Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation

被引:74
作者
Koczkowska, Magdalena [1 ]
Callens, Tom [1 ]
Gomes, Alicia [1 ]
Sharp, Angela [1 ]
Chen, Yunjia [1 ]
Hicks, Alesha D. [1 ]
Aylsworth, Arthur S. [2 ,3 ]
Azizi, Amedeo A. [4 ]
Basel, Donald G. [5 ]
Bellus, Gary [6 ]
Bird, Lynne M. [7 ]
Blazo, Maria A. [8 ]
Burke, Leah W. [9 ]
Cannon, Ashley [1 ]
Collins, Felicity [10 ]
DeFilippo, Colette [11 ]
Denayer, Ellen [12 ]
Digilio, Maria C. [13 ]
Dills, Shelley K. [14 ]
Dosa, Laura [15 ]
Greenwood, Robert S. [16 ]
Griffis, Cristin [5 ]
Gupta, Punita [17 ]
Hachen, Rachel K. [18 ]
Hernandez-Chico, Concepcion [19 ,20 ]
Janssens, Sandra [21 ]
Jones, Kristi J. [10 ]
Jordan, Justin T. [22 ,23 ]
Kannu, Peter [24 ]
Korf, Bruce R. [1 ]
Lewis, Andrea M. [25 ]
Listernick, Robert H. [26 ]
Lonardo, Fortunato [27 ]
Mahoney, Maurice J. [28 ]
Ojeda, Mayra Martinez [29 ]
McDonald, Marie T. [30 ]
McDougall, Carey [31 ]
Mendelsohn, Nancy [32 ]
Miller, David T. [29 ]
Mori, Mari [33 ]
Oostenbrink, Rianne [34 ]
Perreault, Sebastian [35 ]
Pierpont, Mary Ella [36 ]
Piscopo, Carmelo [37 ]
Pond, Dinel A. [32 ]
Randolph, Linda M. [38 ]
Rauen, Katherine A. [11 ]
Rednam, Surya [39 ]
Rutledge, S. Lane [1 ]
Saletti, Veronica [40 ]
机构
[1] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA
[2] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27515 USA
[3] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA
[4] Med Univ Vienna, Dept Pediat & Adolescent Med, Div Neonatol Pediat Intens Care & Neuropediat, Vienna, Austria
[5] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA
[6] Univ Colorado, Childrens Hosp, Dept Clin Genet & Metab, Sch Med, Aurora, CO USA
[7] Univ Calif San Diego, Dept Pediat, Rady Childrens Hosp, Div Genet Dysmorphol, San Diego, CA 92103 USA
[8] Baylor Scott & White Hosp, Temple, TX USA
[9] Univ Vermont, Med Ctr, Clin Genet Program, Burlington, VT USA
[10] Childrens Hosp Westmead, Dept Clin Genet, Westmead, NSW, Australia
[11] UC Davis MIND Inst, Dept Pediat, Div Genom Med, Sacramento, CA USA
[12] Univ Leuven, KU Leuven, Dept Human Genet, Leuven, Belgium
[13] IRCCS, Med Genet Unit, Bambino Gesu Childrens, Rome, Italy
[14] Carolinas Med Ctr, Charlotte, NC 28203 USA
[15] AOU Meyer, SOC Genet Med, Florence, Italy
[16] Univ N Carolina, Sch Med, Dept Neurol, Div Child Neurol, Chapel Hill, NC 27515 USA
[17] St Josephs Childrens Hosp, Neurofibromatosis Diagnost & Treatment Program, Paterson, NJ USA
[18] Childrens Hosp Philadelphia, Neurofibromatosis Program, Philadelphia, PA 19104 USA
[19] Hosp Univ Ramon y Cajal, Inst Hlth Res IRYCIS, Dept Genet, Madrid, Spain
[20] Ctr Biomed Res Network Rare Dis CIBERER, Madrid, Spain
[21] Ghent Univ Hosp, Ctr Med Genet, Ghent, Belgium
[22] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA
[23] Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA
[24] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON, Canada
[25] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[26] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA
[27] G Rummo Hosp, Med Genet Unit, Benevento, Italy
[28] Yale Univ, Dept Genet, New Haven, CT USA
[29] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA
[30] Duke Univ, Dept Pediat, Sch Med, Div Med Genet, Durham, NC 27706 USA
[31] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA
[32] Childrens Hosp Minnesota, Genom Med Program, Minneapolis, MN USA
[33] Brown Univ, Dept Pediat, Warren Alpert Med Sch, Providence, RI 02912 USA
[34] Erasmus MC Sophia, Dept Gen Pediat, Rotterdam, Netherlands
[35] CHU St Justine, Mother & Child Univ Hosp Ctr, Montreal, PQ, Canada
[36] Univ Minnesota, Dept Pediat & Ophthalmol, Minneapolis, MN USA
[37] AORN A Cardarelli, UOSC Med Genet, Naples, Italy
[38] Univ Southern Calif, Childrens Hosp Los Angeles, Keck Sch Med, Div Med Genet, Los Angeles, CA USA
