Both Neurofibromatosis Type 1 (NF1; 1: 3,000) and Noonan Syndrome (NS; 1: 500–2,500 births) are caused by distinct gene mutations in the RAS-MAPK pathway. A subset of NF1 patients present with variable features seen in both Neurofibromatosis and Noonan Syndrome broadly described as Neurofibromatosis-Noonan Syndrome (NFNS). Despite repeated reports exploring this concomitant presentation, the discussion remains open on the classification of NFNS as a variant of NF1, or as an entirely different clinical diagnosis.

Case Description

A 19 month male patient with clinical features of both Neurofibromatosis Type 1 and Noonan Syndrome with a family history of clinically suspected Noonan syndrome presented at birth with two cafe-au-lait spots, one on the right thigh and one on the abdomen, with an otherwise normal physical exam. At two months of age, the patient failed to thrive due to poor weight gain and short stature. In addition to two new cafe-au-lait spots and hypertelorism, auscultation revealed a new murmur, later identified as an isolated mild pulmonary valve stenosis. Genetic testing revealed a heterozygous variant missense mutation in the NF1 gene, leading to a formal diagnosis of NF1 Variant of Unknown Significance, with no concomitant PTPN11 mutation. Further assessment of the patient will require routine follow ups with ophthalmology, cardiology, and neurology, as well as genetic testing of the mother to confirm inheritance. 

Maternal history of congenital heart defect, hypertelorism, triangular face, and developmental delay further supported the need for genetic evaluation of the patient. After testing of multiple RASopathy-related genes, a heterozygous variant missense mutation in the NF1 gene was found, leading to a formal diagnosis of NF1 Variant of Unknown Significance.

As evidenced by our case, a majority of NFNS cases have identified isolated mutations in the NF1 gene, as opposed to mutations in both the PTPN11 and NF1 genes.