神经纤维瘤病-努南综合征：26例患者的前瞻性单中心研究及文献综述

Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review.

作者信息

Bessis Didier, Vidaud Dominique, Meyer Pierre, Pacot Laurence, G de La Villeon, Bonnard Adeline Alice, Capri Yline, Coubes Christine, Herman Fanchon, Lacombe Didier, Molinari Nicolas, Poujade Laura, Roubertie Agathe, Van Gils Julien, Verloes Alain, Geneviève David, Cavé Hélène, Willems Marjolaine

机构信息

Department of Dermatology and Reference Center for Rare Skin Diseases, Filière Maladies Rares Dermatologiques (FIMARAD), MAGEC-Sud Montpellier, Saint-Eloi Hospital and Univ Montpellier, Montpellier, France.

Fédération de Génétique et Médecine Génomique, Hôpital Cochin, DMU BioPhyGen, AP-HP, Centre-Université Paris Cité, Paris, France.

出版信息

Orphanet J Rare Dis. 2025 Apr 27;20(1):201. doi: 10.1186/s13023-025-03706-3.

DOI:10.1186/s13023-025-03706-3

PMID:40289159

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12036184/

Abstract

BACKGROUND

Data on clinical manifestations of neurofibromatosis-Noonan syndrome (NF-NS) remain heterogeneous, with limited validated descriptions.

METHODS

This study aims to better define the clinical and molecular features of NF-NS and compare them with existing literature. Secondary objectives include evaluating inter-rater diagnostic agreement among experienced clinicians and assessing the utility of deep-learning algorithms (Face2Gene [F2G]). Additionally, we assess the prevalence of congenital heart malformations (CHM) in NF-NS compared to 'classic' neurofibromatosis type 1 (NF1). A 9-year, prospective, monocentric study was conducted, involving patients with NF1 pathogenic variants (PVs) and Noonan syndrome-like facial phenotype (NSLFP).

RESULTS

Twenty-six patients were enrolled. NSLFP was categorized as 'suggestive' in 69% of cases and 'typical' in 31%. The presence of at least two facial abnormalities (e.g., low-set ears, downslanted palpebral fissures, hypertelorism, and ptosis) was consistently observed in 'typical' cases. Inter-rater concordance was substantial (0.65 [95% CI = 0.56; 0.74]), while concordance between clinicians and F2G was almost perfect at (0.821 [CI 95% = 0.625; 1.000]). Missense NF1 PVs were observed in 38.5% of cases. Apart from NSLP and a high frequency of pectus excavatum (62.5%), no significant differences in anthropometric, dermatological, neurological, skeletal, or ocular clinical features were observed between NF-NS and 'classic' NF1. CHM were found in 19.2% of NF-NS patients, with pulmonic stenosis present in 7.7%.

CONCLUSION

NF-NS is a distinct phenotypic variant of NF1, marked by NSLP with consistent facial features -, and frequent pectus excavatum. F2G demonstrated high diagnostic concordance, reinforcing its clinical utility. Given the elevated risk of CHM, especially pulmonic stenosis, proactive cardiovascular assessment similar to other RASopathies is recommended for NS-NF patients, regardless of NF1 PV type.

摘要

背景

神经纤维瘤病-努南综合征（NF-NS）的临床表现数据仍然存在异质性，经过验证的描述有限。

方法

本研究旨在更好地界定NF-NS的临床和分子特征，并将其与现有文献进行比较。次要目标包括评估经验丰富的临床医生之间的诊断一致性，以及评估深度学习算法（Face2Gene [F2G]）的实用性。此外，我们评估了与“经典”1型神经纤维瘤病（NF1）相比，NF-NS中先天性心脏畸形（CHM）的患病率。进行了一项为期9年的前瞻性单中心研究，纳入了具有NF1致病变异（PVs）和努南综合征样面部表型（NSLFP）的患者。

结果

共纳入26例患者。69%的病例中NSLFP被归类为“疑似”，31%为“典型”。在“典型”病例中始终观察到至少两种面部异常（如低位耳、下斜睑裂、眼距增宽和上睑下垂）。评分者间的一致性较高（0.65 [95%CI = 0.56; 0.74]），而临床医生与F2G之间的一致性几乎完美，为0.821 [CI 95% = 0.625; 1.000]）。38.5%的病例中观察到错义NF1 PVs。除了NSLP和高频率的漏斗胸（62.5%）外，NF-NS与“经典”NF1在人体测量、皮肤、神经、骨骼或眼部临床特征方面未观察到显著差异。19.2%的NF-NS患者发现有CHM，其中肺动脉狭窄占7.7%。