Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Neurofibromatosis-Noonan Syndrome (NF/NS) [Q81.9]

OMIM numbers: 601321, 613113 (NF1), 176876 (PTPN11)

Dr. rer. biol hum. Soheyla Chahrokh-Zadeh

Scientific Background

Neurofibromatosis type 1 is one of the most frequently occurring autosomal dominant diseases, caused by mutations in the NF1 gene. The affected protein, the RAS-specific GTPase neurofibromin, is involved in the RAS/Mitogen-activated protein kinase signaling pathway, which is why the disease falls into the category of what is known as RASopathies. Although inheritance is monogenic, the clinical picture is highly variable, even within one family. Clinical signs and symptoms of the Noonan syndrome were repetitively observed in patients with neurofibromatosis type 1; therefore, the question whether this is an independent clinical picture, the “neurofibromatosis-Noonan syndrome” or if the NF1 Noonan phenotype is an allelic variant of one of the two clinical pictures was subject of discussion. So far, there is no clear answer; however, the available data suggests that NF/NS is a phenotypical variant of NF1.

Some signs such as short stature, disorder of the psychomotor development and skeletal deformities occur in both diseases with similar frequency. NF/NS patients moreover display café au lait spots, neurofibromas, optic glioma, and clinical signs and symptoms of the Noonan syndrome such as facial dysmorphia and cardiac defect.

NF/NS patients have mutations mainly in the NF1 gene. They predominantly affect what is called the “GAP related domain”, occasionally also other regions of neurofibromin. The NF1 mutations detected in NF/NS patients may in some cases cause the typical NF1 phenotype. Other NF1 mutations cause the NF/NS phenotype without fibromas. Moreover, the literature describes NF/NS patients with mutations in two genes, NF1 and PTPN11. In addition, families affected by neurofibromatosis type 1 are described, in which later generations for the first time developed the combined “NF/NS syndrome” with the full Noonan phenotype. None of the NF1 patients, however, had the full Noonan syndrome spectrum with cardiac defects.