新生儿Noonan综合征2例并文献复习

Neonatal-Onset Noonan Syndrome: Two Cases Reports and Literature Review

摘要: 目的：探讨合并血小板减少的新生儿Noonan综合征(Noonan syndrome, NS)的临床表型和基因特点。方法：对青岛大学附属医院新生儿科收治的2例新生儿Noonan综合征患儿临床资料进行回顾性分析。并以“新生儿”、“Noonan综合征”、“努南综合征”、“翼状颈综合征”、“假性Turner综合征”、“Turner男性表型”、“男性Turner综合征”为关键词检索中国知网、万方数据库、维普数据库、中华医学期刊全文数据库；以“nenatal”、“Noonan syndrome”、“Pterygium Colli Syndrome”、“Pseudo-Turner Syndrome”、“Male Turner Syndrome”、“Turner Phenotype in Male”为关键词检索生物医学文献数据库(PubMed)、荷兰医学文摘(Embase)；检索时间自建库至2024年12月31日收录的文献，选取其中合并血小板减少的文献，总结合并血小板减少的新生儿Noonan综合征的临床表型和基因特点。结果：本院共收治新生儿Noonan综合征2例，男女各1例，均在生后出现血小板减少。例1全外显子测序分析回报示基因PTPN11杂合变异，外显子13错义突变，C.1507G>A (p.Gly503Arg)，随访至70天，发生Noonan综合征相关骨髓增生性疾病/幼年型粒单核细胞白血病，给予水化碱化治疗后失访。例2全外显子测序分析回报示基因RAF1杂合变异，外显子7错义突变，C.770C>T (p.Ser257Leu)，随访至35天，因颅内出血后进行性加重的脑积水死亡，为RAF1基因突变首次报道的新生儿Noonan综合征血小板减少合并颅内出血后脑积水的致死病例。检索国内外文献24篇共收集28例患儿，加上本文2例共30例，死亡13例，因血小板减少死亡1例。综合30例新生儿Noonan综合征患儿的临床特点，除存在血小板减少外，主要表现为心脏异常、特殊面容、产前检查异常、呼吸困难、隐睾、淋巴发育不良、神经系统异常等，携带PTPN11基因突变的25例，包括错义突变24例、缺失突变1例，共死亡9例；携带SHOC2基因错义突变的2例，死亡2例；携带RAF1基因错义突变的1例，死亡1例；携带NRAS基因错义突变的1例，死亡1例；其余1例未行基因检测，临床诊断为Noonan综合征。结论：合并血小板减少的新生儿Noonan综合征患儿主要表现为心脏异常、特殊面容、产前检查异常、呼吸困难、隐睾、淋巴发育不良、神经系统异常等，在本研究的小样本异质性队列中，未观察到血小板减少与不良预后存在明确的相关性，初步观察提示携带SHOC2、RAF1、NRAS基因变异的患儿可能具有较严重的临床表型。

Abstract: Objective: To study the clinical phenotypes and genetic characteristics of neonatal Noonan syndrome (NS) complicated by thrombocytopenia. Methods: Clinical data of two neonates with NS admitted to the Neonatal Department of the Affiliated Hospital of Qingdao University were retrospectively analyzed. Literature databases, including CNKI, Wanfang, VIP, Chinese Medical Journal Full-text Database, PubMed, Embase, were searched using keywords such as “neonatal”, “Noonan syndrome”, “Pterygium Colli Syndrome”, “Pseudo-Turner Syndrome”, “Male Turner Syndrome”, and “Turner Phenotype in Male” (Chinese and English terms) from inception to December 31, 2024. Articles reporting NS neonates with thrombocytopenia were selected to summarize the clinical phenotypes and genetic features. Results: Two neonates with NS (one male, one female) were admitted to our hospital, both presenting with thrombocytopenia after birth. Case 1 had a heterozygous variant in the PTPN11 gene (exon 13 missense mutation, c.1507G>A, p.Gly503Arg). Follow-up at 70 days revealed NS-associated myeloproliferative disorder/juvenile myelomonocytic leukemia; the patient was lost to follow-up after hydration and alkalization therapy. Case 2 had a heterozygous variant in the RAF1 gene (exon 7 missense mutation, c.770C>T, p.Ser257Leu). The patient died at 35 days due to progressive hydrocephalus following intracranial hemorrhage, representing the first reported fatal case of neonatal NS with thrombocytopenia complicated by post-hemorrhagic hydrocephalus associated with a RAF1 mutation. Literature review identified 24 articles reporting 28 cases; combined with our 2 cases, a total of 30 neonates were included. Thirteen died, with one death attributed to thrombocytopenia. The main clinical manifestations among the 30 neonates with NS and thrombocytopenia, beyond thrombocytopenia, included cardiac abnormalities, characteristic facial features, prenatal anomalies, respiratory distress, cryptorchidism, lymphatic dysplasia, and neurological abnormalities. Twenty-five cases harbored PTPN11 mutations (24 missense, 1 deletion), with 9 deaths. Two cases had SHOC2 missense mutations, both fatal. One case had a RAF1 missense mutation and died. One case had an NRAS missense mutation and died. One case was clinically diagnosed with NS without genetic testing. Conclusion: In neonates with Noonan syndrome and concomitant thrombocytopenia, the predominant clinical manifestations included cardiac anomalies, characteristic facies, abnormal prenatal findings, respiratory distress, cryptorchidism, lymphatic dysplasia, and neurological abnormalities. Within this small, heterogeneous cohort study, no clear correlation was observed between thrombocytopenia and adverse outcomes. Preliminary observations suggest that infants harboring variants in the SHOC2, RAF1, and NRAS genes may be associated with more severe clinical phenotypes.