Posted on Authorea 18 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161603894.43007305/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. e yang Lei literature and report case a review mutation: Noonan gene in RIT1 stenosis with duct syndrome thoracic to due Refractory oeta er g,terpi fara etldfc,creto fploayvleseoi,, valve pulmonary ago, years of 4 correction than More defect, unknown). septal (details atrial performed of was family occlusion repair no arteriosus the had ductus unremarkable patient patent an ago, and The after years widening gestation 7 of period. days than was neonatal 4 She More her and during chylothorax. years. weeks or 38 found 4 NS at than were of born more abnormalities history was for obvious defect, and edema No septal parents limb (atrial her lower disease pregnancy. to arteriosus), in child congenital ductus of Medicine first-born patent operation the of the and after School stenosis years University valve 7 Tong medicine- of pulmonary internal complaints Jiao of chief department Shanghai with the 2020 Center, to June admitted Medical was China Children’s of Shanghai Province Yunnan cardiovascular, the in born girl 8-year-old An Turner or 21 Trisomy Report as Case such mutation. abnormalities gene chromosomal RIT1 1:30,000 as with about NS well Optiz of as Gorham-Stout, rate as NS, incidence such syndrome and syndromes an respectively Milroy malformation 5% with Hennekam, lymphoid than disease, congenital G/BBB, less include life-threatening and negative syndromes potentially still 10% genetic are and with 13%, NS rare for confirmed accounting a clinically genes, with is with patients KRAS gene, patients (PTPN11) of and of 11 30% RAF1 50% type About non-receptor SOS1, About phosphatase in tyrosine expressiveness. mutations protein variable retar- in less mutations but developmental missense penetrance have moderate births NS complete to live domi- with with mild diseases autosomal 1/2,500 myeloproliferative disease defects, common to and dominant heart cryptorchidism autosomal a 1/1,000 congenital abnormalities, is of and skeletal disabilities, 163950] stature, rate dation/learning short # incidence features, (MIM) estimated facial man an obvious in with inheritance disease, [Mendelian nant gene (NS) RIT1 syndrome with Noonan syndrome Noonan review in literature Introduction and stenosis report duct case thoracic a to mutation: due the chylothorax tissue, surrounding Refractory and the vessel releasing lymphatic After right The obstruction. in rare. resulting very tissue, is mutation surrounding gene the disappeared. chylothorax by RIT1 compressed with chylothorax were refractory duct with thoracic Noonan of occurrence The Abstract 2021 18, March 1 hnhiCide’ eia etr hnhiJa ogUiest colo Medicine of School University Tong Jiao Shanghai Center, Medical Children’s Shanghai 6 1 pt o,teei orprsaotterfatr hltoa u otoai utseoi in stenosis duct thoracic to due chylothorax refractory the about reports no is there now, to Up . igguo Ying , 1 iy Xu Xinyi , 1 uZhang Xu , 1 e Gao Wei , 1 1 n igin liu tingliang and , 4 nrcal hltoa nchildhood in chylothorax Intractable . 1 ti hrceie by characterized is It . 1 5 Associations . 2 ti an is It . 