NF1 – Neurofibromatosis-Noonan Syndrome

Neurofibromatosis-Noonan syndrome (NFNS) is a rare RASopathy combining clinical features of neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Affected individuals exhibit café-au-lait macules, Lisch nodules, and plexiform neurofibromas typical of NF1 alongside characteristic NS facies, short stature, and occasional congenital heart defects.

Multiple independent studies have identified heterozygous NF1 variants in NFNS patients, supporting a strong gene–disease relationship. Over 14 unrelated probands with NFNS harboring NF1 variants have been described across six publications, including an informative multigenerational family segregating c.2970_2972del (p.Met992del) ([PMID:16542390]) and eight individuals from three families with diverse NF1 variants ([PMID:24357598]).

The inheritance of NFNS due to NF1 is autosomal dominant. Segregation analysis in the 2006 family demonstrated co-segregation of c.2970_2972del (p.Met992del) with NFNS features in four additional relatives ([PMID:16542390]). Case reports have documented at least six additional unrelated probands carrying NF1 nonsense variants (e.g., c.7549C>T (p.Arg2517Ter) ([PMID:22965773]), c.7909C>T (p.Arg2637Ter) ([PMID:26758488])) and frameshift or exon-level deletions (e.g., NF1 exons 1–58 deletion ([PMID:32357851])).

The NF1 variant spectrum in NFNS includes in-frame deletions (c.2970_2972del (p.Met992del)), nonsense substitutions (c.7549C>T (p.Arg2517Ter)), frameshifts (c.3053_3057del (p.Leu1018Ter)), splice-site mutations, and large multi-exon deletions. The recurrent in-frame deletion c.2970_2972del has been observed in both European and Chinese NFNS cases ([PMID:16542390]; [PMID:32357851]).

Functional assays demonstrate that the NF1 GAP-related domain stimulates Ras GTPase activity, consistent with a loss-of-function mechanism in RAS-MAPK dysregulation. Expression of the NF1 catalytic domain complements yeast ira mutants and enhances GTP hydrolysis of human H-ras, supporting pathogenicity of NF1 variants in NFNS ([PMID:2121369]).

Some NFNS phenotypes may involve additional RASopathy genes: rare cases harbor concurrent PTPN11 and NF1 mutations, suggesting additive effects but NF1 allelic heterogeneity alone suffices for NFNS ([PMID:19449407]). No studies have conclusively refuted NF1 involvement in bona fide NFNS individuals.

In summary, heterozygous NF1 loss-of-function variants cause NFNS via autosomal dominant inheritance, with robust genetic and functional evidence. NF1 testing should be incorporated into RASopathy panels for patients with overlapping NF1 and NS features to enable accurate diagnosis and management. Key take-home: NF1 allelic heterogeneity underlies NFNS and informs targeted genetic testing for this dual-phenotype disorder.

References

• Clinical genetics • 2006 • Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype. PMID:16542390
• American journal of medical genetics. Part A • 2014 • Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. PMID:24357598
• Cell • 1990 • The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. PMID:2121369
• BMC pediatrics • 2020 • Chinese patient with neurofibromatosis-Noonan syndrome caused by novel heterozygous NF1 exons 1-58 deletion: a case report. PMID:32357851
• Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery • 2012 • A new nonsense mutation in the NF1 gene with neurofibromatosis-Noonan syndrome phenotype. PMID:22965773
• American journal of medical genetics. Part A • 2009 • Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome. PMID:19449407

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