SCIENTIFIC BACKGROUND

NF1, PTPN11

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Scientific Background

 

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant inherited disorders caused by pathogenic variants in the NF1 gene. The corresponding protein, Ras-specific GTPase neurofibromin, is involved in the Ras/mitogen-activated protein kinase signaling pathway. Therefore, NF1 is classified as RASopathy. Although being monogenically inherited, the clinical presentation is highly variable, even within a family. Repeated observations of clinical symptoms of Noonan syndrome in NF1 patients initially led to a discussion as to whether this is an independent clinical picture, the so-called “Neurofibromatosis Noonan syndrome”, or whether the NF1 Noonan phenotype represents an allelic variant of one of the two clinical pictures. So far, this has not been clarified. According to the available data, it is more likely that NF/NS should be classified as a phenotypic variant of NF1.

 

Several symptoms such as short stature, psychomotor developmental disorder and skeletal deformities occur in both disorders with a comparable frequency. Otherwise, café-au-lait spots, neurofibromas, optic gliomas, and clinical symptoms of Noonan syndrome such as facial dysmorphia and cardiac defects are also present in NF/NS patients.

 

In the NF/NS patient group, variants are mainly found in the NF1 gene with the majority affecting the so-called “GAP-related domain”, and in isolated cases also other regions of the neurofibromin. In some cases, the NF1 variants detected in NF/NS patients can also lead to the typical NF1 phenotype. Other NF1 variants result in an NF/NS phenotype without neurofibromas. In addition, NF/NS patients with pathogenic variants in two genes, NF1 and PTPN11, have also been described in the literature. There are also reports of NF1 families in which the combined “NF/NS syndrome” with the complete Noonan phenotype first appeared in later generations. However, none of the NF1 patients had the complete Noonan syndrome spectrum with cardiac defects.

 

References

Cizmárová et al. 2016, Annals of Hum Genet 80:50 / Ben-Shachar et al. 2012, Eur J Hum Genet. 21:535 / Gámez & Truchuelo 2011, Dermatology Online Journal 17:4 / Tartaglia et al. 2011, Best Pract Res Clin Endocrin Metab. 25:161 / Nyström et al. 2009, Clin Genet. 76:524 / Carey 1998, Am J Med Genet. 75:263

GENES

NF1, PTPN11
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