, and E. V. Zaklyazminskaya
- Subjects
Marfan syndrome ,musculoskeletal diseases ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,business.industry ,Genetic counseling ,Marfanoid ,Genetic variants ,spontaneous pneumothorax ,Surgery planning ,fbn1 ,medicine.disease ,Surgery ,infundibular chest deformity ,Internal medicine ,RC666-701 ,medicine ,Mutation screening ,Diseases of the circulatory (Cardiovascular) system ,Cardiology and Cardiovascular Medicine ,Surgical treatment ,business ,marfan syndrome ,aortic aneurysm ,dna-diagnostics - Abstract
Aim . To invent a complex approach to patients with “marfanoid phenotype” undergoing surgery, applying the DNA-diagnostics of the gene FBN1 and medical genetic counseling. Material and methods. In the group of 37 patients with suspected Marfan syndrome we conducted analysis of coding exones and attached enthrones of the gene FBN1 with highly performing sequencing on platform IonTorrent. Results. After mutation screening in the sequences of gene FBN1, in 25 patients we confirmed the Marfan syndrome, and four of genetic mutation carriers did not have complete Ghent criteria. All genetic variants were analyzed and were applied at the stage of surgery planning for maximum radical result of surgical treatment and for medical genetic counseling of the families. Conclusion . The analysis performed, of clinical presentation, surgery indications and spectrum of post-operation complications in Marfan syndrome patients.
- Published
- 2016
24. Ehlers-Danlos Syndrome Type IVB and Tracheobronchomegaly
- Author
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Yakup Cag, Ozge Karatas, Tamer Baysal, Saniye Girit, and Ebru Senol
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Tracheobronchomegaly ,medicine.medical_specialty ,Adolescent ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,03 medical and health sciences ,0302 clinical medicine ,Bronchoscopy ,Humans ,Medicine ,Kyphosis ,Kyphoscoliosis ,Syndrome type ,business.industry ,Marfanoid ,medicine.disease ,Dermatology ,Hypotonia ,Scoliosis ,030228 respiratory system ,Ehlers–Danlos syndrome ,Etiology ,Ehlers-Danlos Syndrome ,medicine.symptom ,Tomography, X-Ray Computed ,business ,Rare disease - Abstract
Tracheobronchomegaly (TBM) is a rare disease of unknown etiology, characterized by dilatation of the trachea and main bronchi. Despite its rarity, TBM has been reported to accompany several conditions, particularly Ehlers-Danlos syndrome. Herein, we report on a 15-year-old patient who was diagnosed with TBM on the basis of radiologic and endoscopic findings and with Ehlers-Danlos syndrome type IVB presenting with marfanoid features, severe kyphoscoliosis, increased skin elasticity, and ongoing hypotonia since the neonatal period.
- Published
- 2018
25. A Case of Charcot–Marie–Tooth Disease with Marfanoid Features
- Author
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TK Biswas and Arjun S Shenoi
- Subjects
Tooth disease ,medicine.medical_specialty ,business.industry ,Marfanoid ,Medicine ,business ,medicine.disease ,Dermatology - Published
- 2018
26. An Unusual Cause of Chronic Headache in an Adolescent Boy: A Case Report
- Author
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Ramamani Mariappan, Sniya Valsa Sudhakar, Sangeetha Yoganathan, Fouzia Nambiathayil Aboobacker, Vivek Mathew, Sunithi Mani, and Maya Thomas
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Adolescent ,Headache Disorders ,Dura mater ,Migraine Disorders ,Physical examination ,Fibrin Tissue Adhesive ,030105 genetics & heredity ,Migraine prophylaxis ,Marfan Syndrome ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Meninges ,medicine ,Humans ,Fibrin glue ,Epidural blood patch ,medicine.diagnostic_test ,Cerebrospinal Fluid Leak ,business.industry ,Marfanoid ,Brain ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Spine ,Surgery ,Diverticulum ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,Etiology ,Disease Progression ,Spinal Diseases ,Neurology (clinical) ,business ,Tomography, X-Ray Computed ,030217 neurology & neurosurgery ,Blood Patch, Epidural - Abstract
Spontaneous intracranial hypotension (SIH) is an under-diagnosed cause of headache in children and adolescents. SIH results from cerebrospinal fluid (CSF) leak due to breach in the dura mater and the etiology for dural breach is often diverse. We report an adolescent boy who presented with chronic episodic headache that later progressed to daily headache. There was a typical history of worsening of headache on upright position and relief of headache on lying down. He was treated with migraine prophylaxis in another hospital but there was no response. Marfanoid features and brisk deep tendon reflexes were observed on clinical examination. Brain magnetic resonance imaging (MRI) revealed sagging of the brain stem, pachymeningeal enhancement, and tonsillar herniation. MRI of spine myelogram confirmed multiple levels of CSF leak. He was initially managed with supportive measures and fluoroscopic-guided fibrin glue injection. Although child remained symptom-free for the next 6 months, he again developed headache. MRI and computed tomography spine myelogram revealed a meningeal diverticulum in the lumbar spine. He was managed with an autologous epidural blood patch and he has been well since then. In this report, we highlight the clinical and radiological pointers to the presence of SIH in children with recurrent headache.
