Hostname: page-component-8448b6f56d-42gr6 Total loading time: 0 Render date: 2024-04-17T21:37:14.230Z Has data issue: false hasContentIssue false

Cardiac features of Noonan syndrome in Japanese patients

Published online by Cambridge University Press:  27 April 2022

Yasuhiro Ichikawa*
Affiliation:
Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan
Hiroyuki Kuroda
Affiliation:
Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan
Takeshi Ikegawa
Affiliation:
Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan
Shun Kawai
Affiliation:
Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan
Shin Ono
Affiliation:
Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan
Ki-Sung Kim
Affiliation:
Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan
Sadamitsu Yanagi
Affiliation:
Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan
Kenji Kurosawa*
Affiliation:
Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan
Yoko Aoki
Affiliation:
Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan
Hideaki Ueda
Affiliation:
Department of Cardiology, Kanagawa Children’s Medical Center, Yokohama, Japan
*
Author for correspondence: Yasuhiro Ichikawa or Kenji Kurosawa, Kanagawa Children’s Medical Center, Yokohama, Japan, 2-138-4 Mutsukawa, Minami-ku, Yokohama 232-8555, Japan. Tel: +81 45 711 2351; Fax: +81-45-721-3324. E-mail: yas1lll@yahoo.co.jp or kkurosawa@kcmc.jp
Author for correspondence: Yasuhiro Ichikawa or Kenji Kurosawa, Kanagawa Children’s Medical Center, Yokohama, Japan, 2-138-4 Mutsukawa, Minami-ku, Yokohama 232-8555, Japan. Tel: +81 45 711 2351; Fax: +81-45-721-3324. E-mail: yas1lll@yahoo.co.jp or kkurosawa@kcmc.jp

Abstract

Background:

Cardiovascular disease is one of the most important problems in long-term follow-up for Noonan syndrome. We examined cardiovascular issues and clinical manifestations, with a focus on the cardiovascular disease and prognosis of patients with Noonan syndrome.

Methods:

This single-centre study evaluated patients who were clinically and genetically diagnosed with Noonan syndrome.

Results:

Forty-three patients diagnosed with Noonan syndrome were analysed. The most prevalent responsible mutation was found in PTPN11 (25/43). The second and third most prevalent causative genes were SOS1 (6/43) and RIT1 (5/43), respectively, and 67.4% of genetically diagnosed patients with Noonan syndrome had structural cardiovascular abnormalities. Pulmonary valve stenosis was prevalent in patients with mutations in PTPN11 (8/25), SOS1 (4/6), and RIT1 (4/5). Hypertrophic cardiomyopathy was found in two of three patients with mutations in RAF1. There was no difference in the cardiovascular events or cardiovascular disease prevalence in patients with or without PTPN11 mutations. The proportion of RIT1 mutation-positive patients who underwent intervention due to cardiovascular disease was significantly higher than that of patients with PTPN11 mutations. Patients who underwent any intervention for pulmonary valve stenosis exhibited significantly higher pulmonary flow velocity than patients who did not undergo intervention, when they visited our hospital for the first time. All patients who underwent intervention for pulmonary valve stenosis had a pulmonary flow velocity of more than 3.0 m/s at first visit.

Conclusions:

These findings suggest that genetic information can provide a clinical prognosis for cardiovascular disease and may be part of genotype-based follow-up in Noonan syndrome.