3 . Posted on Authorea 18 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161603894.43007305/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. hltoa sarr aeo btuto ritruto flmhtcdang ntelwrbd and body lower the in drainage lymphatic of syndrome interruption danlo or Elles obstruction and 21 of express case which tract rare cells, gastrointestinal NIH3T3 a in is observed Chylothorax been has patients transactivation NS in ELK mutations enhanced RAF1 that shown have studies n orsod oRAS to corresponds changes and acid RIT1 amino of to function lead molecular > and the 95, ensure and to 82 modification regions regulators 57, II post-translational codons and for affect I motif switch specifically specific in mutations a RIT1 motif, related CAAX NS C-terminal reported have not does state and binding GDP inactive development and state binding more were GTP and retardation growth less proteins exons had mutation six cardiomyopathy and RIT1 to of with MAP2K1 susceptible consists patients LZTR1, mutation, and BRAF, PTPN11 1q22 5%, with than chromosome associated approx- less in for KRAS accounting located 5%, SOS1 1% is for with than accounting showed PTPN11, each analysis less of RIT1 variants genetic NRAS pathogenic and Molecular had RAF1 studies. individuals 13%, chromosome affected diagnosis imately normal the genetic have of always the 50% individuals and that affected arteriosus, the ductus NS, ductus patent In persistent and 5%, stenosis 1). defect in (Fig. confirmed septal occurs structure was atrial valve defect valve, mitral abnormal septal pulmonary and ventricular had obstruction sub-aortic patients, with of associated defects 6%-10% 3% 20% in for (50%-62%) for accounted present leaflets accounted arteriosus dysplastic is hypertrophy with septal defect stenosis asymmetric valve septal with pulmonary cardiomyopathy is obstructive disease heart Hypertrophic congenital common most malformations retardation, The lymphatic growth and features, abnormalities, facial difficulties renal obvious bleeding disease, by and heart characterized congenital is stature, short which difficulties, disease, learning multisystem hereditary a is the NS tissue, surrounding Discussion were the and duct releasing thoracic review and After Literature vessel disappeared. obstruction. lymphatic chylothorax right in and the relieved resulting day, that was every tissue, found obstruction least surrounding was Tab.1. at the it in ml hospitals, by Edema shown 110 boundary. other compressed are and tenderness. in in tests most no clear operation at laboratory joint, and the ml of ankle texture During 610 and results in was leg The soft fluid in chylous. ribs, drainage obvious light the thoracic limb, was below the lower which 2cm admission, the left was After the and liver in abdomen even perineum. the The edema was of of sternum. depression rate edge left no lower of heart was intercostal The the 2-3 There between soft. beats/min, heard and was 100 murmur flat was systolic was 2/6 rate edema. strong. heart extremity was elastic sound the lower Because wearing heart revealed still meal. after were examination chylous edema there physical drainage, and repeated clear, General closed hospital, not had thoracic was local still right chylothorax of continuous limbs of department with lower skin cause outpatient treated the no the the were long but was a patients visited stockings, was There for The once walking elastic knee She stockings. perineum. and wear the standing obvious. and to disease, After was limb suggested the breathing. edema lower was of sitting limb right beginning groundless lower the and the the to edema, At time, eyelid spread pain, edema. gradually limb limb lower swelling lower flush, the left then for and inducement obvious, obvious no was there ,pPe2e)ecdsacag ntesic Irgo,wihi osre oiinaogspecies among position conserved a is which region, II switch the in change a encodes p.Phe82Leu) A, 11 tat samlclrsic fgaiencetd euaini el ycagn ewe active between changing by cells in regulation nucleotide guanine of switch molecular a as acts It . 11 tsae bu 0 eunehmlg ihRS a diinlNtria extension, N-terminal additional has RAS, with homology sequence 50% about shares It . 