- Published
- 2019
27. L-looped Transposition of the Great Arteries in a Patient with Marfanoid Habitus: First Reported Case in Literature
- Author
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Abdul Majid, Syed Hamza Bin Waqar, Farah Yasmin, Anosh Aslam Khan, and Osama Mohiuddin
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,marfanoid ,Cardiology ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Ductus arteriosus ,Internal medicine ,Internal Medicine ,Medicine ,dextrocardia ,Tetralogy of Fallot ,Dextrocardia ,pda ,business.industry ,General Engineering ,Marfanoid ,transposition of great arteries ,medicine.disease ,discordancy ,l-tga ,medicine.anatomical_structure ,Great vessels ,Great arteries ,Heart failure ,atrial-switch ,vsd ,business ,Pulmonary atresia ,030217 neurology & neurosurgery - Abstract
L-looped transposition of great arteries (L-TGA) is an extremely rare heart condition. It is associated with physiologically corrected transposition of great vessels, leading to the normal return of deoxygenated systemic venous blood to the heart and transport of oxygenated pulmonary venous blood to the main systemic circulation. Anatomic discordancy and anomalous coronary artery distribution predispose the right ventricle to excessive workload and eventual heart failure. This mandates anatomic correction or proper medical management of heart failure. Herein, we present a case of a 14-year-old girl who presented to our cardiology consults with a false impression of pre-made clinical diagnosis of tetralogy of Fallot. She had increasing dyspnea and cyanosis on presentation. Striking marfanoid habitus and unusual echocardiographic findings of tripartite geometry of heart with parallel and discordant positioning of atria, ventricles, and great arteries led us to cardiac computed tomography which confirmed the diagnosis of L-TGA. Our patient also had associated patent ductus arteriosus, dextrocardia, ventricular septal defect (VSD), and pulmonary atresia. Due to the complex nature of heart disease and unavailability of resources, she was treated with a comprehensive heart failure protocol and followed up clinically and radiologically at regular intervals and showed massive improvement. This is the first-ever documented case of L-TGA with complex shunting and marfanoid habitus.
- Published
- 2019
28. Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1
- Author
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Wesley You, Shengru Wang, Yanxue Zhao, Jiaqi Liu, Weisheng Chen, Yixin Chen, Gang Liu, Guixing Qiu, James R. Lupski, Sen Liu, Jianguo Zhang, Yuchen Niu, Xu Yang, Nan Wu, Xu Qiming, Lianlei Wang, Shuyang Zhang, Bintao Qiu, Tianshu Sun, Jiachen Lin, Xiaoxin Li, Sen Zhao, Zihui Yan, Zhihong Wu, Zhenlei Liu, Mao Lin, Zeynep Coban Akdemir, Chen Ding, Xiaofei Song, Ye Zhang, Pengfei Liu, Claudia Fonseca, Jennifer E. Posey, Chao Li, and Xinzhuang Yang
- Subjects
Genetics ,musculoskeletal diseases ,0303 health sciences ,Mutation ,congenital, hereditary, and neonatal diseases and abnormalities ,030305 genetics & heredity ,Nonsense-mediated decay ,Marfanoid ,Biology ,medicine.disease_cause ,medicine.disease ,Phenotype ,Null allele ,3. Good health ,Frameshift mutation ,03 medical and health sciences ,medicine ,Allele ,Gene ,030304 developmental biology - Abstract
The molecular and genetic mechanisms by which different single nucleotide variant (SNV) alleles in specific genes, or at the same genetic locus, bring about distinct disease phenotypes often remain unclear. Allelic truncating mutations of fibrillin-1(FBN1) cause either classical Marfan syndrome (MFS) or a more severe phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). A total of three Marfan syndrome/Marfanoid patients (2 singletons and 1 parent-offspring trio) were recruited. Targeted next-generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, patient clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. We investigated a small cohort, consisting of two classical MFS and one MPLS patient from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. We provide evidence that most nonsense and frameshift mutations lead to FBN1 null alleles due to mutant mRNA transcript degradation. In contrast, the more severe disease phenotype, MPLS, is caused by mutant mRNAs that are predicted to escape the nonsense mediated decay (NMD) surveillance pathway, making a mutant protein that exerts a dominant negative interference effect to FBN1 thus generating a gain-of-function (GoF) rather than a loss-of-function (LoF) allele as in MFS. Overall, we provide direct evidence that a dominant negative interaction of FBN1 potentially explains the distinct clinical phenotype in MPLS patients through genetic and functional analysis of the first Chinese patient with MPLS. Moreover, our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS patients.
- Published
- 2019
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29. Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection : further delineation of the phenotype
- Author
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Janneke Timmermans, Dimitra Micha, Sébastien Chénier, Thatjana Gardeitchik, Elyssa Cannaerts, Bart Loeys, Nils Peeters, Aline Verstraeten, Julie Richer, Paul Vermeersch, Gerarda van de Beek, Alessandra Maugeri, Carlo Marcelis, Dorien Schepers, Maaike Alaerts, Lut Van Laer, Marlies Kempers, Nathalie Meyten, Luc M. Beauchesne, Medical Genetics, Clinical sciences, Cardiology, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Amsterdam Movement Sciences - Restoration and Development, and ACS - Microcirculation
- Subjects
0301 basic medicine ,Marfan syndrome ,Pathology ,medicine.medical_specialty ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Connective tissue ,Dissection (medical) ,030105 genetics & heredity ,Loeys–Dietz syndrome ,SMAD2 ,03 medical and health sciences ,Genetics ,Medicine ,Missense mutation ,Genetics(clinical) ,Hypertelorism ,Genetics (clinical) ,Loeys-Dietz Syndrome ,business.industry ,Marfanoid ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,medicine.disease ,Connective tissue disease ,030104 developmental biology ,medicine.anatomical_structure ,connective tissue disease ,aortic aneurysm and dissection ,Human medicine ,medicine.symptom ,business ,arterial aneurysmal disease ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
BackgroundMissense variants inSMAD2, encoding a key transcriptional regulator of transforming growth factor beta signalling, were recently reported to cause arterial aneurysmal disease.ObjectivesThe aims of the study were to identify the genetic disease cause in families with aortic/arterial aneurysmal disease and to further defineSMAD2genotype–phenotype correlations.Methods and resultsUsing gene panel sequencing, we identified aSMAD2nonsense variant and fourSMAD2missense variants, all affecting highly conserved amino acids in the MH2 domain. The premature stop codon (c.612dup; p.(Asn205*)) was identified in a marfanoid patient with aortic root dilatation and in his affected father. A p.(Asn318Lys) missense variant was found in a Marfan syndrome (MFS)-like case who presented with aortic root aneurysm and in her affected daughter with marfanoid features and mild aortic dilatation. In a man clinically diagnosed with Loeys-Dietz syndrome (LDS) that presents with aortic root dilatation and marked tortuosity of the neck vessels, another missense variant, p.(Ser397Tyr), was identified. This variant was also found in his affected daughter with hypertelorism and arterial tortuosity, as well as his affected mother. The third missense variant, p.(Asn361Thr), was discovered in a man presenting with coronary artery dissection. Variant genotyping in three unaffected family members confirmed its absence. The last missense variant, p.(Ser467Leu), was identified in a man with significant cardiovascular and connective tissue involvement.ConclusionTaken together, our data suggest that heterozygous loss-of-functionSMAD2variants can cause a wide spectrum of autosomal dominant aortic and arterial aneurysmal disease, combined with connective tissue findings reminiscent of MFS and LDS.
