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1. A Review on Cutaneous and Musculoskeletal Manifestations of CLOVES Syndrome

Author

Öztürk Durmaz E, Demircioğlu D, Yalınay Dikmen P, Alanay Y, Alanay A, Demirkesen C, Tokat F, and Karaarslan E

Subjects
cloves syndrome, pik3ca-related overgrowth spectrum, cutaneous manifestations, port wine stains, lympangiomas, lipomas, epidermal nevi., Dermatology, RL1-803
Abstract

Emel Öztürk Durmaz,1 Deniz Demircioğlu,1 Pınar Yalınay Dikmen,2 Yasemin Alanay,3 Ahmet Alanay,4 Cüyan Demirkesen,5 Fatma Tokat,5 Ercan Karaarslan6 1Department of Dermatology, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 2Department of Neurology, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 3Department of Pediatrics, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 4Department of Orthopedics, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 5Department of Pathology, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey; 6Department of Radiology, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, TurkeyCorrespondence: Emel Öztürk Durmaz, Acıbadem Maslak Hospital, Büyükdere Caddesi 40, Maslak, Istanbul, 34457, Turkey, Tel +90 (212) 304 46 19, Fax +90 (212) 286 15 66, Email emelerkek@yahoo.comAbstract: CLOVES syndrome is a novel sporadic mosaic segmental overgrowth syndrome, currently categorized under the canopy of PROS (PIK3CA-related overgrowth spectrum) disorders. All PROS disorders harbor heterozygous postzygotic activating somatic mutations involving the PIK3CA gene. As an upstream regulator of the PI3K/AKT/mTOR signal transduction pathway, activating mutations of PIK3CA gene commence in uncontrolled growth of cutaneous, vascular (capillaries, veins, and lymphatics), adipose, neural, and musculoskeletal tissues. The excessive growth is segmental, patchy, asymmetric, and confined to body parts affected by the mutation. The term ‘CLOVES’ is an acronym denoting congenital lipomatous overgrowth, vascular malformations, epidermal nevi and spinal (scoliosis) and/ or skeletal anomalies. The syndrome is characterized by an admixture of overgrown tissues, derived mainly from mesoderm and neuroectoderm. Among PROS disorders, CLOVES syndrome represents the extreme end of the spectrum with massive affection of almost the entire body. The syndrome might judiciously be treated with medications hampering with the PI3K/AKT/mTOR signal transduction pathway. This article aims at reviewing the cutaneous and musculoskeletal manifestations of CLOVES syndrome, as the paradigm for PROS disorders. CLOVES syndrome and other PROS disorders are still misdiagnosed, underdiagnosed, underreported, and undertreated by the dermatology community.Keywords: CLOVES syndrome, PIK3CA-related overgrowth spectrum, cutaneous manifestations, port wine stains, lymphangiomas, lipomas, epidermal nevi

Published
2022

2. A Multidisciplinary Approach to the Management of Individuals with Fragile X Syndrome

Author

Alanay, Y., Unal, F., and Turanli, G.

Abstract

Background: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Since the identification of the responsible gene ("FMR1") and its protein (FMRP), there has been enormous progress in both clinical and pathogenetic research on the neurobehavioural aspects of the condition. However, studies regarding other medical problems anticipated in individuals with FXS are limited. A multidisciplinary study evaluating various causes of morbidity in the same group has not been published yet. Methods: Twenty-four boys with FXS full mutation were recruited out of a larger group of 103 diagnosed in one centre over the past 10 years. Ear nose and throat, eye and cardiac examinations were performed in addition to routine cognitive, behavioural, neurological and speech and language assessments. Results: The average IQ score was 49.8 plus or minus 20 (range 25-90). There were four patients (18%) with IQ above 70. Using DSM-IV, attention deficit hyperactivity disorder was diagnosed in five boys out of 22 examined (23%), while 32% were diagnosed with pervasive developmental disorder. The seizure frequency was 17%. A psychiatric disorder was diagnosed in six out of eight boys with electroencephalogram abnormalities (75%). Minimal conductive hearing loss was found in five (522) patients. There was significant delay in both expressive and receptive language skills. Ocular findings were refractive errors (13%) and strabismus (4.4%). Mitral valve prolapsus (MVP) was observed in 322 (13.7%) patients and aortic annulus dilatation was present in 222 (9%) patients. Conclusions: Frequency of psychiatric diagnoses made with DSM-IV were in parallel to those reported in the literature. Comorbidity of seizures and psychiatric disorders was noteworthy. The percentage of high-functioning full mutation males supports the previous observations. Ear nose and throat and eye examination revealed remarkably lower prevalence of abnormal findings than reported. MVP was slightly less frequent compared with the single study in the literature. Age at the time of examination had an effect on the outcome of cardiac evaluation. These findings will guide us in future management of the group of patients followed in our institution. The protocol applied provides an applicable outline for multidisciplinary institutional settings dealing with individuals with FXS.

Published
2007
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3. Growth parameters in children with achondroplasia: A 7-year, prospective, multinational, observational study.