4 5 hscs samtto fRT eei c.246T in gene RIT1 of mutation a is case This . ypoddsae r oeie soitdwt unr onn n Trisomy and Noonan, Turner, with associated sometimes are diseases Lymphoid . 7 h niec aeo Si siae ob ewe :00ad120 iebirths live 1:2500 and 1:1000 between be to estimated is NS of rate incidence The . 11 12 hs w rti oisaeivle ntebnigo uloie,eetr and effectors nucleotides, of binding the in involved are motifs protein two These . hsRT uainsoe infiathg L1transactivation ELK1 high significant showed mutation RIT1 This . 1 te ogntlhatdfcsmr omni Saearoetiua canal atrioventricular are NS in common more defects heart congenital Other . 15 10 hltoa scaatrzdb yp oe otiigtilcrdsand triglycerides containing nodes lymph by characterized is Chylothorax . 14 I1blnst A uefml flwmlclrwih T binding GTP weight molecular low of superfamily RAS to belongs RIT1 . . 12 10 2 nti eot h dnie I1mtto (c.246T mutation RIT1 identified the report, this In . I1i xrse nmn ise n throughout and tissues many in expressed is RIT1 . 9 oprdwt h yia onnphenotype Noonan typical the with Compared . > ,pPe2e Fg ) RIT1 1). (Fig. p.Phe82Leu A, 2 nti ae h patient the case, this In . 9 13 ofr the far, So . Previous . 1 Atrial . 1 8 . . Posted on Authorea 18 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161603894.43007305/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. emigF vr ,Hh ,Hme ,Is ,KhetA,Le ,VlaiecoLrn ,Ballesta- P, S, Villavicencio-Lorini Unkelbach A, H, Lieb Seidel L AK, R, V, Kahlert Satanovskij Lopez-Gonzalez U, Puchmajerov´a A, A, Issa A, Riess M, Ovens-Raeder D, Hempel S, A, Mitter Nampoothiri Hahn MJ, S, C, Martinez Spranger Evers C, F, Lissewski Deimling K, 15; Galeas Mar Kouz 2019 A, Tankka 10. Science. DK, proteolysis. LZTR1-mediated Simanshu escape AG, oncoproteins Papageorge 2:4. RIT1 DB, 14; 363(6432):1226-1230. F. Everman Jan McCormick A, 2007 A, Cuevas-Navarro Dis. Urisman A, J, Rare Cheng J P, Orphanet Castel syndrome. 9. 50(10):E14-20. Noonan Oct; I. 2014 Burgt Health. der Child 84(6):268-273. van Paediatr 2017; 8. J Sch. syndrome. Med after Noonan Nippon Chylothorax AM. J Intractable Turner Report. Yoshimatsu Postoperative 7. Case H, in Yokomizo A Useful K, Cancer: Was Yamaguchi Esophageal Lymphangiography A, for T. Shimazaki Surgery S, Katsube Injury Asaka S, Duct M, Shiozawa Miyazawa Thoracic K, Y, for Naritaka Therapies T, 34(4):258-265. Interventional Shimakawa Jul; M. 6. 2019 Sanchez Imaging. Villa Thorac AA, Chylothorax.J Frazier Intractable EG, and Chan PM, Suspect Novelli 38(8):1081-1084. Syndrome: to 5. Sep; Clues Noonan Which S. 2017 Impairment. Marlin Neurotol. Hearing V, Otol Sensorineural Couloigner Profound S, Diagnosis? to Gherbi the Severe G, of Cav´e Baujat Cause L, H, Underestimated Jonard 381(9863):333- An N, 26; Loundon Jan A, 2013 Ziegler Lancet. 4. syndrome. 89(1):37-43. Noonan 1; BD. Jan Gelb 2014 M, Tartaglia Physician. JE, 42. Endocrinol Fam Allanson Opin Am AE, Curr Roberts syndrome. 3. development. Noonan M. and Muenke growth V, on Bhambhani update 2. an 25(1):67-73. Feb; syndrome: 2018 Noonan T. Obes. Edouard A, Yart 1. References effusion examination classification pleural Hydrothorax right the 1 exudation, Table to lung lower According right shadow, gnomAD: region. heart databases, Large mutation mutation. gnomAD diseases// spot “pathogenic” X-ray and as hot other Chest HGMD classified known 2 and be in Figure the can c.246t included syndrome in they mutation mutation, (not located Noonan ACMG The found are of cause standard which newly dominant. can are 0.000%), autosomal sample mutation all: this are gene in them RIT1 p.Phe82leu of literature, )Most literature. the