- Published
- 2019
30. Friedreich’s ataxia associated with marfanoid features & alopecia areata-rare disease manifestations or chance association?
- Author
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Maulik Panchal, Banshilal Kumawat, Kaushik Rana, and Chandramohan Sharma
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Ataxia ,Cerebellar ataxia ,business.industry ,Marfanoid ,General Medicine ,Disease ,Alopecia areata ,Audiology ,medicine.disease ,Dermatology ,03 medical and health sciences ,Dysarthria ,0302 clinical medicine ,Disease Presentation ,030225 pediatrics ,medicine ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Rare disease - Abstract
Friedreich’s ataxia is the commonest cause of inherited ataxia and has an autosomal recessive mode of inheritance. The disease manifestations usually start appearing before the end of puberty and in most of the patients before 20 years of age. Classical disease presentation consists of slowly progressive sensory and cerebellar ataxia, absent deep tendon reflexes in lower limbs with subsequent development of dysarthria and other features. Apart from neurological features it has cardiac, skeletal and endocrine manifestations but its association with marfanoid features or alopecia areata has not been described in literature.
- Published
- 2017
31. A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings
- Author
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Moritz Hebebrand, Christian Thiel, Cornelia Kraus, Georgia Vasileiou, André Reis, Bernt Popp, Steffen Uebe, Arif B. Ekici, and Mandy Krumbiegel
- Subjects
Adult ,Male ,0301 basic medicine ,Heterozygote ,Connective Tissue Disorder ,Microarray ,media_common.quotation_subject ,Nonsense ,Genes, Recessive ,Carboxypeptidases ,Biology ,03 medical and health sciences ,Loss of Function Mutation ,Genetics ,medicine ,Humans ,Exome ,Genetic Predisposition to Disease ,Connective Tissue Diseases ,Gene ,Genetics (clinical) ,Exome sequencing ,media_common ,Siblings ,Homozygote ,Marfanoid ,High-Throughput Nucleotide Sequencing ,medicine.disease ,Pedigree ,Repressor Proteins ,Phenotype ,030104 developmental biology ,Codon, Nonsense ,Connective Tissue ,Ehlers–Danlos syndrome ,Ehlers-Danlos Syndrome ,Female ,CTD - Abstract
Biallelic variants in the AEBP1 gene cause a novel autosomal-recessive connective tissue disorder (CTD) reminiscent of Ehlers-Danlos Syndrome (EDS). The four previously reported individuals show considerable clinical variability. Unbiased high-throughput sequencing enables the rapid identification of additional cases for such rare entities. We identified the homozygous nonsense variant c.917dup, p.Tyr306* in AEBP1 using clinical exome sequencing in a female individual with previously unsolved CTD. Segregation testing confirmed homozygosity in the clinically affected brother and heterozygous carrier status in the healthy mother. Chromosomal microarray showed that the variant lies in a run of homozygosity, suggesting a common origin of this genomic segment. RT-PCR analysis in the mother revealed a monoallelic expression of the normal transcript supporting a nonsense-mediated mRNA decay and functional nullizygosity as disease mechanism. We describe two individuals from a fourth family with AEBP1-associated CTD. Our results further verify that autosomal-recessive inherited LOF variants in the AEBP1 gene cause clinical features of different EDS subtypes, but also of the marfanoid spectrum. As identification of further individuals is necessary to inform the clinical characterization, we stress the added value of exome sequencing for such rare diseases.
- Published
- 2018
32. Adult-onset dystonia with marfanoid features
- Author
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Scott A. Norris, Anja Pogarcic, Marwan Shinawi, Joel S. Perlmutter, and Matt Hicks
- Subjects
Marfan syndrome ,Dystonia ,Aortic dissection ,medicine.medical_specialty ,Weakness ,business.industry ,Anterior cruciate ligament ,Marfanoid ,Case ,medicine.disease ,Trunk ,Surgery ,medicine.anatomical_structure ,medicine ,Neurology (clinical) ,medicine.symptom ,business ,Ectopia lentis - Abstract
A 43-year-old Asian American man with asthma and hypertension was referred to the movement disorder center with a 5-year history of gradually progressive action-induced ankle inversion followed by trunk tightness and painful neck twisting with right shoulder elevation. He was born in the United States and successfully graduated college as a B/C student with mild learning difficulties. He always had disproportionally long limbs and digits and at age 12 developed ectopia lentis (medial-inferior displacement). Numerous ocular surgeries were performed including intraocular lens exchange with iris fixation. Marfan syndrome was previously diagnosed based on physical findings. There was no family history of Marfan syndrome, marfanoid features, or early death due to aortic dissection. FBN1 mutations were not tested and serial echocardiograms demonstrated no aortic root dilation. Diagnosis was later refined to ectopia lentis syndrome per updated guidelines. At age 29, he required allograft repair of an anterior cruciate ligament following minor impact. Four years later, while walking, he had musculoskeletal trauma in the left foot with subsequent toe extension weakness. Nerve conduction studies confirmed absence of compound motor action potentials in the left peroneal nerve lateral terminal branch. At age 38, he developed left foot pain with tendency for dorsiflexion and ankle inversion when walking. Severity gradually progressed and tightness extended to the trunk within 2 years. At age 41, he developed elevation of the right shoulder and several weeks later rightward rotation of the neck and back. Dystonia gradually progressed. Symptoms were exacerbated by stress but not relieved by alcohol or muscle relaxers.