[39] Baylor Coll Med, Dept Pediat, Sect Hematol Oncol, Houston, TX 77030 USA
[40] IRCCS Fdn, Carlo Besta Neurol Inst, Dev Neurol Unit, Milan, Italy
[41] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Div Med Genet, Little Rock, AR 72205 USA
[42] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA
[43] Univ Nebraska Med Ctr, Munroe Meyer Inst, Genet Med, Omaha, NE USA
[44] DCH Reg Med Ctr, Northport, AL USA
[45] Northport Med Ctr, Northport, AL USA
[46] Univ Iowa Hosp & Clin, Stead Family Dept Pediat, Iowa City, IA 52242 USA
[47] Boston Childrens Hosp, Dept Neurol, Boston, MA USA
[48] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA
[49] Med Univ Innsbruck, Div Human Genet, Innsbruck, Austria
[50] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands
关键词
NF1; p.Met992del; genotype-phenotype correlation; neurofibroma; learning difficulties; OPTIC PATHWAY TUMORS; NERVE SHEATH TUMORS; SOUTH EAST WALES; VONRECKLINGHAUSEN NEUROFIBROMATOSIS; TYPE-1; NEUROFIBROMATOSIS; NOONAN SYNDROME; MUTATIONS; CHILDREN; ASSOCIATION; GUIDELINES;
D O I
10.1038/s41436-018-0269-0
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
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收藏
页码:867 / 876
页数:10
相关论文
共 46 条
[1]   Growth rate characteristics of acoustic neuromas associated with neurofibromatosis type 2 [J].
Abaza, MM ;
Makariou, E ;
Armstrong, M ;
Lalwani, AK .
LARYNGOSCOPE, 1996, 106 (06) :694-699
[2]   Systematic MRI in NF1 children under six years of age for the diagnosis of optic pathway gliomas. Study and outcome of a French cohort [J].
Blanchard, Gaelle ;
Lafforgue, Marie-Pierre ;
Lion-Francois, Laurence ;
Kemlin, Isabelle ;
Rodriguez, Diana ;
Castelnau, Pierre ;
Carneiro, Maryline ;
Meyer, Pierre ;
Rivier, Francois ;
Barbarot, Sebastien ;
Chaix, Yves .
EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY, 2016, 20 (02) :275-281
[3]   Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1 [J].
Blazo, MA ;
Lewis, RA ;
Chintagumpala, MM ;
Frazier, M ;
McCluggage, C ;
Plon, SE .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2004, 127A (03) :224-229
[4]   Review and update of SPRED1 mutations causing legius syndrome [J].
Brems, Hilde ;
Pasmant, Eric ;
Van Minkelen, Rick ;
Wimmer, Katharina ;
Upadhyaya, Meena ;
Legius, Eric ;
Messiaen, Ludwine .
HUMAN MUTATION, 2012, 33 (11) :1538-1546
[5]  
Burgoyne AM, 2017, JCO PRECIS ONCOL, V1, DOI 10.1200/PO.17.00014
[6]   A prospective 10 year follow up study of patients with neurofibromatosis type 1 [J].
Cnossen, MH ;
de Goede-Bolder, A ;
van den Broek, KM ;
Waasdorp, CME ;
Oranje, AP ;
Stroink, H ;
Simonsz, HJ ;
van den Ouweland, AMW ;
Halley, DJJ ;
Niermeijer, MF .
ARCHIVES OF DISEASE IN CHILDHOOD, 1998, 78 (05) :408-412
[7]   Novel Association of Neurofibromatosis Type 1-Causing Mutations in Families With Neurofibromatosis-Noonan Syndrome [J].
Ekvall, Sara ;
Sjors, Kerstin ;
Jonzon, Anders ;
Vihinen, Mauno ;
Anneren, Goran ;
Bondeson, Marie-Louise .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2014, 164 (03) :579-587
[8]   Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1 [J].
Evans, D. Gareth R. ;
Salvador, Hector ;
Chang, Vivian Y. ;
Erez, Ayelet ;
Voss, Stephan D. ;
Schneider, Kami Wolfe ;
Scott, Hamish S. ;
Plon, Sharon E. ;
Tabori, Uri .
CLINICAL CANCER RESEARCH, 2017, 23 (12) :E46-E53
[9]   Malignant peripheral nerve sheath tumours in neurofibromatosis 1 [J].
Evans, DGR ;
Baser, ME ;
McGaughran, J ;
Sharif, S ;
Howard, E ;
Moran, A .
JOURNAL OF MEDICAL GENETICS, 2002, 39 (05) :311-314
[10]   Guidelines for the diagnosis and management of individuals with neurofibromatosis 1 [J].
Ferner, Rosalie E. ;
Huson, Susan M. ;
Thomas, Nick ;
Moss, Celia ;
Willshaw, Harry ;
Evans, D. Gareth ;
Upadhyaya, Meena ;
Towers, Richard ;
Gleeson, Michael ;
Steiger, Christine ;
Kirby, Amanda .
JOURNAL OF MEDICAL GENETICS, 2007, 44 (02) :81-88