Author

Savarirayan, R, Irving, M, Harmatz, P, Delgado, B, Wilcox, WR, Philips, J, Owen, N, Bacino, CA, Tofts, L, Charrow, J, Polgreen, LE, Hoover-Fong, J, Arundel, P, Ginebreda, I, Saal, HM, Basel, D, Font, RU, Ozono, K, Bober, MB, Cormier-Daire, V, Le Quan Sang, K-H, Baujat, G, Alanay, Y, Rutsch, F, Hoernschemeyer, D, Mohnike, K, Mochizuki, H, Tajima, A, Kotani, Y, Weaver, DD, White, KK, Army, C, Larrimore, K, Gregg, K, Jeha, G, Milligan, C, Fisheleva, E, Huntsman-Labed, A, Day, J, Savarirayan, R, Irving, M, Harmatz, P, Delgado, B, Wilcox, WR, Philips, J, Owen, N, Bacino, CA, Tofts, L, Charrow, J, Polgreen, LE, Hoover-Fong, J, Arundel, P, Ginebreda, I, Saal, HM, Basel, D, Font, RU, Ozono, K, Bober, MB, Cormier-Daire, V, Le Quan Sang, K-H, Baujat, G, Alanay, Y, Rutsch, F, Hoernschemeyer, D, Mohnike, K, Mochizuki, H, Tajima, A, Kotani, Y, Weaver, DD, White, KK, Army, C, Larrimore, K, Gregg, K, Jeha, G, Milligan, C, Fisheleva, E, Huntsman-Labed, A, and Day, J

Abstract

PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.

Published
2022

5. Vosoritide treatment accelerates bone growth in children with achondroplasia

Author

Savarirayan, R, Irving, M, Hoover-Fong, J, Bacino, CA, Ozono, K, Mohnike, K, Cormier-Daire, V, Leiva-Gea, A, Alanay, Y, Andrews, M, Crews, C, Klafehn, C, Jayaram, K, Jeha, GS, Fisheleva, E, Huntsman-Labed, A, Day, J, Savarirayan, R, Irving, M, Hoover-Fong, J, Bacino, CA, Ozono, K, Mohnike, K, Cormier-Daire, V, Leiva-Gea, A, Alanay, Y, Andrews, M, Crews, C, Klafehn, C, Jayaram, K, Jeha, GS, Fisheleva, E, Huntsman-Labed, A, and Day, J

Abstract

Vosoritide is a drug developed for the treatment of achondroplasia and has demonstrated increases in the growth velocity of children with this condition. Achondroplasia is a skeletal dysplasia (a condition affecting children’s bones and joints meaning they do not grow in the typical way) and is also referred to as dwarfism. There are currently no approved treatments for achondroplasia, except for growth hormone in Japan. When a new drug is being developed, it is essential to conduct clinical studies after many other steps to assess how well the drug works and whether it has any side effects. These studies of new drugs are carried out before the drug is approved to treat, improve, or reduce physical problems of certain conditions. This summary reports the results from two clinical studies looking at vosoritide as a potential treatment for children with achondroplasia. Study A compared different doses of vosoritide to find out which is the safest and shows the best results with the fewest side effects. Study B looked at how well vosoritide works compared with a nonactive medicine (known as a placebo) and the side effects. In these studies, vosoritide increased bone growth velocity in children with achondroplasia. Children receiving the drug every day generally only had mild side effects. Serious health conplications were generally medical events seen in children with achondroplasia even if they do not take vosoritide. No children stopped taking vosoritide during the studies due to safety reasons. How well vosoritide works and the side effects in children over a longer period of time are still being studied. ClinicalTrials.gov NCT numbers: NCT02055157 and NCT03197766 .

Published
2021

19. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome (vol 21, pg 1295, 2019)

Author

Sluijs, P.J. van der, Jansen, S., Vergano, S.A., Adachi-Fukuda, M., Alanay, Y., AlKindy, A., Baban, A., Bayat, A., Beck-Wodl, S., Berry, K., Bijlsma, E.K., Bok, L.A., Brouwer, A.F.J., Burgt, I. van der, Campeau, P.M., Canham, N., Chrzanowska, K., Chu, Y.W.Y., Chung, B.H.Y., Dahan, K., Rademaeker, M. de, Destree, A., Dudding-Byth, T., Earl, R., Elcioglu, N., Elias, E.R., Fagerberg, C., Gardham, A., Gener, B., Gerkes, E.H., Grasshoff, U., Haeringen, A. van, Heitink, K.R., Herkert, J.C., Hollander, N.S. den, Horn, D., Hunt, D., Kant, S.G., Kato, M., Kayserili, H., Kersseboom, R., Kilic, E., Krajewska-Walasek, M., Lammers, K., Laulund, L.W., Lederer, D., Lees, M., Lopez-Gonzalez, V., Maas, S., Mancini, G.M.S., Marcelis, C., Martinez, F., Maystadt, I., McGuire, M., Mckee, S., Mehta, S., Metcalfe, K., Milunsky, J., Mizuno, S., Moeschler, J.B., Netzer, C., Ockeloen, C.W., Oehl-Jaschkowitz, B., Okamoto, N., Olminkhof, S.N.M., Orellana, C., Pasquier, L., Pottinger, C., Riehmer, V., Robertson, S.P., Roifman, M., Rooryck, C., Ropers, F.G., Rosello, M., Ruivenkamp, C.A.L., Sagiroglu, M.S., Sallevelt, S.C.E.H., Calvo, A.S., Simsek-Kiper, P.O., Soares, G., Solaeche, L., Sonmez, F.M., Splitt, M., Steenbeek, D., Stegmann, A.P.A., Stumpel, C.T.R.M., Tanabe, S., Uctepe, E., Utine, G.E., Veenstra-Knol, H.E., Venkateswaran, S., Vilain, C., Vincent-Delorme, C., Vulto-van Silfhout, A.T., Wheeler, P., Wilson, G.N., Wilson, L.C., Wollnik, B., Kosho, T., Wieczorek, D., Eichler, E., Pfundt, R., Vries, B.B.A. de, Clayton-Smith, J., Santen, G.W.E., and Acibadem University Dspace