- Published
- 2016
33. Severe Rheumatic Mitral Stenosis in Marfanoid Young Man Successfully Managed with Percutaneous Mitral Balloon Valvotomy
- Author
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Geetesh Manik, Mohammed Sadiq Azam, and Premchand Rajendra Kumar
- Subjects
medicine.medical_specialty ,Percutaneous ,business.industry ,Internal medicine ,Rheumatic mitral stenosis ,Cardiology ,Marfanoid ,Medicine ,business ,medicine.disease ,Mitral Balloon Valvotomy ,Surgery - Published
- 2016
34. Management of Aortic Dissection in Marfanoid young patient with Ebstein anomaly: Rare Case Report
- Author
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Naresh Sen
- Subjects
Aortic dissection ,medicine.medical_specialty ,EBSTEIN ANOMALY ,business.industry ,Rare case ,medicine ,Marfanoid ,medicine.disease ,business ,Surgery - Published
- 2016
35. Marfanoid–progeroid–lipodystrophy syndrome: a newly recognized fibrillinopathy
- Author
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Luitgard Graul-Neumann, Eberhard Passarge, and Peter N. Robinson
- Subjects
Adult ,Male ,musculoskeletal diseases ,0301 basic medicine ,Marfan syndrome ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Lipodystrophy ,Fibrillin-1 ,Medizin ,Biology ,Progeroid facial appearance ,Marfan Syndrome ,03 medical and health sciences ,Exon ,Progeria ,Viewpoint ,Molecular genetics ,Genotype ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,Marfanoid ,Genetic Pleiotropy ,medicine.disease ,Dermatology ,030104 developmental biology ,Child, Preschool ,Medical genetics ,Female - Abstract
We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in exon 64 of the FBN1 gene. A distinctive phenotype consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals. We suggest that this previously unknown genotype/phenotype relationship constitutes a new fibrillinopathy for which the name marfanoid–progeroid–lipodystrophy syndrome would be appropriate.
- Published
- 2016
36. Marfanoid appearance as a risk factor for atrial fibrillation in patients with osteoporosis
- Author
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I. A. Zolotovskaya and I. L. Davydkin
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Deoxypyridinoline ,Immunology ,Osteoporosis ,Connective tissue ,Urine ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,Rheumatology ,Internal medicine ,medicine ,Immunology and Allergy ,atrial fibrillation ,Pharmacology (medical) ,High concentration ,business.industry ,Marfanoid ,Atrial fibrillation ,medicine.disease ,osteoporosis ,Surgery ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,marfanoid appearance ,Medicine ,business ,Body mass index - Abstract
Objective: to investigate the relationship between some signs of hereditary connective tissue disorders (HCTDs) as a Marfanoid appearance (MA) and the risk of atrial fibrillation (AF) in female patients with osteoporosis (OP). Subjects and methods. In 2014–2015, the investigation enrolled consecutively 104 women aged 58 to 70 years (mean age, 64.7±3.8 years) who had a verified diagnosis of primary OP and a body mass index of ≤25.0 kg/m2. The entries in the outpatient medical records and in the automated information system «Polyclinic» were retrospectively analyzed to divide the patients into 2 groups according to the sign of the documented diagnosis of AF. A study group consisted of 53 women (mean age, 65.6±5.2 years) with AF and OP; a control group included 38 patients (mean age, 64.9±4.7 years) with OP without AF; a control group comprised 38 patients (mean age, 65.1±3.9 years) without OP and AF. Anthropometric and phenotypical parameters and cardiovascular visceral signs were analyzed; the levels of transforming growth factor-β1 (TGFβ1) and interleukin (IL) 1β and 6 in the serum and those of deoxypyridinoline (DPD) in the urine were measured. Results. Analysis of the phenotypical signs of HCTDs in the patients with OP has shown that those with OP and AF have external signs of dysmorphogenesis and meet the criteria of MA. Statistically significant correlations were found between the frequency of MA signs and the magnitude of all cardiac morphometric parameters and the visceral signs of HCTDs in the study group. The serum levels of IL-1β, IL-6, and TGFβ1 in these patients were significantly higher than in the comparison and control groups. There was also a high correlation between the signs of MA and the content of DPD in the study group. Conclusion. The patients with OP and AF was found to have a statistically significant correlation of the phenotypical signs of dysmorphogenesis with the frequency of visceral signs of HCTD, the morphofunctional parameters of the heart, and the high concentration of cytokines and DPD. It may be suggested that there exists a genetically determined mechanism of connective tissue dysembryogenesis in OP, which is associated with the risk of AF.
