Noonan 综合征

在多达 50% 的病例中，Noonan 综合征是一种常染色体显性遗传性疾病。[11]Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8.http://www.ncbi.nlm.nih.gov/pubmed/11704759?tool=bestpractice.com[12]Tartaglia M, Kalidas K, Shaw A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC379142/http://www.ncbi.nlm.nih.gov/pubmed/11992261?tool=bestpractice.com 假如近亲携带有同样的突变，可能出现身材矮小、先天性心脏病和/或学习困难。

可能为一种表现病征。

童年生长情况倾向于位于第三百分位，但青春期暴发式发育通常减弱或缺如。[32]Witt DR, Keena BA, Hall JG, et al. Growth curves for height in Noonan syndrome. Clin Genet. 1986 Sep;30(3):150-3.http://www.ncbi.nlm.nih.gov/pubmed/3780030?tool=bestpractice.com

无论患者年龄如何，都能看到特定的面容特征。[Figure caption and citation for the preceding image starts]: 患 Noonan 综合征的年轻男性，3 个月 (A)、2 岁 (B)、6 岁 (C) 和 17 岁 (D) 时由 Judith E. Allanson 提供资料 [Citation ends]. 这些包括双眼间距大且向下倾斜，虹膜呈碧蓝色或蓝绿色；耳朵低位后旋；倒三角形脸型，下颔小；宽颈或蹼状颈。[Figure caption and citation for the preceding image starts]: 患有 Noonan 综合征的女性， 4 个月 (A)、4 岁 (B) 和成年 (C) 时由 Judith E. Allanson 提供资料 [Citation ends].

睾丸未降是大部分男孩 (60%-69%) 的表现特征，可能与青春发育延迟相关。[1]Jorge AA, Malaquias AC, Arnhold IJ, et al. Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm Res. 2009;71(4):185-93.https://www.karger.com/Article/FullText/201106http://www.ncbi.nlm.nih.gov/pubmed/19258709?tool=bestpractice.com

肺动脉瓣狭窄和/或发育不良、间隔缺损及其他不太常见的结构性心脏缺陷是 Noonan 综合征的主要特征。[30]Shaw AC, Kalidas K, Crosby AH, et al. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007 Feb;92(2):128-32.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2083343/http://www.ncbi.nlm.nih.gov/pubmed/16990350?tool=bestpractice.com

肥厚型心肌病可能发生于子宫内、出生时、婴儿期或幼儿期。

男性可能会出现青春发育延迟。[1]Jorge AA, Malaquias AC, Arnhold IJ, et al. Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm Res. 2009;71(4):185-93.https://www.karger.com/Article/FullText/201106http://www.ncbi.nlm.nih.gov/pubmed/19258709?tool=bestpractice.com[51]Marcus KA, Sweep CG, van der Burgt I, et al. Impaired Sertoli cell function in males diagnosed with Noonan syndrome. J Pediatr Endocrinol Metab. 2008 Nov;21(11):1079-84.http://www.ncbi.nlm.nih.gov/pubmed/19189703?tool=bestpractice.com

女性青春期轻度滞后，月经初潮出现的平均年龄为 14 岁。[30]Shaw AC, Kalidas K, Crosby AH, et al. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007 Feb;92(2):128-32.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2083343/http://www.ncbi.nlm.nih.gov/pubmed/16990350?tool=bestpractice.com

可见容易出现淤伤，有些患者有易出血体质：凝血因子缺乏、血小板功能障碍或两者皆有。[39]Sharland M, Patton MA, Talbot S, et al. Coagulation-factor deficiencies and abnormal bleeding in Noonan's syndrome. Lancet. 1992 Jan 4;339(8784):19-21.http://www.ncbi.nlm.nih.gov/pubmed/1345952?tool=bestpractice.com[40]van der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007 Jan 14;2:4.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781428/http://www.ncbi.nlm.nih.gov/pubmed/17222357?tool=bestpractice.com

应考虑出血体质，如果合适，应进行凝血异常筛查，若存在 Noonan 综合征，则转诊至血液病专科医师。

不到 20% 的病例有淋巴异常。[29]Sharland M, Burch M, McKenna WM, et al. A clinical study of Noonan syndrome. Arch Dis Child. 1992 Feb;67(2):178-83.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1793396/http://www.ncbi.nlm.nih.gov/pubmed/1543375?tool=bestpractice.com