www.omim.org/entry/609591 duct English in thoracic to first to the According due report is chylothorax test mutation, refractory sequencing gene the Gene RIT1 depicting 1: with ours Figure NS of of report by case this compressed a knowledge, was in our stenosis stenosis of duct the best thoracic obstruction. subclavian near the the removing the To that after aorta, before proved cured the descending operation was enters the The Chylothorax subclavian duct and duct. and tissue. trunk thoracic thoracic surrounding vein vein the The jugular azygos carotid of left thyroid the parts 1). the various and between to Tab. artery spine, finally and vertebral the and artery, 2 of pericardium, side (Fig. and right effusion esophagus the pleural in hiatus to esophageal positive mediastinum diaphragm was the through chyle cavity and thoracic L, / confirmed is mmol diagnosis the cavity dl), pleural / the in granules chylous 16 nti ae h ocnrto ftilcrd nperleuinws2.62 was effusion pleural in triglyceride of concentration the case, this In . 16 hntetilcrd ee shge hn12 ml/L(1 mg (110 L / mmol 1.24 than higher is level triglyceride the When . 3 17 17 tsat rmotieteper fteposterior the of pleura the outside from starts It . hr a emn ntmclvrain in variations anatomical many be may There . tgnS yi ,von H, Aydin S, uttgen ¨ > and A Posted on Authorea 18 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161603894.43007305/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. eitc f1 ainsadaRve fteLtrtr.Ac rnoeml 07Jl 53(7):407-408. Jul; Charac- 2017 Adults. Bronconeumol. in Arch Chylothorax Literature. Bronc the Arch of Review Literature. a the and of Patients Review 17 a of and teristics Patients 17 133(4):722-33. of Apr; Characteristics 2014 Persiva Pediatrics. V´azquez 22(4):234-239. J´auregui A, Alem´an children. A, Garc´ıa Aug; C, J, and 17. 2017 infants Med. in T, Neonatal Chylothorax Fetal N, Arbogast JD. Semin Tutor Katsanis 6; chylothorax. H, 16. EE, Jun Congenital Kihara Davis 2019 SM. A, Donn Genet. N, MA, Hum Harada Matsumoto Attar J IC, S, 15. Am Tsai Okada Syndrome. SI, N, Noonan Inoue Okamoto Cause T, Mutations H, 104(6):1233-1240. RRAS2 Abe Ohashi Germline-Activating K, Y. A, Nakayama Aoki Fujita M, S, Shirota K, Hasegawa R, Nagai Jul Funayama 2013 T, T, Genet. Nagashima Hum Niihori Gain-of-function J Ando T, 14. Y. Am M, Okutani syndrome. Matsubara Yano pathway T, T, F, RAS/MAPK Ogura Takada a Hasegawa Y, 93(1):173-80. syndrome, T, H, Watanabe 11; Noonan Ogata S, cause Kawame K, Inoue RIT1 Kurosawa H, in K, S, Nakayama mutations Ohashi Jan; Mizuno T, 2016 C, Nagashima N, Genet. R, Okamoto Barnett Funayama Hum T, T, J Banjo Hoshika RASopathies. T, T, in Niihori advances Y, Recent Aoki acute Y. 13. RIT1 in Matsubara in involved S, Mutations Inoue not T, A. are Roume 61(1):33-9. Niihori Verloes but 24(8):1124-31. Y, M, C, Aug; leukemia Aoki Rio 2016 Baumann 12. myelomonocytic L, Genet. M, juvenile Hum Perrin O, J Willems possible S, Fenneteau Eur Dulac C, Lyonnet leukemia. C, with B, lymphoblastic Vincent-Delorme D, Vignal Doray syndrome A, A, Lacombe A, Noonan Coeslier Trimouille Toutain B, Dieux cause N, S, Isidor A, David Fillot H´eron D, Sauvion P, N, G´erard M, Bouvagnet J, O, Pouvreau V, RIT1 Boute Y, Drouin-Garraud a P, Blanchet Capri and O, JL, N, syndrome Alessandri Noonan Ghedira Y, with Alembik A, patients Caye in Cav´e H, phenotype 11. 18(12):1226-1234. and Dec; Genotype 2016 M. Med. Zenker Genet mutation. K, Kutsche B, Zabel 4 ,Fr´ne eSvlaT hltoa nAdults. in Chylothorax T. Sevilla Fern´andez de O, ´ Posted on Authorea 18 Mar 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161603894.43007305/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 5