- Published
- 2016
37. AN ORPHAN PHENOTYPE OF CARDIOGENITAL LAMINOPATHY — MALOUF SYNDROME
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T. G. Vaykhanskaya, L. N. Sivitskaya, N. G. Danilenko, T. V. Kurushko, O. G. Nizhnikova, and O. G. Davydenko
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Progeria ,Pathology ,medicine.medical_specialty ,integumentary system ,business.industry ,Cardiomyopathy ,Marfanoid ,Dystrophy ,medicine.disease ,hypergonadotropic hypogonadism ,dilation cardiomyopathy ,LMNA ,Dysgenesis ,Dysplasia ,RC666-701 ,Turner syndrome ,medicine ,Diseases of the circulatory (Cardiovascular) system ,lamin gene mutations а/с ,Cardiology and Cardiovascular Medicine ,business - Abstract
Recent decades significantly increased the spectrum of monogenic diseases associated with mutations in the gene of lamin A/C (LMNA), that codes the proteins group performing important functions in the nucleus. This pathology presents with diverse systemic tissue involvement. Mutations of the gene LMNA are the cause of more than ten different inherited disorders — laminopathies. In clinical practice, there are cardial phenotypes common, i. e. dilation cardiomyopathy (DCMP), skeletal-muscular dystrophies (Emery-Dreifuss dystrophy, inherited and limbleveled) and more rare forms — lipodystrophies, progeroid phenotypes (acromandibular dysplasia, Hutchinson-Gilford progeria, atypical Werner syndrome), Malouf syndrome. Malouf syndrome, known nowadays as cardiogenital syndrome, is rare inborn pathology with DCMP phenotype and ovarial dysgenesis (females) or primary testicular failure (males), with cognitive delay and variety of skeletal abnormalities (usually facial dysmorphism and marfanoid signs). The arcticle presents a clinical case of female patient with primary amenorrhea, hypogonadism, DCMP, cognitive deficiency, hypodeveloped secondary gender signs, body mass deficiency, and facial dysmorphism. Radiation, viral parotitis, autoimmunity and Turner syndrome were ruled out. Signs if bone dysplasia typical for mandibular-acral dysplasia are absent. Relatives of the 1st line are normal. With sequencing method, we searched for mutations in the gene LMNA, but there were no mutations. Results make it to suggest that pathogenetic mechanisms of Malouf syndrome are not only of “lamin” nature but of other genetic causes too. The article also points on the key issues of diagnostics and treatment, presents differential criteria and clinical signs of an orphan disease.
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- 2016
38. Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features
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Cyril Goizet, Christophe Philippe, P. Charles, M. Assoum, N. Houcinat, Elisabeth Sarrazin, Martin Chevarin, Sébastien Moutton, Antonio Vitobello, A. Charollais, Ange-Line Bruel, Yannis Duffourd, Christel Thauvin-Robinet, F. Tran-Mau-Them, A. Faudet, Anne-Marie Guerrot, Laurence Faivre, Delphine Héron, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France], Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de chimie bactérienne (LCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,Proband ,Adult ,Male ,Adolescent ,marfanoid ,synaptopathy ,Biology ,Frameshift mutation ,Marfan Syndrome ,whole exome sequencing ,Cohort Studies ,03 medical and health sciences ,Young Adult ,Intellectual disability ,Genetics ,medicine ,Humans ,RNA, Messenger ,Child ,Gene ,PSD-95 ,Genetics (clinical) ,Exome sequencing ,Genetic Association Studies ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Genome, Human ,Marfanoid ,Middle Aged ,medicine.disease ,DLG4 ,030104 developmental biology ,intellectual disability ,Mutation ,Female ,Haploinsufficiency ,Disks Large Homolog 4 Protein - Abstract
IF 3.512; International audience; Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.
- Published
- 2018
39. Truncated C-terminus of fibrillin-1 induces Marfanoid-progeroid-lipodystrophy (MPL) syndrome in rabbit
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HaoBing Yao, Jichao Deng, Bing Yao, Zhanjun Li, Yuanyuan Xu, Liangxue Lai, Hongsheng Ouyang, Qiangbing Yang, Mao Chen, Daxin Pang, Tingting Sui, Lina Zhou, and Yuning Song
- Subjects
0301 basic medicine ,Marfan syndrome ,Pathology ,Lipodystrophy ,Fibrillin-1 ,Medicine (miscellaneous) ,lcsh:Medicine ,Rabbit ,Gene mutation ,Eye ,Marfan Syndrome ,Pathogenesis ,Exon ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,skin and connective tissue diseases ,Aorta ,Skin ,Marfanoid-progeroid-lipodystrophy (MPL) syndrome ,Marfanoid ,Ear ,Phenotype ,Growth and Development ,Rabbits ,Fibrillin ,Dilatation, Pathologic ,lcsh:RB1-214 ,musculoskeletal diseases ,Heterozygote ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Neuroscience (miscellaneous) ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,lcsh:Pathology ,Animals ,Amino Acid Sequence ,Resource Article ,Muscle, Skeletal ,CRISPR/Cas9 ,Base Sequence ,Wasting Syndrome ,lcsh:R ,Elastic Tissue ,medicine.disease ,Cartilage ,Glucose ,030104 developmental biology ,030217 neurology & neurosurgery - Abstract
Various clinical differences have been observed between patients with the FBN1 gene mutation and those with the classical Marfan phenotype. Although FBN1 knockout (KO) or dominant-negative mutant mice are widely used as an animal model for Marfan syndrome (MFS), these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy (MPL) syndrome, which is caused by a mutation in the C-terminus of fibrillin-1, the penultimate exon of the FBN1 gene. Here, we describe the generation of a rabbit MPL model with C-terminal truncation of fibrillin-1 using a CRISPR/Cas9 system. FBN1 heterozygous (FBN1 Het) rabbits faithfully recapitulated the phenotypes of MFS, including muscle wasting and impaired connective tissue, ocular syndrome and aortic dilation. Moreover, skin symptoms, lipodystrophy, growth retardation and dysglycemia were also seen in these FBN1 Het rabbits, and have not been reported in other animal models. In conclusion, this novel rabbit model mimics the histopathological changes and functional defects of MPL syndrome, and could become a valuable model for studies of pathogenesis and drug screening for MPL syndrome., Summary: A novel genetically engineered rabbit model of MPL syndrome, generated by CRISPR/Cas9-mediated mutation of FBN1, mimics the histopathological changes and functional defects of MPL syndrome seen in the clinic.