Abstract

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

21. PORCN mutations in focal dermal hypoplasia: coping with lethality

Author

Bornholdt, D., Oeffner, F., Konig, A., Happle, R.H.G., Alanay, Y., Ascherman, J., Benke, P.J., Boente Mdel, C., Burgt, I. van der, Chassaing, N., Ellis, I., Francisco, C.R., Giovanna, P. Della, Hamel, B.C.J., Has, C., Heinelt, K., Janecke, A., Kastrup, W., Loeys, B.L., Lohrisch, I., Marcelis, C.L.M., Mehraein, Y., Nicolas, M.E., Pagliarini, D., Paradisi, M., Patrizi, A., Piccione, M., Piza-Katzer, H., Prager, B., Prescott, K., Strien, J., Utine, G.E., Zeller, M.S., Grzeschik, K.H., Bornholdt, D, Oeffner, F, König, A, Happle, R, Alanay, Y, Ascherman, J, Benke, PJ, Boente Mdel C, van der Burgt I, Chassaing, N, Ellis, I, Francisco, CR, Della Giovanna P, Hamel, B, Has, C, Heinelt, K, Janecke, A, Kastrup, W, Loeys, B, Lohrisch, I, Marcelis, C, Mehraein, Y, Nicolas, ME, Pagliarini, D, Paradisi, M, Patrizi, A, Piccione, M, Piza-Katzer, H, Prager, B, Prescott, K, Strien, J, Utine, GE, Zeller, MS, Grzeschik, KH, Bornholdt D, Oeffner F, König A, Happle R, Alanay Y, Ascherman J, Benke PJ, Chassaing N, Ellis I, Francisco CR, Hamel B, Has C, Heinelt K, Janecke A, Kastrup W, Loeys B, Lohrisch I, Marcelis C, Mehraein Y, Nicolas ME, Pagliarini D, Paradisi M, Patrizi A, Piccione M, Piza-Katzer H, Prager B, Prescott K, Strien J, Utine GE, Zeller MS, and Grzeschik KH

Subjects
Adult, Male, Adolescent, Base Sequence, DNA Mutational Analysis, Molecular Sequence Data, Infant, Newborn, Infant, Membrane Proteins, Genomic disorders and inherited multi-system disorders [IGMD 3], Focal Dermal Hypoplasia, Settore MED/38 - Pediatria Generale E Specialistica, Settore MED/03 - Genetica Medica, Child, Preschool, Mutation, Goltz syndrome, FDH, PORCN, WNT, skewed X-inactivation, postzygotic mosaic, Humans, Protein Isoforms, Female, Amino Acid Sequence, Child, Acyltransferases
Abstract

Contains fulltext : 81709.pdf (Publisher’s version ) (Closed access) The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hunermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Published
2009

24. Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases

Author

Ranza, E., Huber, C., Levin, N., Baujat, G., Bole-Feysot, C., Nitschke, P., Masson, C., Alanay, Y., Al-Gazali, L., Bitoun, P., Boute, O., Campeau, P., Coubes, C., McEntagart, M., Elcioglu, N., Faivre, Laurence, Gezdirici, A., Johnson, D., Mihci, E., Nur, B., Perrin, L., Quelin, C., Terhal, P., Tuysuz, B., Cormier-Daire, V., Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Universitaire de Genève, Plateforme de génomique [Necker], Structure Fédérative de Recherche Necker ( SFR Necker - UMS 3633 / US24 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Plate Forme Paris Descartes de Bioinformatique ( BIP-D ), Université Paris Descartes - Paris 5 ( UPD5 ), Department of Pediatrics, Istanbul Faculty of Medicine, Department of Pediatrics, Faculty of Medicine and Health Sciences, UAE University, Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Département de Pédiatrie [CHU Sainte -Justine Montréal], Université de Montréal-CHU Sainte Justine [Montréal], Service de Génétique Clinique, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Head of the Department of Medical Genetics, Department of Pediatric Genetics, Marmara University Medical Faculty, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), 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 ), 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 ), Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Service de génétique clinique [Debré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, CHU Pontchaillou [Rennes], Wilhelmina Childrens Hosp, Pediatrics, Istanbul University Cerrahpasa, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Sainte Justine [Montréal], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Sheffield Children's NHS Foundation Trust, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré

Subjects
Adult, Male, Spondyloepimetaphyseal Dysplasia, Adolescent, Joint Dislocations, Osteochondrodysplasias, Gene, Catel-Manzke Syndrome, Intellectual Disability, Exome Sequencing, Proteoglycan Synthesis, Humans, Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetic Association Studies, Larsen-Syndrome, Targeted Ngs, Joint Laxity, Infant, Newborn, Infant, Phenotypic Spectrum, Musculoskeletal Abnormalities, Radiography, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Chondrodysplasia, Genotype-Phenotype Correlation, Deficiency, Female, Proteoglycans, Desbuquois Dysplasia, Mutations
Abstract

IF 3.326; International audience; The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.

