{"orpha":453499,"name":"Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome","type":"Malformation syndrome","group":"Disorder","status":"active","flags":[],"synonyms":["Au-Kline syndrome","HNRNPK-related neurodevelopmental disorder","Okamoto syndrome"],"definition":"A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, craniofacial dysmorphism (such as ridged metopic sutures, long palpebral fissures, broad nasal bridge, hypoplastic alae nasi, low-set, prominent ears, prominent midline tongue groove, and downturned mouth), congenital heart defects, and variable skeletal abnormalities including hip dysplasia, vertebral anomalies, and scoliosis. Additional reported manifestations include high pain tolerance and genitourinary anomalies. Brain imaging may show a thin corpus callosum or white matter abnormalities.","note":null,"url":"https://raremap.alftech.space/d/ORPHA-453499/","orphanet_url":"https://www.orpha.net/en/disease/detail/453499","names":{"fr":{"name":"Syndrome de dysmorphie craniofaciale-anomalies squelettiques-cardiopathie-trouble neurologique du développement","synonyms":["Syndrome d'Au-Kline","Syndrome d'Okamoto"],"definition":"Syndrome génétique rare d'anomalies congénitales multiples/dysmorphie, caractérisé par un retard global de développement, une déficience intellectuelle, une hypotonie, une dysmorphie craniofaciale (sutures métopiques striées, longues fentes palpébrales, pont nasal large, ailes du nez hypoplasiques, oreilles implantées bas et proéminentes, sillon lingual proéminent et commissures de lèvres tombantes), des anomalies cardiaques congénitales et des anomalies squelettiques variables, notamment une dysplasie de la hanche, des anomalies vertébrales et une scoliose. Parmi les autres manifestations rapportées figurent une tolérance élevée à la douleur et des anomalies génito-urinaires. L'imagerie cérébrale peut montrer un corps calleux mince ou des anomalies de la substance blanche."},"de":{"name":"Neurologische Entwicklungsstörungen-kranio-faziale Dysmorphie-Herzfehler-Skelettanomalie-Syndrom","synonyms":["Au-Kline-Syndrom","HNRNPK-bedingte neurologische Entwicklungsstörung","Okamoto-Syndrom"],"definition":"Ein seltenes genetisch bedingtes Dysmorphie-Syndrom, das gekennzeichnet ist durch eine globale Entwicklungsverzögerung, Intelligenzminderung, Hypotonie und kraniofaziale Dysmorphien (wie z. B. vorzeitiger Verschluss der metopischen Naht, lange Lidspalten, breiter Nasenrücken, hypoplastische Nasenflügel, tief angesetzte, abstehende Ohren, ausgeprägte Zungenfurche in der Mittellinie und nach unten gerichteter Mund). Weitere Kennzeichen sind angeborene Herzfehler und variable Skelettanomalien, einschließlich Hüftdysplasie, Wirbelsäulenanomalien und Skoliose. Einige Patienten zeigen eine hohe Schmerztoleranz und urogenitale Anomalien. Die Bildgebung des Gehirns kann ein dünnes Corpus Callosum oder Anomalien der weißen Substanz zeigen."},"es":{"name":"Síndrome de trastorno del neurodesarrollo-dismorfia craneofacial-defecto cardíaco-anomalías esqueléticas","synonyms":["Síndrome de Au-Kline","Trastorno del neurodesarrollo asociado a HNRNPK"],"definition":"Es un síndrome dismórfico/ de múltiples anomalías congénitas de base genética y poco frecuente caracterizado por retraso global del desarrollo, discapacidad intelectual, hipotonía, dismorfia craneofacial (como suturas metópicas estriadas, fisuras palpebrales amplias, puente nasal ancho, hipoplasia de las alas nasales, orejas prominentes y de baja implantación, prominencia del surco lingual medio y boca de inclinación descendente), defectos cardíacos congénitos y anomalías esqueléticas variables que incluyen displasia de cadera, anomalías vertebrales y escoliosis. Otras manifestaciones adicionales descritas incluyen elevada tolerancia al dolor y anomalías genitourinarias. La neuroimagen puede mostrar adelgazamiento del cuerpo calloso o anomalías de la sustancia blanca."},"it":{"name":"Malattia del neurosviluppo-dismorfismi craniofacciali-cardiopatie-anomalie scheletriche","synonyms":["Malattia del neurosviluppo correlata a HNRNPK","Sindrome di Au-Kline","Sindrome di Okamoto"],"definition":"Si tratta di una malattia genetica rara da anomalie/dismorfismi congeniti multipli, caratterizzata da ritardo dello sviluppo globale, disabilità intellettiva, ipotonia, dismorfismi craniofacciali (cresta metopica, rime palpebrali lunghe, sella nasala ampia, ali del naso ipoplastiche, orecchie prominenti a basso impianto, solco centrale della lingua prominente e bocca rivolta verso il basso), cardiopatie congenite e anomalie scheletriche variabili (displasia dell'anca, anomalie delle vertebre e scoliosi). I pazienti possono presentare anche un'elevata tolleranza del dolore e anomalie genitourinarie. Le neuroimmagini mostrano un assottigliamento del corpo calloso e anomalie della sostanza bianca."},"nl":{"name":"Neurologische ontwikkelingsstoornis - craniofaciale dysmorfie - hartdefect - skeletanomalieën-syndroom","synonyms":["HNRNPK-gerelateerde neurologische ontwikkelingsstoornis","Syndroom van Au-Kline","Syndroom van Okamoto"],"definition":"Een zeldzaam, genetisch syndroom met multipele congenitale anomalieën/dysmorfie, gekarakteriseerd door algehele ontwikkelingsachterstand, intellectuele achterstand, hypotonie, craniofaciale dysmorfie (waaronder richel aan voorhoofdsnaad, lange ooglidspleten, brede neusbrug, hypoplastische neusvleugels, laagstaande en prominente oren, prominente mediane tonggroeve, en naar beneden gekeerde mond), congenitale hartdefecten, en variabele skeletanomalieën waaronder dysplasie van heup, vertebrale anomalieën, en scoliose. Bijkomende manifestaties die werden gerapporteerd, zijn onder meer hoge pijntolerantie en urogenitale anomalieën. Beeldvorming van hersenen toont mogelijk dun corpus callosum of afwijkingen van witte stof."