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- 2018
40. Patient with Marfan syndrome and a novel variant in FBN1 presenting with bilateral popliteal artery aneurysm
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Paldeep S. Atwal, Ahmed N. Mohammad, and Haytham Helmi
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0301 basic medicine ,Marfan syndrome ,musculoskeletal diseases ,medicine.medical_specialty ,Connective Tissue Disorder ,congenital, hereditary, and neonatal diseases and abnormalities ,lcsh:QH426-470 ,Connective tissue ,Case Report ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Aneurysm ,medicine.artery ,medicine ,Mitral valve prolapse ,cardiovascular diseases ,Thrombus ,business.industry ,Marfanoid ,General Medicine ,medicine.disease ,Popliteal artery ,lcsh:Genetics ,030104 developmental biology ,medicine.anatomical_structure ,cardiovascular system ,Radiology ,business - Abstract
We present a 43-year-old man with aortic root dilation, mitral valve prolapse, and marfanoid appearance, who presented with acute onset left leg pain. He underwent a Doppler ultrasound that revealed left popliteal artery aneurysm with thrombus. CT angiogram showed bilateral popliteal artery aneurysms. After repairing of his left popliteal artery aneurysm, he was sent for genetic evaluation. He was diagnosed with Marfan syndrome (MFS) based on the revised Ghent criteria and then underwent FBN1 sequencing and deletion/duplication analysis, which detected a novel pathogenic variant in gene FBN1, denoted by c.5872 T>A (p.Cys1958Ser). MFS is a connective tissue disorder with an autosomal dominant inheritance due to pathogenic variants in FBN1 that encodes Fibrillin-1, a major element of the extracellular matrix, and connective tissue throughout the body. MFS involves multiple systems, most commonly the cardiovascular, musculoskeletal, and visual systems. In our case we present a rare finding of bilateral popliteal artery aneurysms in a male patient with MFS.
- Published
- 2018
41. Shprintzen-Goldberg Syndrome: A Rare Disorder
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Attia Bari, Nadia Nawaz, Nadia Sadaqat, and Iqbal Bano
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Dolichocephaly ,business.industry ,Chromosomal analysis ,Marfanoid ,Shprintzen–Goldberg syndrome ,Aortic root dilatation ,General Medicine ,030105 genetics & heredity ,Gene mutation ,medicine.disease ,Craniosynostosis ,03 medical and health sciences ,Facial dysmorphism ,030104 developmental biology ,Medicine ,business - Abstract
The Shprintzen-Goldberg syndrome (SGS) or velo-cardio-facial syndrome (VCFS) is an extremely rare disorder of connective tissue with a characteristic facial dysmorphism, marfanoid features, craniosynostosis, dolichocephaly, cardiovascular anomalies and mild to moderate mental retardation. It may be a de novo gene mutation or inherited as an autosomal dominant disorder having SKI gene and Fibrillin-1 gene (FBN1) mutations, located on chromosome 15q21.1. We report a case of a 3-month, developmentally delayed male infant admitted to the hospital with syndromic facies, craniosynostosis, joint laxity and on echocardiography, aortic root dilatation. A probable diagnosis of SGS was made on the clinical grounds. We did not have the facility for genetic chromosomal analysis. He was discharged with family counselling and follow-up for future developmental rehabilitation.
- Published
- 2019
42. Skeletal overgrowth syndrome caused by overexpression of C-type natriuretic peptide in a girl with balanced chromosomal translocation, t(1;2)(q41;q37.1)
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Sun Kyung Oh, Jin Sun Choi, Jung Min Ko, Woong-Yang Park, Jun Seok Bae, Keiichi Ozono, Nayoung K.D. Kim, Choon Ki Lee, Tae Joon Cho, In Ho Choi, Ok Hwa Kim, Kohji Miura, and Hye Ran Lee
- Subjects
medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Balanced Chromosomal Translocation ,Chromosomal translocation ,Haploinsufficiency ,Biology ,Loeys–Dietz syndrome ,Translocation, Genetic ,Transforming Growth Factor beta2 ,Internal medicine ,Genetics ,medicine ,Natriuretic peptide ,Humans ,Genetics (clinical) ,Loeys-Dietz Syndrome ,Coxa valga ,Marfanoid ,Natriuretic Peptide, C-Type ,medicine.disease ,Phenotype ,Endocrinology ,Gene Expression Regulation ,Chromosomes, Human, Pair 1 ,Chromosomes, Human, Pair 2 ,Karyotyping ,Overgrowth syndrome ,Female ,medicine.symptom - Abstract
Chromosomal translocation of 2q37.1 just distal to the NPPC gene coding for C-type natriuretic peptide (CNP) and subsequent overproduction of CNP have been reported to cause a skeletal overgrowth syndrome. Loeys-Dietz syndrome (LDS) is one of marfanoid overgrowth syndromes, of which subtype IV is caused by haploinsufficiency of transforming growth factor beta 2 (TGFB2). We report on a girl with clinical phenotypes of overgrowth syndrome, including long and slim body habitus, macrodactyly of the big toe, scoliosis, ankle valgus deformity, coxa valga, slipped capital femoral epiphysis, and aortic root dilatation. Karyotyping revealed a balanced chromosomal translocation between 1q41 and 2q37.1, and the breakpoints could be mapped by targeted resequencing analysis. On chromosome 2q37.1, the translocation took place 200,365 bp downstream of NPPC, and serum level of the amino terminal of CNP was elevated. The contralateral site of translocation on chromosome 1q41 disrupted TGFB2 gene, presumed to cause its haploinsufficiency. This case supports the concept that NPPC is overexpressed because of the loss of a specific negative regulatory control in the normal chromosomal location, and demonstrates the effectiveness of targeted resequencing in the mapping of breakpoints.