Type
Original Article
Copyright
© The Author(s), 2022. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Noonan, JA. Hypertelorism with Turner phenotype. a new syndrome with associated congenital heart disease. Am J Dis Child 1968; 116: 373380.CrossRefGoogle ScholarPubMed
Mendez, HM, Opitz, JM. Noonan syndrome: a review. Am J Med Genet 1985; 21: 493506.CrossRefGoogle ScholarPubMed
Roberts, AE, Allanson, JE, Tartaglia, M, Gelb, BD. Noonan syndrome. Lancet 2013; 381: 333342.CrossRefGoogle ScholarPubMed
Baban, A, Olivini, N, Lepri, FR et al. SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review. Am J Med Genet A 2019; 179: 20832090.CrossRefGoogle Scholar
Calcagni, G, Adorisio, R, Martinelli, S et al. Clinical Presentation and natural history of Hypertrophic Cardiomyopathy in RASopathies. Heart Fail Clin 2018; 14: 225235.CrossRefGoogle ScholarPubMed
Tekendo-Ngongang, C, Agenbag, G, Bope, CD, Esterhuizen, AI, Wonkam, A. Noonan syndrome in South Africa: clinical and molecular profiles. Front Genet 2019; 10: 333.CrossRefGoogle ScholarPubMed
Yu, KPT, Luk, HM, Leung, GKC et al. Genetic landscape of RASopathies in Chinese: three decades’ experience in Hong Kong. Am J Med Genet C 2019; 181: 208217.Google ScholarPubMed
Aoki, Y, Niihori, T, Banjo, T et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet 2013; 93: 173180.CrossRefGoogle ScholarPubMed
Prendiville, TW, Gauvreau, K, Tworog-Dube, E et al. Cardiovascular disease in Noonan syndrome. Arch Dis Child 2014; 99: 629634.CrossRefGoogle ScholarPubMed
Gelb, BD, Roberts, AE, Tartaglia, M. Cardiomyopathies in Noonan syndrome and the other RASopathies. Prog Pediatr Cardiol 2015; 39: 1319.CrossRefGoogle ScholarPubMed
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; 70: 15551563.CrossRefGoogle ScholarPubMed
Pandit, B, Sarkozy, A, Pennacchio, LA et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 2007; 39: 10071012.CrossRefGoogle ScholarPubMed
van der Burgt, I. Noonan syndrome. Orphanet J Rare Dis 2007; 2: 4.CrossRefGoogle ScholarPubMed
Narumi, Y, Aoki, Y, Niihori, T et al. Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. Am J Med Genet A 2007; 143: 799807.CrossRefGoogle Scholar
Umeki, I, Niihori, T, Abe, T et al. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Hum Genet 2019; 138: 2135.CrossRefGoogle ScholarPubMed
Nishimura, N, Murakami, H, Hayashi, T, Sato, H, Kurosawa, K. Multiple craniosynostosis and facial dysmorphisms with homozygous IL11RA variant caused by maternal uniparental isodisomy of chromosome 9. Congenit Anom (Kyoto). 2020; 60: 153155.Google ScholarPubMed
Athota, JP, Bhat, M, Nampoothiri, S et al. Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. BMC Med Genet 2020; 21: 50.CrossRefGoogle ScholarPubMed
Shoji, Y, Ida, S, Niihori, T et al. Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome. Endocr J 2019; 66: 983994.CrossRefGoogle ScholarPubMed
Shaw, AC, Kalidas, K, Crosby, AH, Jeffery, S, Patton, MA. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child 2007; 92: 128132.CrossRefGoogle ScholarPubMed
Zenker, M, Horn, D, Wieczorek, D et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet 2007; 44: 651656.CrossRefGoogle ScholarPubMed
Calcagni, G, Limongelli, G, D’Ambrosio, A et al. Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results. Int J Cardiol 2017; 245: 9298.CrossRefGoogle ScholarPubMed
Wilkinson, JD, Lowe, AM, Salbert, BA et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry. Am Heart J 2012; 164: 442448.CrossRefGoogle ScholarPubMed
Colan, SD, Lipshultz, SE, Lowe, AM et al. Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007; 115: 773781.CrossRefGoogle ScholarPubMed
Yaoita, M, Niihori, T, Mizuno, S et al. Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. Hum Genet 2016; 135: 209222.CrossRefGoogle ScholarPubMed
Calcagni, G, Baban, A, Lepri, FR et al. Congenital heart defects in Noonan syndrome and RIT1 mutation. Genet Med 2016; 18: 1320.CrossRefGoogle ScholarPubMed
Kouz, K, Lissewski, C, Spranger, S et al. Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation. Genet Med 2016; 18: 12261234.CrossRefGoogle Scholar
Colquitt, JL, Noonan, JA. Cardiac findings in Noonan syndrome on long-term follow-up. Congenit Heart Dis 2014; 9: 144150.CrossRefGoogle ScholarPubMed
Holzmann, J, Tibby, SM, Rosenthal, E et al. Results of balloon pulmonary valvoplasty in children with Noonan’s syndrome. Cardiol Young 2018; 28: 647652.CrossRefGoogle ScholarPubMed
Linglart, L, Gelb, BD. Congenital heart defects in Noonan syndrome: diagnosis, management, and treatment. Am J Med Genet C 2020; 184: 7380.CrossRefGoogle ScholarPubMed
Mangovski, L, Farkić, M, Jovović, L. Transcatheter closure of atrial septal defect in a patient with Noonan syndrome after corrective surgery. Vojnosanit Pregl 2015; 72: 557560.CrossRefGoogle Scholar
Supplementary material: File

Ichikawa et al. supplementary material

Table S1

Download Ichikawa et al. supplementary material(File)
File 18.5 KB
Supplementary material: File

Ichikawa et al. supplementary material

Table S3

Download Ichikawa et al. supplementary material(File)
File 16.9 KB
Supplementary material: File

Ichikawa et al. supplementary material

Table S2

Download Ichikawa et al. supplementary material(File)
File 17.6 KB
Supplementary material: File

Ichikawa et al. supplementary material

Table S4

Download Ichikawa et al. supplementary material(File)
File 16.9 KB