Published
2017
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25. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Author

van der Sluijs, E.P.J. (Eline (P.J.)), Jansen, S. (Sandra), Vergano, S.A. (Samantha A.), Adachi-Fukuda, M. (Miho), Alanay, Y. (Yasemin), AlKindy, A. (Adila), Baban, A. (Anwar), Bayat, A. (Allan), Beck-Wödl, S. (Stefanie), Berry, K. (Katherine), Bijlsma, E.K. (Emilia), Bok, L.A. (Levinus), Brouwer, A.F.J. (Alwin F. J.), Burgt, I. (Ineke) van der, Campeau, P.M. (Philippe M.), Canham, N. (Natalie), Chrzanowska, K.H. (Krystyna), Chu, Y.W.Y. (Yoyo W. Y.), Chung, B.H.Y. (Brain H. Y.), Dahan, K. (Karin), De Rademaeker, M. (Marjan), Destrée, A. (Anne), Dudding-Byth, T. (Tracy), Earl, R. (Rachel), Elcioglu, N.H. (Nursel), Elias, E.R. (Ellen R.), Fagerberg, C. (Christina), Gardham, A. (Alice), Gener, B. (Blanca), Gerkes, E.H. (Erica H), Grasshoff, U. (Ute), Haeringen, A. (Arie) van, Heitink, K.R. (Karin R.), Herkert, J.C. (Johanna), Hollander, N.S. (Nicolette) den, Horn, D. (Denise), Hunt, D. (David), Kant, S.G. (Sarina), Kato, M. (Mitsuhiro), Kayserili, H. (Hülya), Kersseboom, R. (Rogier), Kilic, E. (Esra), Krajewska-Walasek, M. (Malgorzata), Lammers, K. (Kylin), Laulund, L.W. (Lone W.), Lederer, D. (Damien), Lees, M.M. (Melissa), López-González, V. (V.), Maas, S.M. (Saskia), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Martinez, F. (Francisco), Maystadt, I. (Isabelle), McGuire, M. (Marianne), McKee, S., Mehta, S. (Sarju), Metcalfe, K. (Kay), Milunsky, J.M. (Jeff), Mizuno, S. (Seiji), Moeschler, J.B. (John B.), Netzer, C. (Christian), Ockeloen, C. (Charlotte), Oehl-Jaschkowitz, B. (Barbara), Okamoto, N. (Nobuhiko), Olminkhof, S.N.M. (Sharon N. M.), Orellana, C. (Carmen), Pasquier, L. (Laurent), Pottinger, C. (Caroline), Riehmer, V. (Vera), Robertson, S.P. (Stephen), Roifman, M. (Maian), Rooryck, C. (Caroline), Ropers, F.G. (Fabienne G.), Rosello, M. (Monica), Ruivenkamp, C.A. (Claudia), Sagiroglu, M.S. (Mahmut S.), Sallevelt, S.C.E.H. (Suzanne), Sanchis Calvo, A. (Amparo), Simsek-Kiper, P.O. (P.), Soares, G. (Gabriela), Solaeche, L. (Lucia), Mujgan Sonmez, F. (Fatma), Splitt, M. (M.), Steenbeek, D. (Duco), Stegmann, A.P.A. (Alexander P. A.), Stumpel, C. (Connie), Tanabe, S. (Saori), Uctepe, E. (Eyyup), Utine, G.E. (G. Eda), Veenstra-Knol, H.E. (Hermine), Venkateswaran, S. (Sunita), Vilain, C. (Catheline), Vincent-Delorme, C. (Catherine), Vulto-van Silfhout, A.T. (Anneke), Wheeler, P. (Patricia), Wilson, G.N. (Golder N.), Wilson, L.C. (Louise), Wollnik, B. (Bernd), Kosho, T. (Tomoki), Wieczorek, D. (Dagmar), Eichler, E.E. (Evan), Pfundt, R. (Rolph), Vries, B. (Boukje) de, Clayton-Smith, J., Santen, G.W.E. (Gijs), van der Sluijs, E.P.J. (Eline (P.J.)), Jansen, S. (Sandra), Vergano, S.A. (Samantha A.), Adachi-Fukuda, M. (Miho), Alanay, Y. (Yasemin), AlKindy, A. (Adila), Baban, A. (Anwar), Bayat, A. (Allan), Beck-Wödl, S. (Stefanie), Berry, K. (Katherine), Bijlsma, E.K. (Emilia), Bok, L.A. (Levinus), Brouwer, A.F.J. (Alwin F. J.), Burgt, I. (Ineke) van der, Campeau, P.M. (Philippe M.), Canham, N. (Natalie), Chrzanowska, K.H. (Krystyna), Chu, Y.W.Y. (Yoyo W. Y.), Chung, B.H.Y. (Brain H. Y.), Dahan, K. (Karin), De Rademaeker, M. (Marjan), Destrée, A. (Anne), Dudding-Byth, T. (Tracy), Earl, R. (Rachel), Elcioglu, N.H. (Nursel), Elias, E.R. (Ellen R.), Fagerberg, C. (Christina), Gardham, A. (Alice), Gener, B. (Blanca), Gerkes, E.H. (Erica H), Grasshoff, U. (Ute), Haeringen, A. (Arie) van, Heitink, K.R. (Karin R.), Herkert, J.C. (Johanna), Hollander, N.S. (Nicolette) den, Horn, D. (Denise), Hunt, D. (David), Kant, S.G. (Sarina), Kato, M. (Mitsuhiro), Kayserili, H. (Hülya), Kersseboom, R. (Rogier), Kilic, E. (Esra), Krajewska-Walasek, M. (Malgorzata), Lammers, K. (Kylin), Laulund, L.W. (Lone W.), Lederer, D. (Damien), Lees, M.M. (Melissa), López-González, V. (V.), Maas, S.M. (Saskia), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Martinez, F. (Francisco), Maystadt, I. (Isabelle), McGuire, M. (Marianne), McKee, S., Mehta, S. (Sarju), Metcalfe, K. (Kay), Milunsky, J.M. (Jeff), Mizuno, S. (Seiji), Moeschler, J.B. (John B.), Netzer, C. (Christian), Ockeloen, C. (Charlotte), Oehl-Jaschkowitz, B. (Barbara), Okamoto, N. (Nobuhiko), Olminkhof, S.N.M. (Sharon N. M.), Orellana, C. (Carmen), Pasquier, L. (Laurent), Pottinger, C. (Caroline), Riehmer, V. (Vera), Robertson, S.P. (Stephen), Roifman, M. (Maian), Rooryck, C. (Caroline), Ropers, F.G. (Fabienne G.), Rosello, M. (Monica), Ruivenkamp, C.A. (Claudia), Sagiroglu, M.S. (Mahmut S.), Sallevelt, S.C.E.H. (Suzanne), Sanchis Calvo, A. (Amparo), Simsek-Kiper, P.O. (P.), Soares, G. (Gabriela), Solaeche, L. (Lucia), Mujgan Sonmez, F. (Fatma), Splitt, M. (M.), Steenbeek, D. (Duco), Stegmann, A.P.A. (Alexander P. A.), Stumpel, C. (Connie), Tanabe, S. (Saori), Uctepe, E. (Eyyup), Utine, G.E. (G. Eda), Veenstra-Knol, H.E. (Hermine), Venkateswaran, S. (Sunita), Vilain, C. (Catheline), Vincent-Delorme, C. (Catherine), Vulto-van Silfhout, A.T. (Anneke), Wheeler, P. (Patricia), Wilson, G.N. (Golder N.), Wilson, L.C. (Louise), Wollnik, B. (Bernd), Kosho, T. (Tomoki), Wieczorek, D. (Dagmar), Eichler, E.E. (Evan), Pfundt, R. (Rolph), Vries, B. (Boukje) de, Clayton-Smith, J., and Santen, G.W.E. (Gijs)