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- 2015
43. Assessment of arterial stiffness in Marfan syndrome and marfanoid phenotype
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Lidia Woźniak-Mielczarek, Robert Sabiniewicz, Joanna Wdowczyk, Natalia Sobczyk, Paulina Kowalska, Paulina Furman, and Joanna Kulczycka
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Physics ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Internal medicine ,Internal Medicine ,medicine ,Cardiology ,Arterial stiffness ,Marfanoid ,Cardiology and Cardiovascular Medicine ,medicine.disease - Abstract
Wstep. Zespol Marfana jest uwarunkowaną genetycznie chorobą tkanki lącznej spowodowaną nieprawidlową syntezą bialka fibryliny. U chorych wystepuje wiele objawow klinicznych, zwlaszcza wiązanych z ukladem sercowo- naczyniowym, szkieletem i narządem wzroku. Fenotyp marfanoidalny definiuje sie jako wystepowanie niektorych cech zespolu Marfana, jednak niespelniających kryteriow rozpoznania tego zespolu. Nieprawidlowa synteza fibryliny powoduje zaburzenia struktury wlokien elastycznych. To prowadzi do zwiekszenia sztywności tetnic, ktorą mozna mierzyc za pomocą szybkości fali tetna (PWV, pulse wave velocity) i wskaźnika wzmocnienia (AI, augmentation index). Material i metody. Do badania wlączono 72 chorych z podejrzeniem zespolu Marfana. Na podstawie zmodyfikowanych kryteriow Ghenta chorych podzielono na dwie grupy: u 37 osob rozpoznano zespol Marfana, a u 35 stwierdzono fenotyp marfanoidalny. W badaniu uwzgledniono ponadto grupe kontrolną zlozoną z 36 zdrowych osob. Wartości PWV i AI uzyskano metodą tonometrii aplanacyjnej. Wyniki. Średnia wartośc PWV byla wyzsza u osob z zespolem Marfana niz w grupie z fenotypem marfanoidalnym i w grupie kontrolnej. Najnizszą wartośc PWV stwierdzono u osob z fenotypem marfanoidalnym. Najwyzszą średnią wartością AI cechowala sie grupa z zespolem Marfana, natomiast najnizszą — osoby z fenotypem marfanoidalnym. Wnioski. U chorych z zespolem Marfana wartości PWV i AI byly wyzsze niz u osob z fenotypem marfanoidalnym i zdrowych osob z grupy kontrolnej. Najnizsze wartości PWV i AI stwierdzono u osob z fenotypem marfanoidalnym. Chorzy ci są wyzsi niz pozostali, jednak w ich przypadku ściany tetnic mają zwykle prawidlową budowe, co zapewnia korzystne warunki hemodynamiczne.
- Published
- 2017
44. A comprehensive review on MEN2B
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Lois M. Mulligan, Frederic Castinetti, Jeffrey F. Moley, and Steven G. Waguespack
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Cancer Research ,Pediatrics ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Disease ,Multiple Endocrine Neoplasia Type 2b ,Thyroid carcinoma ,Pheochromocytoma ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Medicine ,Animals ,Humans ,Thyroid Neoplasms ,Germ-Line Mutation ,business.industry ,Thyroid ,Proto-Oncogene Proteins c-ret ,Marfanoid ,Thyroidectomy ,Medullary thyroid cancer ,medicine.disease ,3. Good health ,Carcinoma, Neuroendocrine ,Natural history ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,business - Abstract
MEN2B is a very rare autosomal dominant hereditary tumor syndrome associated with medullary thyroid carcinoma (MTC) in 100% cases, pheochromocytoma in 50% cases and multiple extra-endocrine features, many of which can be quite disabling. Only few data are available in the literature. The aim of this review is to try to give further insights into the natural history of the disease and to point out the missing evidence that would help clinicians optimize the management of such patients. MEN2B is mainly characterized by the early occurrence of MTC, which led the American Thyroid Association to recommend preventive thyroidectomy before the age of 1 year. However, as the majority of mutations are de novo, improved knowledge of the nonendocrine signs would help to lower the age of diagnosis and improve long-term outcomes. Future large-scale studies will be aimed at characterizing more in detail the main characteristics and outcomes of MEN2B.
- Published
- 2017
45. P160 Scoliosis in paediatric clinic
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S. Giacomini and Tiziana Greggi
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Dorsum ,medicine.medical_specialty ,Paediatric clinic ,medicine.diagnostic_test ,Genetic syndromes ,business.industry ,Marfanoid ,Physical examination ,Scoliosis ,medicine.disease ,Lumbar ,medicine ,Physical therapy ,Medical history ,business - Abstract
Early diagnosis of scoliosis is important for a good orthopaedic treatment. Paediatrician is fondamental in first scoliosis recognising and sending to the specialist. This protocol is a simple instrument for a quick, safe an uniform metod to recognise and treat scoliosis in paediatric clinic. Medical history Genetic syndrome with malformations………………………2 points Familiar history of scoliosis………………………………….……1 point Statural growth≥5 cm in last 6 months………………1 point Peri-puberty period ……………………………………………...…..1 point Physical examination Dorsal hump…………………………………………..3 points Lumbar rotation……………………………….3 points Cut triangles asymmetry……………………2 points Shoulder asymmetry……………………………….…1 point Pelvic asymmetry………………………………………1 point Hyperkyphosis…………………………………………..1 point Hyperlordosis…………………………………1 point Scapular winging………………………………………….1 point Marfanoid aspect……………………………….1 point Skin caffe-latte spots………………………………….1 point Treatment 0–2 points: clinical monitoring (4–6 months) 3–4 points: spine x-ray -scoliosis in x-ray: send to specialist - no scoliosis in x-ray: clinical monitoring (4–6 months) ≥5 points: send to specialist with spine x-ray
- Published
- 2017
46. Malar rash in classical homocystinuria
- Author
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Hansashree Padmanabha, Pratibha Singhi, Arushi Gahlot Saini, and Savita Verma Attri
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medicine.medical_specialty ,Vision Disorders ,Physical examination ,Homocystinuria ,Article ,Arachnodactyly ,Intellectual Disability ,medicine ,Humans ,Severe Myopia ,Child ,Subluxation ,medicine.diagnostic_test ,business.industry ,Marfanoid ,General Medicine ,medicine.disease ,Dermatology ,Hyperpigmentation ,eye diseases ,Cheek ,Female ,medicine.symptom ,Malar rash ,business ,Facial Dermatoses - Abstract
