Genetic Defects in Children with Cardiac Anomalies/Malformations: Noonan and CFC Syndromes

Abstract

Cardiac defects presenting in childhood show significant phenotypic and genetic heterogeneity. With availability of advanced genetic technologies, these can be detected early using specialized testing. Prenatal testing is currently feasible with improved ultrasonography and fetal echocardiography. Here, we report two cases of Noonan's and cardiofaciocutaneous syndromes in patients seen in the genetic unit of a tertiary care center presenting with cardiac defect with or without developmental delay, short stature, and dysmorphism. In these conditions, there is also increased risk of malignancy such as juvenile myelomonocytic leukemia. With the advent of next-generation sequencing, definitive diagnosis and counseling is possible in this group of conditions.

Keywords

dysmorphism - Noonan's syndrome - NGS - septal defect - cardiomyopathy - LZTR1

Authors' Contributions

All authors helped in collection of data for the manuscript. I.P. was involved in management and follow-up of the patients. M.K.R. was involved in the cardiac evaluation and management. D.K. was involved in drafting of the manuscript. All authors have read and approved the final manuscript.

Publication History

Received: 16 August 2020

Accepted: 25 October 2020

Article published online:
10 December 2020

• References

• 1 Richards AA, Garg V. Genetics of congenital heart disease. Curr Cardiol Rev 2010; 6 (02) 91-97
• 2 Calcagni G, Unolt M, Digilio MC. et al. Congenital heart disease and genetic syndromes: new insights into molecular mechanisms. Expert Rev Mol Diagn 2017; 17 (09) 861-870
• 3 Pierpont ME, Basson CT, Benson Jr DW. et al; American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115 (23) 3015-3038
• 4 Tafazoli A, Eshraghi P, Koleti ZK, Abbaszadegan M. Noonan syndrome - a new survey. Arch Med Sci 2017; 13 (01) 215-222
• 5 Romano AA, Allanson JE, Dahlgren J. et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 2010; 126 (04) 746-759
• 6 Rodriguez-Viciana P, Tetsu O, Tidyman WE. et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 2006; 311 (5765): 1287-1290
• 7 Yamamoto GL, Aguena M, Gos M. et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet 2015; 52 (06) 413-421
• 8 Jorge AA, Malaquias AC, Arnhold IJ, Mendonca BB. Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm Res 2009; 71 (04) 185-193
• 9 van der Burgt I. Noonan syndrome. Orphanet J Rare Dis 2007; 2: 4
• 10 Gripp KW, Morse LA, Axelrad M. et al. Costello syndrome: clinical phenotype, genotype, and management guidelines. Am J Med Genet A 2019; 179 (09) 1725-1744
• 11 Ko JM. Genetic syndromes associated with congenital heart disease. Korean Circ J 2015; 45 (05) 357-361
• 12 Lepri FR, Scavelli R, Digilio MC. et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet 2014; 15: 14
• 13 Fahed AC, Gelb BD, Seidman JG, Seidman CE. Genetics of congenital heart disease: the glass half empty. Circ Res 2013; 112 (04) 707-720
• 14 Ranza E, Guimier A, Verloes A. et al. Overlapping phenotypes between SHORT and Noonan syndromes in patients with PTPN11 pathogenic variants. Clin Genet 2020; 98 (01) 10-18
• 15 Malaquias AC, Noronha RM, Souza TTO. et al. Impact of growth hormone therapy on adult height in patients with PTPN11 mutations related to Noonan syndrome. Horm Res Paediatr 2019; 91 (04) 252-261