},"pt":{"name":"Síndrome de doença do neurodesenvolvimento-dismorfia craniofacial-anomalia cardíaca-anomalias esqueléticas","synonyms":["Doença do neurodesenvolvimento HNRNPK-relacionada","Síndrome Au-Kline","Síndrome Okamoto"]},"pl":{"name":"Zespół zaburzeń neurorozwojowych-dysmorfii twarzoczaszki-wady serca-anomalii szkieletowych","synonyms":["Zespół zaburzeń neurorozwojowych, dysmorfii czaszkowo-twarzowej, z towarzyszącymi wadami serca i kości"]},"cs":{"name":"Syndrom zahrnující neurovývojovou poruchu, kraniofaciální dysmorfismus, srdeční vady a kyčelní dysplázii","synonyms":["Au-Kline syndrome","HNRNPK-related neurodevelopmental disorder","Okamoto syndrome"]},"uk":{"name":"Синдром порушення нейророзвитку-черепно-лицьового дизморфізму-серцевої вади-скелетних аномалій","synonyms":["Синдром Ау-Клайна","Повязане з HNRNPK порушення нейророзвитку","Синдром Окамото"],"definition":"A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, craniofacial dysmorphism (such as ridged metopic sutures, long palpebral fissures, broad nasal bridge, hypoplastic alae nasi, low-set, prominent ears, prominent midline tongue groove, and downturned mouth), congenital heart defects, and variable skeletal abnormalities including hip dysplasia, vertebral anomalies, and scoliosis. Additional reported manifestations include high pain tolerance and genitourinary anomalies. Brain imaging may show a thin corpus callosum or white matter abnormalities."},"zh":{"name":"神经发育障碍-颅面畸形-心脏缺损-骨骼异常综合征","synonyms":["金氏综合征"]},"tr":{"name":"Nörogelişimsel bozukluk-kraniyofasiyal dismorfizm-kalp defekti-iskelet anomalileri sendromu","synonyms":["Au-Kline sendromu"]}},"xrefs":[{"source":"OMIM","code":"616580","qualifier":"BTNT","icd_relation":null,"validated":true},{"source":"ICD-10","code":"Q87.8","qualifier":"NTBT","icd_relation":"attributed","validated":true},{"source":"ICD-11","code":"LD2F.1Y","qualifier":"NTBT","icd_relation":"attributed","validated":true},{"source":"MONDO","code":"18681","qualifier":"E","icd_relation":null,"validated":true},{"source":"UMLS","code":"C4225274","qualifier":"E","icd_relation":null,"validated":true}],"associations":[],"incoming_associations":[{"type":"Moved to","orpha":2729,"name":"Okamoto syndrome","status":"inactive"}],"preferential_parent":{"orpha":93890,"name":"Rare developmental defect during embryogenesis"},"parents":[{"orpha":93454,"name":"Dysostosis with predominant vertebral and costal involvement","classifications":[147,156,199]},{"orpha":611327,"name":"Genetic multiple congenital anomalies/dysmorphic syndrome-intellectual disability","classifications":[156]},{"orpha":102283,"name":"Multiple congenital anomalies/dysmorphic syndrome-intellectual disability","classifications":[147,181]},{"orpha":156532,"name":"Rare syndrome with cardiac malformations","classifications":[147,148,156]}],"children":[{"orpha":352665,"name":"Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to 9q21.3 microdeletion","type":"Etiological subtype"},{"orpha":453504,"name":"Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to a point mutation","type":"Etiological subtype"}],"genes":[],"genes_via_subtypes":[{"symbol":"HNRNPK","name":"heterogeneous nuclear ribonucleoprotein K","gene_type":"gene with protein product","association":"Disease-causing germline mutation(s) (loss of function) in","status":"Assessed","source":"26173930[PMID]","hgnc":"5044","ensembl":"ENSG00000165119","omim":"600712","loci":["9q21.32"],"via":{"orpha":453504,"name":"Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to a point mutation"}},{"symbol":"HNRNPK","name":"heterogeneous nuclear ribonucleoprotein K","gene_type":"gene with protein product","association":"Role in the phenotype of","status":"Assessed","source":"26173930[PMID]_24501764[PMID]_25348648[PMID]","hgnc":"5044","ensembl":"ENSG00000165119","omim":"600712","loci":["9q21.32"],"via":{"orpha":352665,"name":"Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to 9q21.3 microdeletion"}}],"inheritance":["Autosomal dominant","Not applicable"],"onset":["Antenatal","Infancy","Neonatal"],"prevalence":[{"type":"Cases/families","qualification":"Case(s)","class":null,"value":25.0,"area":"Worldwide","status":"Validated","source":"29904177[PMID]_30998304[PMID]"},{"type":"Point prevalence","qualification":"Class only","class":"<1 / 1 000 000","value":0.0,"area":"Worldwide","status":"Validated","source":"ORPHANET_30998304[PMID]"}],"phenotypes":{"validation_status":"y","online":"y","validation_date":"2019-12-10","source":"30998304[PMID]_29904177[PMID]","terms":[{"hpo":"HP:0001627","label":"Abnormal heart morphology","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0011039","label":"Abnormal helix morphology","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000119","label":"Abnormality of the genitourinary system","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000280","label":"Coarse facial features","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000750","label":"Delayed speech and language development","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000126","label":"Hydronephrosis","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0001252","label":"Hypotonia","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0001249","label":"Intellectual disability","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000276","label":"Long face","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000637","label":"Long palpebral