An 8-year-old girl with intellectual disability and severe myopia presented with subacute bilateral painless loss of vision. Anthropometric examination showed a weight of 26 kg (−0.1 Z score), height of 122.5 cm (between −1 and −2 Z score), arm span of 129 cm (6.5 cm longer than the height) and head circumference of 51 cm (between −1 and −2 Z score). Physical examination showed thin, hypopigmented hair with malar rash (figure 1A), acral hyperpigmentation, bilateral inferonasal subluxation of lens and bilateral optic atrophy. Other marfanoid features such as arachnodactyly, high-arched palate, joint hyperlaxity and cardiac anomalies were absent. A clinical diagnosis of classical homocystinuria was …
- Published
- 2017
47. A COMPREHENSIVE REVIEW ON MEN2B
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Castinetti, Frederic, Moley, Jeffrey, Mulligan, Lois, Waguespack, Steven, Castinetti, Frederic, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV] Life Sciences [q-bio] ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,[SDV]Life Sciences [q-bio] ,Marfanoid ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,ganglioneuromas ,RET ,medullary thyroid cancer ,pheochromocytoma ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2017
48. ADAMTSL4 assessment in ectopia lentis reveals a recurrent founder mutation in Polynesians
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Verity F. Oliver, Andrea L Vincent, Katherine van Bysterveldt, Rasha Al Taie, and Will Ikink
- Subjects
0301 basic medicine ,Proband ,Marfan syndrome ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA Mutational Analysis ,Procollagen-Proline Dioxygenase ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Ectopia Lentis ,Polynesia ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,ADAMTS Proteins ,Missense mutation ,Medicine ,Humans ,Prospective Studies ,Ectopia lentis ,Child ,Genetics (clinical) ,Genetics ,business.industry ,Haplotype ,Marfanoid ,medicine.disease ,Founder Effect ,Pedigree ,Ophthalmology ,030104 developmental biology ,Haplotypes ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,030221 ophthalmology & optometry ,Female ,business ,Founder effect ,New Zealand - Abstract
Background: To clinically characterize a cohort of patients with ectopia lentis (EL), or Marfanoid features in whom a definite genetic diagnosis of Marfan syndrome (MFS) had been excluded (atypical MFS), and to evaluate the contribution of mutations in ADAMTSL4 (OMIM * 610113), and P3H2 (LEPREL1; OMIM * 610341) to disease in this population. Materials and Methods: Subjects underwent comprehensive ophthalmic examination, including keratometry. Mutational analysis of ADAMTSL4 and P3H2 was undertaken using PCR, high resolution melting analysis, and sequencing. The frequency of c.2237G>A; p.(Arg746His) was determined in an unaffected Polynesian cohort. Haplotype analysis used tagged single nucleotide polymorphic markers. Results: Mutational analysis of ADAMTSL4 identified two pathogenic variants in ADAMTSL4 in 11/31 (35%) probands, consistent with the autosomal recessive EL phenotype. A recurrent, rare missense variant in ADAMTSL4, c.2237G>A; p.(Arg746His), was present in 10 probands –(8 homozygotes), predominantly of Polynesian descent, and all shared the same haplotype. p.(Arg746His) affects the Thrombospondin1 (TSP1) domain of the protein and is predicted to be pathogenic. No pathogenic variants in P3H2 were identified. Conclusion: A recurrent pathogenic ADAMTSL4 variant is a major cause of early onset autosomal recessive EL in a Cook Island Māori population and associated with a common haplotype, suggesting a founder effect. Children presenting under the age of 5 years, particularly of Cook Island or New Zealand Māori descent, with isolated ectopia lentis, should in the first instance be tested for this single variant.
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- 2017
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49. Autoimmune thyroiditis: Centennial jubilee of a social disease and its comorbidity
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O.M. Kaminova-Mudzhikova, L. R. Mikhailova, N.A. Nitsa, Leonid P. Churilov, A. N. Gvozdetsky, I.Yu. Serdyuk, Yu. I. Stroev, and I.V. Belyaeva
- Subjects
business.industry ,Marfanoid ,Connective tissue ,Disease ,medicine.disease ,Comorbidity ,Pathophysiology ,Pathology and Forensic Medicine ,Autoimmune thyroiditis ,Pathogenesis ,medicine.anatomical_structure ,Physiology (medical) ,Immunology ,Medicine ,Metabolic syndrome ,business - Abstract
The history of autoimmune thyroiditis (AIT) and its role in pathophysiology of transition from adolescent hypothalamic syndrome (obesity with rose striae) into early metabolic syndrome is reviewed. Marfanoid phenotype and chronic disequilibrium between local, autacoid-mediated and systemic, hormone-mediated regulation, typical for inherited connective tissue disorders, may promote this transition. Pathogenetic roles of hyperprolactinemia and cytokine misbalance are evaluated and discussed in its pathogenesis.
- Published
- 2014
50. Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3′ end of FBN1 gene
- Author
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Uwe Kornak, Bert Callewaert, Alain Verloes, Lionel Van Maldergem, Frederic Lebrun, Anne De Paepe, Jacques Lombet, Gérald Pierard, Sofie Symoens, François-Guillaume Debray, Adeline Jacquinet, Paul Coucke, Peter N. Robinson, and Christine Coremans
- Subjects
Marfan syndrome ,endocrine system ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pathology ,Adolescent ,Lipodystrophy ,Fibrillin-1 ,DNA Mutational Analysis ,Molecular Sequence Data ,Biology ,Fibrillins ,Progeroid syndromes ,Marfan Syndrome ,Frameshift mutation ,Diagnosis, Differential ,Exon ,Progeria ,Internal medicine ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,Genetics (clinical) ,Fetal Growth Retardation ,Base Sequence ,Microfilament Proteins ,Marfanoid ,General Medicine ,medicine.disease ,Phenotype ,Endocrinology ,Molecular Diagnostic Techniques ,Female ,Differential diagnosis ,Fibrillin - Abstract
We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann–Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid–progeroid–lipodystrophy syndrome) and frameshift mutations at the 3′ end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.
- Published
- 2014
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