Abstract

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

Published
2018
Full Text
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26. Targeted custom gene panel sequencing for cardiac ion channelopathies: Efficiently detects candidate pathogenic mutations in Long QT syndrome

Author

Temel, S.G., primary, Turkgenc, B., additional, Karadag, O., additional, Aykan, H.H., additional, Uysal, F., additional, Bastuhan, I.Y., additional, Sulu, A., additional, Atik, S.U., additional, Cinar, B., additional, Dedeoglu, R., additional, Gunay, E., additional, Ramoglu, M., additional, Cilsal, E., additional, Sahin, M., additional, Mese, T., additional, Ciftci, O., additional, Oztunc, F., additional, Karagoz, T., additional, Baspinar, O., additional, Bostan, O.M., additional, Akalin, F., additional, Kervanoglu, M., additional, Ayabakan, C., additional, Cil, E., additional, Alanay, Y., additional, Celiker, A., additional, Ozer, S.A., additional, and Yakicier, M.C., additional

Published
2017
Full Text
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27. Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa

Author

Damme, T. Van, Gardeitchik, T., Mohamed, M., Guerrero Castillo, S., Freisinger, P., Guillemyn, B., Kariminejad, A., Dalloyaux, D., Kraaij, S.A.W. van, Lefeber, D.J., Syx, D., Steyaert, W., Rycke, R. de, Hoischen, A., Kamsteeg, E.J., Wong, S.Y.W., Scherpenzeel, M. van, Jamali, P., Brandt, U., Nijtmans, L.G.J., Korenke, G.C., Chung, B.H., Mak, C.C., Hausser, I., Kornak, U., Fischer-Zirnsak, B., Strom, T.M., Meitinger, T., Alanay, Y., Utine, G.E., Leung, P.K., Ghaderi-Sohi, S., Coucke, P., Symoens, S., Paepe, A. De, Thiel, C., Haack, T.B., Malfait, F., Morava, E., Callewaert, B., Wevers, R.A., Damme, T. Van, Gardeitchik, T., Mohamed, M., Guerrero Castillo, S., Freisinger, P., Guillemyn, B., Kariminejad, A., Dalloyaux, D., Kraaij, S.A.W. van, Lefeber, D.J., Syx, D., Steyaert, W., Rycke, R. de, Hoischen, A., Kamsteeg, E.J., Wong, S.Y.W., Scherpenzeel, M. van, Jamali, P., Brandt, U., Nijtmans, L.G.J., Korenke, G.C., Chung, B.H., Mak, C.C., Hausser, I., Kornak, U., Fischer-Zirnsak, B., Strom, T.M., Meitinger, T., Alanay, Y., Utine, G.E., Leung, P.K., Ghaderi-Sohi, S., Coucke, P., Symoens, S., Paepe, A. De, Thiel, C., Haack, T.B., Malfait, F., Morava, E., Callewaert, B., and Wevers, R.A.

Abstract

Contains fulltext : 169752.pdf (publisher's version ) (Closed access), Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.