背侧肢体淋巴水肿可能在出生时出现，会导致出生体重增加，并在童年期消退。

淋巴管发育异常可导致肢体水肿、肺或肠淋巴管扩张以及阴囊或阴茎水肿；淋巴管发育异常不太常见但可发生于任何年龄。

治疗具有挑战性，且需要转诊至专科医生。

可见咖啡牛奶斑、雀斑、痣和角化病。

在大多数情况下，与 SOS1、BRAF 和 MAP2K1 基因突变有关。

现已观察到脾肿大，可能是脊髓发育不良的表现。

妊娠期间，提示 Noonan 综合征诊断的最常见的特征是羊水过多（羊水过量）和囊性水瘤（囊性淋巴病变）。[29]Sharland M, Burch M, McKenna WM, et al. A clinical study of Noonan syndrome. Arch Dis Child. 1992 Feb;67(2):178-83.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1793396/http://www.ncbi.nlm.nih.gov/pubmed/1543375?tool=bestpractice.com[43]Achiron R, Heggesh J, Grisaru D, et al. Noonan syndrome: a cryptic condition in early gestation. Am J Med Genet. 2000 May 29;92(3):159-65.http://www.ncbi.nlm.nih.gov/pubmed/10817648?tool=bestpractice.com[44]Benacerraf BR, Greene MF, Holmes LB. The prenatal sonographic features of Noonan's syndrome. J Ultrasound Med. 1989 Feb;8(2):59-63.http://www.ncbi.nlm.nih.gov/pubmed/2651692?tool=bestpractice.com[45]Houweling AC, de Mooij YM, van der Burgt I, et al. Prenatal detection of Noonan syndrome by mutation analysis of the PTPN11 and the KRAS genes. Prenat Diagn. 2010 Mar;30(3):284-6.http://www.ncbi.nlm.nih.gov/pubmed/20112233?tool=bestpractice.com

超声所见的其他特征包括头皮水肿、颈项透明带增厚、胸腔或心包积液、腹水和/或积液（体腔内液体）。[43]Achiron R, Heggesh J, Grisaru D, et al. Noonan syndrome: a cryptic condition in early gestation. Am J Med Genet. 2000 May 29;92(3):159-65.http://www.ncbi.nlm.nih.gov/pubmed/10817648?tool=bestpractice.com[46]Bawle EV, Black V. Nonimmune hydrops fetalis in Noonan's syndrome. Am J Dis Child. 1986 Aug;140(8):758-60.http://www.ncbi.nlm.nih.gov/pubmed/3728401?tool=bestpractice.com

常见胸部宽阔（乳头间距远且位置低）和特定的胸廓畸形（上部鸡胸，下部漏斗状胸）。[Figure caption and citation for the preceding image starts]: 胸部显示典型的胸部畸形，有显著的下部漏斗胸和轻微的上部鸡胸由 Judith E. Allanson 提供资料 [Citation ends].

多达 33% 的病例可见轻度认知障碍，IQ 介于 64-127 之间。[29]Sharland M, Burch M, McKenna WM, et al. A clinical study of Noonan syndrome. Arch Dis Child. 1992 Feb;67(2):178-83.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1793396/http://www.ncbi.nlm.nih.gov/pubmed/1543375?tool=bestpractice.com[34]Allanson JE. Noonan syndrome. J Med Genet. 1987 Jan;24(1):9-13.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1049850/http://www.ncbi.nlm.nih.gov/pubmed/3543368?tool=bestpractice.com

即使 IQ 正常，也可能会出现特异性视觉结构问题、语言表达差异及语言能力滞后或障碍。[29]Sharland M, Burch M, McKenna WM, et al. A clinical study of Noonan syndrome. Arch Dis Child. 1992 Feb;67(2):178-83.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1793396/http://www.ncbi.nlm.nih.gov/pubmed/1543375?tool=bestpractice.com[35]Lee DA, Portnoy S, Hill P, et al. Psychological profile of children with Noonan syndrome. Dev Med Child Neurol. 2005 Jan;47(1):35-8.http://www.ncbi.nlm.nih.gov/pubmed/15686287?tool=bestpractice.com[36]Sarimski K. Developmental and behavioural phenotype in Noonan syndrome? Genet Couns. 2000;11(4):383-90.http://www.ncbi.nlm.nih.gov/pubmed/11140417?tool=bestpractice.com[37]Pierpont EI, Weismer SE, Roberts AE, et al. The language phenotype of children and adolescents with Noonan syndrome. J Speech Lang Hear Res. 2010 Aug;53(4):917-32.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086511/http://www.ncbi.nlm.nih.gov/pubmed/20543023?tool=bestpractice.com

50% 的病例可见肘外翻（前臂的提携角增大），多达三分之一的病例可见手指短且指尖粗钝。

30% 的病例可见关节伸展过度。[29]Sharland M, Burch M, McKenna WM, et al. A clinical study of Noonan syndrome. Arch Dis Child. 1992 Feb;67(2):178-83.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1793396/http://www.ncbi.nlm.nih.gov/pubmed/1543375?tool=bestpractice.com

较为少见的骨骼异常包括马蹄内翻足（畸形足）、关节挛缩、脊柱侧凸及桡尺骨骨性结合（桡骨与尺骨融合）等。

现已证实握力测量可显示肌无力。[41]Stevenson DA, Allen S, Tidyman WE, et al. Peripheral muscle weakness in RASopathies. Muscle Nerve. 2012 Sep;46(3):394-9.http://www.ncbi.nlm.nih.gov/pubmed/22907230?tool=bestpractice.com

见于多达 10% 的病例。肾脏畸形包括双重集合系统、远端输尿管狭窄、肾脏发育不良、单侧肾脏缺如或单侧肾脏异位等畸形。[47]George CD, Patton MA, El Sawi M, et al. Abdominal ultrasound in Noonan syndrome: a study of 44 patients. Pediatr Radiol. 1993;23(4):316-8.http://www.ncbi.nlm.nih.gov/pubmed/8414765?tool=bestpractice.com