Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review
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 objec...
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2025-04-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-025-03706-3 |
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| author | Didier Bessis Dominique Vidaud Pierre Meyer Laurence Pacot de La Villeon G Adeline Alice Bonnard Yline Capri Christine Coubes Fanchon Herman Didier Lacombe Nicolas Molinari Laura Poujade Agathe Roubertie Julien Van Gils Alain Verloes David Geneviève Hélène Cavé Marjolaine Willems |
| author_facet | Didier Bessis Dominique Vidaud Pierre Meyer Laurence Pacot de La Villeon G Adeline Alice Bonnard Yline Capri Christine Coubes Fanchon Herman Didier Lacombe Nicolas Molinari Laura Poujade Agathe Roubertie Julien Van Gils Alain Verloes David Geneviève Hélène Cavé Marjolaine Willems |
| author_sort | Didier Bessis |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-dc11ce227a1c4df4b54ddf742c1ccb15 |
| institution | DOAJ |
| issn | 1750-1172 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-dc11ce227a1c4df4b54ddf742c1ccb152025-08-20T02:55:36ZengBMCOrphanet Journal of Rare Diseases1750-11722025-04-0120111010.1186/s13023-025-03706-3Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature reviewDidier Bessis0Dominique Vidaud1Pierre Meyer2Laurence Pacot3de La Villeon G4Adeline Alice Bonnard5Yline Capri6Christine Coubes7Fanchon Herman8Didier Lacombe9Nicolas Molinari10Laura Poujade11Agathe Roubertie12Julien Van Gils13Alain Verloes14David Geneviève15Hélène Cavé16Marjolaine Willems17Department of Dermatology and Reference Center for Rare Skin Diseases, Filière Maladies Rares Dermatologiques (FIMARAD), MAGEC-Sud Montpellier, Saint-Eloi Hospital and Univ MontpellierFédération de Génétique et Médecine Génomique, Hôpital Cochin, DMU BioPhyGen, AP-HP, Centre-Université Paris CitéDepartment of Pediatric Neurology, Gui de Chauliac Hospital and Univ MontpellierFédération de Génétique et Médecine Génomique, Hôpital Cochin, DMU BioPhyGen, AP-HP, Centre-Université Paris CitéDepartment of Pediatric and Congenital Cardiology, M3C Regional Reference Center, Univ MontpellierDepartment of Genetic Biochemistry, Robert-Debré Hospital, AP-HP and University of Paris-DiderotDepartment of Clinical Genetics and Reference Center, Reference Center for Developmental Anomalies and Malformative Syndromes- Île de France, Robert-Debré Hospital, AP-HP and University of Paris-DiderotDepartment of Clinical Genetics, Arnaud de Villeneuve Hospital, and Univ MontpellierDepartment of Medical Information, Epidemiological and Clinical Research Unit, La Colombière Hospital, University of MontpellierDepartment of Clinical Genetics, Pellegrin University Hospital of Bordeaux, AP-HPDepartment of Medical Information, Epidemiological and Clinical Research Unit, La Colombière Hospital, University of MontpellierDepartment of Dermatology and Reference Center for Rare Skin Diseases, Filière Maladies Rares Dermatologiques (FIMARAD), MAGEC-Sud Montpellier, Saint-Eloi Hospital and Univ MontpellierDepartment of Pediatric Neurology, Gui de Chauliac Hospital and Univ MontpellierDepartment of Clinical Genetics, Pellegrin University Hospital of Bordeaux, AP-HPDepartment of Clinical Genetics and Reference Center, Reference Center for Developmental Anomalies and Malformative Syndromes- Île de France, Robert-Debré Hospital, AP-HP and University of Paris-DiderotDepartment of Clinical Genetics, Arnaud de Villeneuve Hospital, and Univ MontpellierDepartment of Genetic Biochemistry, Robert-Debré Hospital, AP-HP and University of Paris-DiderotDepartment of Clinical Genetics, Arnaud de Villeneuve Hospital, and Univ MontpellierAbstract 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.https://doi.org/10.1186/s13023-025-03706-3Neurofibromatosis type 1Noonan syndromeNF1RASopathiesCardiovascular malformation |
| spellingShingle | Didier Bessis Dominique Vidaud Pierre Meyer Laurence Pacot de La Villeon G Adeline Alice Bonnard Yline Capri Christine Coubes Fanchon Herman Didier Lacombe Nicolas Molinari Laura Poujade Agathe Roubertie Julien Van Gils Alain Verloes David Geneviève Hélène Cavé Marjolaine Willems Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review Orphanet Journal of Rare Diseases Neurofibromatosis type 1 Noonan syndrome NF1 RASopathies Cardiovascular malformation |
| title | Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review |
| title_full | Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review |
| title_fullStr | Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review |
| title_full_unstemmed | Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review |
| title_short | Neurofibromatosis-Noonan syndrome: a prospective monocentric study of 26 patients and literature review |
| title_sort | neurofibromatosis noonan syndrome a prospective monocentric study of 26 patients and literature review |
| topic | Neurofibromatosis type 1 Noonan syndrome NF1 RASopathies Cardiovascular malformation |
| url | https://doi.org/10.1186/s13023-025-03706-3 |
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