Published
2017

28. Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta

Author

Alanay, Y., Avaygan, H., Camacho, N., Utine, G.E., Boduroglu, K., Aktas, D., Krakow, D., Alanay, Y., Avaygan, H., Camacho, N., Utine, G.E., Boduroglu, K., Aktas, D., Krakow, D., and Yeditepe Üniversitesi

Subjects
macromolecular substances
Abstract

Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type I procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type I procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the ?1(I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type I procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI. © 2010 The American Society of Human Genetics. McGill University HD22657 National Institutes of Health: R01DE019567 Y.A. was supported by TUBITAK (2219 Program). D.K., D.H.C., D.R.E., and B.L. were supported by NIHCD HD22657. D.K. and D.H.C. were also supported by NIH R01DE019567. B.Z. and A.S.F. are supported by SKELNET and EuroGrow. E.C.D. is a Canada Research Chair. We also acknowledge the support of the Facility for Electron Microscopy Research (FEMR) at McGill University.

Published
2010

30. Cavernous malformation with Poland-Möbius syndrome: Case illustration

Author

Mut, M., Palaoglu, S., Alanay, Y., Ismailoglu, O., Tuncbilek, E., Mut, M., Palaoglu, S., Alanay, Y., Ismailoglu, O., Tuncbilek, E., and Yeditepe Üniversitesi

Subjects
Möbius syndrome, ComputingMilieux_MANAGEMENTOFCOMPUTINGANDINFORMATIONSYSTEMS, ComputingMethodologies_PATTERNRECOGNITION, Cavernous malformation, Poland syndrome, Pediatric neurosurgery, ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS, InformationSystems_MISCELLANEOUS
Abstract

[No abstract available]

Published
2007

32. Genotype-phenotype correlation of coffin-siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A

Author

Kosho, T., Okamoto, N., Imai, Y., Ohashi, H., van Eerde, A. M., Chrzanowska, K., Clayton-Smith, J., Kingston, H., Mari, F., Aggarwal, S., Mowat, D., Niikawa, N., Hiraki, Y., Matsumoto, N., Fukushima, Y., Josifova, D., Dean, J., Smigiel, R., Sakazume, S., Silengo, M., Tinschert, S., Kawame, H., Yano, S., Yamagata, T., van Bon, B. W. M., Vulto-van Silfhout, A. T., Ben-Omran, T., Bigoni, S., Alanay, Y., Miyake, N., Tsurusaki, Y., Santen, G. W. E., Wieczorek, D., Wollnik, B., and Hennekam, R. C. M.

Subjects
Male, Adolescent, Chromosomal Proteins, Non-Histone, BAF (mSWI/SNF) complex, Micrognathism, SMARCB1, Congenital, Young Adult, Intellectual disability (ID), SMARCA4, Intellectual Disability, Humans, Abnormalities, Multiple, Child, Preschool, Genetic Association Studies, DNA Helicases, Nuclear Proteins, Non-Histone, SMARCB1 Protein, Hand Deformities, Toes, ARID1A, SMARCE1, Coffin-siris syndrome, Child, Preschool, DNA-Binding Proteins, Face, Female, Hand Deformities, Congenital, Mutation, Neck, Transcription Factors, Chromosomal Proteins, Abnormalities, Multiple
Abstract

Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.

Published
2014

34. A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype

Author

Terhal, P.A., Nievelstein, R.J., Verver, E.J., Topsakal, V., Dommelen, P. van, Hoornaert, K., Merrer, M. Le, Zankl, A., Simon, M.E., Smithson, S.F., Marcelis, C.L.M., Kerr, B., Clayton-Smith, J., Kinning, E., Mansour, S., Elmslie, F., Goodwin, L., Hout, A.H. van der, Veenstra-Knol, H.E., Herkert, J.C., Lund, A.M., Hennekam, R.C., Mégarbané, A., Lees, M.M., Wilson, L.C., Male, A., Hurst, J., Alanay, Y., Annerén, G., Betz, R.C., Bongers, E.M.H.F., Cormier-Daire, V., Dieux, A., David, A., Elting, M.W., Ende, J. van den, Green, A., Hagen, J.M. van, Hertel, N.T., Holder-Espinasse, M., Hollander, N. den, Homfray, T., Hove, H.D., Price, S., Raas-Rothschild, A., Rohrbach, M., Schroeter, B., Suri, M., Thompson, E.M., Tobias, E.S., Toutain, A., Vreeburg, M., Wakeling, E., Knoers, N.V.A.M., Coucke, P., Mortier, G.R., Terhal, P.A., Nievelstein, R.J., Verver, E.J., Topsakal, V., Dommelen, P. van, Hoornaert, K., Merrer, M. Le, Zankl, A., Simon, M.E., Smithson, S.F., Marcelis, C.L.M., Kerr, B., Clayton-Smith, J., Kinning, E., Mansour, S., Elmslie, F., Goodwin, L., Hout, A.H. van der, Veenstra-Knol, H.E., Herkert, J.C., Lund, A.M., Hennekam, R.C., Mégarbané, A., Lees, M.M., Wilson, L.C., Male, A., Hurst, J., Alanay, Y., Annerén, G., Betz, R.C., Bongers, E.M.H.F., Cormier-Daire, V., Dieux, A., David, A., Elting, M.W., Ende, J. van den, Green, A., Hagen, J.M. van, Hertel, N.T., Holder-Espinasse, M., Hollander, N. den, Homfray, T., Hove, H.D., Price, S., Raas-Rothschild, A., Rohrbach, M., Schroeter, B., Suri, M., Thompson, E.M., Tobias, E.S., Toutain, A., Vreeburg, M., Wakeling, E., Knoers, N.V.A.M., Coucke, P., and Mortier, G.R.

