How to Cite this Article: Prada CE, Zarate YA, Hagenbuch S, Lovell A, Schorry EK, Hopkin RJ. 2011. Lethal presentation of neurofibromatosis and Noonan syndrome. Am J Med Genet Part A 155:1360–1366.
Lethal presentation of neurofibromatosis and Noonan syndrome†
Article first published online: 12 MAY 2011
Copyright © 2011 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 155, Issue 6, pages 1360–1366, June 2011
How to Cite
Prada, C. E., Zarate, Y. A., Hagenbuch, S., Lovell, A., Schorry, E. K. and Hopkin, R. J. (2011), Lethal presentation of neurofibromatosis and Noonan syndrome. Am. J. Med. Genet., 155: 1360–1366. doi: 10.1002/ajmg.a.33996
- Issue published online: 20 MAY 2011
- Article first published online: 12 MAY 2011
- Manuscript Accepted: 20 FEB 2011
- Manuscript Received: 6 MAR 2010
- neurofibromatosis type 1;
- Noonan syndrome;
- neurofibromatosis–Noonan syndrome;
- Ras pathway;
Neurofibromatosis type 1 and Noonan syndrome are both common genetic disorders with autosomal dominant inheritance. Similarities between neurofibromatosis type 1 and Noonan syndrome have been noted for over 20 years and patients who share symptoms of both conditions are often given the diagnosis of neurofibromatosis–Noonan syndrome (NFNS). The molecular basis of these combined phenotypes was poorly understood and controversially discussed over several decades until the discovery that the syndromes are related through disturbances of the Ras pathway. We present an infant male with coarse facial features, severe supravalvar pulmonic stenosis, automated atrial tachycardia, hypertrophic cardiomyopathy, airway compression, severe neurological involvement, and multiple complications that lead to death during early infancy. The severity of clinical presentation and significant dysmorphic features suggested the possibility of a double genetic disorder in the Ras pathway instead of NFNS. Molecular analysis showed a missense mutation in exon 25 of the NF1 gene (4288A>G, p.N1430D) and a pathogenic mutation on exon 8 (922A>G, p.N308D) of the PTPN11 gene. Cardiovascular disease has been well described in patients with Noonan syndrome with PTPN11 mutations but the role of haploinsufficiency for neurofibromin in the heart development and function is not yet well understood. Our case suggests that a double genetic defect resulting in the hypersignaling of the Ras pathway may lead to complex cardiovascular abnormalities, cardiomyopathy, refractory arrhythmia, severe neurological phenotype, and early death. © 2011 Wiley-Liss, Inc.