fissure","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0001270","label":"Motor delay","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0002465","label":"Poor speech","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0000431","label":"Wide nasal bridge","frequency":"Very frequent (99-80%)","criteria":null},{"hpo":"HP:0012332","label":"Abnormal autonomic nervous system physiology","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000175","label":"Cleft palate","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0002019","label":"Constipation","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0001363","label":"Craniosynostosis","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000028","label":"Cryptorchidism","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0002714","label":"Downturned corners of mouth","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0001508","label":"Failure to thrive","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000221","label":"Furrowed tongue","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0002020","label":"Gastroesophageal reflux","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0002579","label":"Gastrointestinal dysmotility","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000365","label":"Hearing impairment","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000218","label":"High palate","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0001385","label":"Hip dysplasia","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0002079","label":"Hypoplasia of the corpus callosum","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0010880","label":"Increased nuchal translucency","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0001511","label":"Intrauterine growth retardation","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0003186","label":"Inverted nipples","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000252","label":"Microcephaly","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000194","label":"Open mouth","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0005487","label":"Prominent metopic ridge","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000508","label":"Ptosis","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0001315","label":"Reduced tendon reflexes","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0002650","label":"Scoliosis","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000586","label":"Shallow orbits","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0001883","label":"Talipes","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000430","label":"Underdeveloped nasal alae","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0001629","label":"Ventricular septal defect","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0003422","label":"Vertebral segmentation defect","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0000076","label":"Vesicoureteral reflux","frequency":"Frequent (79-30%)","criteria":null},{"hpo":"HP:0025487","label":"Abnormality of bladder morphology","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001284","label":"Areflexia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0004970","label":"Ascending tubular aorta aneurysm","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001631","label":"Atrial septal defect","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0006695","label":"Atrioventricular canal defect","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001647","label":"Bicuspid aortic valve","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0000193","label":"Bifid uvula","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0009794","label":"Branchial anomaly","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0003763","label":"Bruxism","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0000589","label":"Coloboma","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0000476","label":"Cystic hygroma","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0002282","label":"Gray matter heterotopia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0002046","label":"Heat intolerance","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0000666","label":"Horizontal nystagmus","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0007550","label":"Hypohidrosis or hyperhidrosis","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0000821","label":"Hypothyroidism","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0007328","label":"Impaired pain sensation","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0000158","label":"Macroglossia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001324","label":"Muscle weakness","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0011470","label":"Nasogastric tube feeding in infancy","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0000677","label":"Oligodontia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0000938","label":"Osteopenia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001357","label":"Plagiocephaly","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0002202","label":"Pleural effusion","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0004467","label":"Preauricular pit","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001954","label":"Recurrent fever","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0001250","label":"Seizure","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0003396","label":"Syringomyelia","frequency":"Occasional (29-5%)","criteria":null},{"hpo":"HP:0011024","label":"Abnormality of the gastrointestinal tract","frequency":"Very rare (<4-1%)","criteria":null}]}}