Abstract

Item does not contain fulltext

Published
2015

36. Mutations in the interleukin receptorcause autosomal recessive Crouzon-like craniosynostosis

Author

Keupp, K, Li, Y, Vargel, I, Hoischen, A, Richardson, R, Neveling, K, Alanay, Y, Uz, E, Elcioğlu, N, Rachwalski, M, Kamaci, S, Tunçbilek, G, Akin, B, Grötzinger, J, Konas, E, Mavili, E, Müller-Newen, G, Collmann, H, Roscioli, T, Buckley, MF, Yigit, G, Gilissen, C, Kress, W, Veltman, J, Hammerschmidt, M, Akarsu, NA, Wollnik, B, Keupp, K, Li, Y, Vargel, I, Hoischen, A, Richardson, R, Neveling, K, Alanay, Y, Uz, E, Elcioğlu, N, Rachwalski, M, Kamaci, S, Tunçbilek, G, Akin, B, Grötzinger, J, Konas, E, Mavili, E, Müller-Newen, G, Collmann, H, Roscioli, T, Buckley, MF, Yigit, G, Gilissen, C, Kress, W, Veltman, J, Hammerschmidt, M, Akarsu, NA, and Wollnik, B

Published
2013

37. Further characterization of ATP6V0A2-related autosomal recessive cutis laxa

Author

Fischer, B., Dimopoulou, A., Egerer, J., Gardeitchik, T., Kidd, A., Jost, D., Kayserili, H., Alanay, Y., Tantcheva-Poor, I., Mangold, E., Daumer-Haas, C., Phadke, S., Peirano, R.I., Heusel, J., Desphande, C., Gupta, N., Nanda, A., Felix, E., Berry-Kravis, E., Kabra, M., Wevers, R.A., van Maldergem, L., Mundlos, S., Morava, E., Kornak, U., Fischer, B., Dimopoulou, A., Egerer, J., Gardeitchik, T., Kidd, A., Jost, D., Kayserili, H., Alanay, Y., Tantcheva-Poor, I., Mangold, E., Daumer-Haas, C., Phadke, S., Peirano, R.I., Heusel, J., Desphande, C., Gupta, N., Nanda, A., Felix, E., Berry-Kravis, E., Kabra, M., Wevers, R.A., van Maldergem, L., Mundlos, S., Morava, E., and Kornak, U.

Abstract

Contains fulltext : 107965.pdf (publisher's version ) (Closed access), Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debre type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H(+)-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-beta signalling and increased TGF-beta1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.

Published
2012

38. Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome.

Author

Iqbal, Z., Cejudo-Martin, P., Brouwer, A., Zwaag, B. van der, Ruiz-Lozano, P., Scimia, M.C., Lindsey, J.D., Weinreb, R., Albrecht, B., Megarbane, A., Alanay, Y., Ben-Neriah, Z., Amenduni, M., Artuso, R., Veltman, J.A., Beusekom, E. van, Oudakker, A.R., Millan, J.L., Hennekam, R., Hamel, B.C.J., Courtneidge, S.A., Bokhoven, J.H.L.M. van, Iqbal, Z., Cejudo-Martin, P., Brouwer, A., Zwaag, B. van der, Ruiz-Lozano, P., Scimia, M.C., Lindsey, J.D., Weinreb, R., Albrecht, B., Megarbane, A., Alanay, Y., Ben-Neriah, Z., Amenduni, M., Artuso, R., Veltman, J.A., Beusekom, E. van, Oudakker, A.R., Millan, J.L., Hennekam, R., Hamel, B.C.J., Courtneidge, S.A., and Bokhoven, J.H.L.M. van

Abstract

Contains fulltext : 88891.pdf (publisher's version ) (Closed access), Frank-Ter Haar syndrome (FTHS), also known as Ter Haar syndrome, is an autosomal-recessive disorder characterized by skeletal, cardiovascular, and eye abnormalities, such as increased intraocular pressure, prominent eyes, and hypertelorism. We have conducted homozygosity mapping on patients representing 12 FTHS families. A locus on chromosome 5q35.1 was identified for which patients from nine families shared homozygosity. For one family, a homozygous deletion mapped exactly to the smallest region of overlapping homozygosity, which contains a single gene, SH3PXD2B. This gene encodes the TKS4 protein, a phox homology (PX) and Src homology 3 (SH3) domain-containing adaptor protein and Src substrate. This protein was recently shown to be involved in the formation of actin-rich membrane protrusions called podosomes or invadopodia, which coordinate pericellular proteolysis with cell migration. Mice lacking Tks4 also showed pronounced skeletal, eye, and cardiac abnormalities and phenocopied the majority of the defects associated with FTHS. These findings establish a role for TKS4 in FTHS and embryonic development. Mutation analysis revealed five different homozygous mutations in SH3PXD2B in seven FTHS families. No SH3PXD2B mutations were detected in six other FTHS families, demonstrating the genetic heterogeneity of this condition. Interestingly however, dermal fibroblasts from one of the individuals without an SH3PXD2B mutation nevertheless expressed lower levels of the TKS4 protein, suggesting a common mechanism underlying disease causation.

Published
2010

39. Mild clinical phenotype and subtle radiographic findings in an infant with cartilage-hair hypoplasia

Author

Türkkani-Asal, G, Alanay, Y, Turul-Özgür, T, Zenker, M, Thiel, C, Rauch, A, Ünal, Ş, Gürgey, A, Tezcan, I, Türkkani-Asal, G, Alanay, Y, Turul-Özgür, T, Zenker, M, Thiel, C, Rauch, A, Ünal, Ş, Gürgey, A, and Tezcan, I

Abstract

Cartilage-hair hypoplasia (CHH) is one of the well-known immuno-osseous dysplasias (IOD), which are a combination of skeletal dysplasia and immunodeficiency. It is characterized by disproportionate short stature, fine sparse hair, ligamentous laxity, hematological abnormalities with anemia, a predisposition to malignant tumors, and recurrent infections usually due to cellular and/or humoral immunodeficiency. However, there is a significant overlap of clinical findings among the other IODS such as Schimke's IOD. Here, we present a case of CHH with mild skeletal changes and immunological findings associated with recurrent otitis media, neutropenia, and lymphopenia. With this report, we once more emphasize the difficulty in assessing young individuals with CHH presenting with mild ectodermal findings and subtle radiographic changes.

Published
2009

43. Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia

Author

Allali, S., primary, Le Goff, C., additional, Pressac-Diebold, I., additional, Pfennig, G., additional, Mahaut, C., additional, Dagoneau, N., additional, Alanay, Y., additional, Brady, A. F., additional, Crow, Y. J., additional, Devriendt, K., additional, Drouin-Garraud, V., additional, Flori, E., additional, Genevieve, D., additional, Hennekam, R. C., additional, Hurst, J., additional, Krakow, D., additional, Le Merrer, M., additional, Lichtenbelt, K. D., additional, Lynch, S. A., additional, Lyonnet, S., additional, MacDermot, K., additional, Mansour, S., additional, Megarbane, A., additional, Santos, H. G., additional, Splitt, M., additional, Superti-Furga, A., additional, Unger, S., additional, Williams, D., additional, Munnich, A., additional, and Cormier-Daire, V., additional

Published
2011
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46. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB

Author

Bicknell, L. S, primary, Farrington-Rock, C., additional, Shafeghati, Y., additional, Rump, P., additional, Alanay, Y., additional, Alembik, Y., additional, Al-Madani, N., additional, Firth, H., additional, Karimi-Nejad, M. H., additional, Kim, C. A., additional, Leask, K., additional, Maisenbacher, M., additional, Moran, E., additional, Pappas, J. G, additional, Prontera, P., additional, de Ravel, T., additional, Fryns, J.-P., additional, Sweeney, E., additional, Fryer, A., additional, Unger, S., additional, Wilson, L C, additional, Lachman, R. S, additional, Rimoin, D. L, additional, Cohn, D. H, additional, Krakow, D., additional, and Robertson, S. P, additional

Published
2006
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47. Perinatal mortality rate – hospital based study during 1998–2001 at Hacettepe University

Author

Durukan, T., primary, Önderoğlu, L., additional, Deren, Ö., additional, Saygan-Karamürsel, B., additional, Erdem, G., additional, Oram, O., additional, Gülsevin, M., additional, Yurdakök, S., additional, Özkutlu, S., additional, Çeliker, A., additional, Kale, G., additional, Çaglar, M., additional, Güçer, S., additional, Bulun, A., additional, Talim, B., additional, Büyükpamukçu, N., additional, Çiftçi, A., additional, Tunçbilek, E., additional, Balci, S., additional, and Alanay, Y., additional

Published
2003
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48. Neurochemical evaluation of brain function with 1H magnetic resonance spectroscopy in patients with fragile X syndrome.

Author

Utine, G.E., Akpınar, B., Arslan, U., Kiper, P.Ö.Ş., Volkan‐Salancı, B., Alanay, Y., Aktaş, D., Haliloğlu, G., Oğuz, K.K., Boduroğlu, K., and Alikaşifoğlu, M.

Abstract

ABSTRACT Fragile X syndrome (FXS) is the most common hereditary disorder of intellectual disability. Cognitive deficits involve executive function, attention, learning and memory. Advanced neuroimaging techniques are available, and 1H magnetic resonance spectroscopy (MRS) can be used as a complementary method to MR imaging to understand disease processes in brain, by in vivo demonstration of brain metabolites. MRS was performed in 13 male patients with FXS full mutation, and 13 age- and sex-matched healthy controls. FXS diagnosis was based on clinical evaluation, followed by detection of FMR1 full mutation. Axial T2 TSE, sagittal T1 SE and coronal 3D MPRAGE images were obtained for both morphological imaging and voxel localization. Following evaluation of conventional images, multivoxel MRS (CSI) through supraventricular white matter and single voxel MRS (svs) with an intermediate echo time (TE:135 ms) from the cerebellar vermis were performed. Choline/Creatine (Cho/Cr), N-acetyl aspartate/Creatine (NAA/Cr), and Choline/N-acetyl aspartate (Cho/NAA) ratios were examined at right frontal (RF), left frontal (LF), right parietal (RP), left parietal (LP), and cerebellar vermian (C) white matter. Statistical analyses were done using t-test and Mann-Whitney U tests. A statistically significant difference was observed in RP Cho/NAA ratio (cell membrane marker/neuroaxonal marker), FXS patients having lower levels than controls ( P = 0.016). The results should be evaluated cautiously in parallel to consequences in brain metabolism leading to alterations in neurotransmitter levels, osmoregulation, energy metabolism and oxidative stress response described in animal models. MRS may serve to define a metabolic signature and biomarkers associated with FXS. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Published
2014
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50. Infantile systemic hyalinosis: a case report.

Author

Gündüz Ö, Evans SE, Boduroglu K, Alanay Y, and Özkaya Ö

Abstract

Copyright of Archives of the Turkish Dermatology & Venerology / Turkderm is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2009

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