Neurofibromatosis-Noonan syndrome

NF1 is a multisystem genetic disorder with marked interindividual phenotypic variability. Clinical manifestations range from isolated pigmentary abnormalities, such as café-au-lait macules and axillary or inguinal freckling, to more severe complications, including intellectual disability, skeletal defects, central and peripheral nervous system tumours, and cerebrovascular disease. NF1 has complete penetrance and shows age-dependent appearance of manifestations. Clinical presentation of NF1 is multisystemic and highly unpredictable, especially in the first years of life when penetrance is still incomplete. Clinical diagnosis of NF1 relies on validated diagnostic criteria (Legius et al., International Consensus Group, 2021, PMID: ) and remains the cornerstone of disease identification. NF1 also shares overlapping clinical features with other RASopathies, including Noonan syndrome (NS), such as pigmentary abnormalities, neurocognitive deficits, dysmorphic features, and tumour predisposition, which may complicate differential diagnosis. NS is frequently caused by activating PTPN11 variants affecting SHP2, a positive regulator of RAS-MAPK signaling, and selected variants have been associated with susceptibility to paediatric malignancies. Previously classified as a separate disorder, NFNS is currently considered a recognisable NF1 subtype linked to a limited number of missense variants. Nevertheless, concomitant pathogenic variants in NF1 and PTPN11 may give rise to a complex phenotype resembling NFNS.

The estimated incidence of NF1 is approximately 1/2,000 to 1/3,000 live births. NF-NS occurs in approximately 12% of individuals with NF1.

NF1 is caused by germline pathogenic variants in NF1, a tumour suppressor gene encoding neurofibromin, a negative regulator of the RAS/MAPK pathway. This explains why NF1 is included in the group of and shares several clinical features with .

NFNS is caused by germline pathogenic variants in NF1. Loss-of-function variants in NF1 increase RAS-MAPK pathway activity, the same downstream mechanism dysregulated in Noonan syndrome and other RASopathies. In a minority of NFNS- individuals, concurrent pathogenic variants in PTPN11 (the gene most often involved in Noonan syndrome) are also identified; in others, only an NF1 variant is present. Missense variants in NF1 at Met1149, Arg1276, and Lys1423 define a genotype-phenotype subgroup of NF1 with Noonan-like features. In particular, Met1149 substitutions are associated with a mild phenotype marked by predominantly cutaneous manifestations and the absence of symptomatic spinal plexiform neurofibromas and optic pathway gliomas.

NFNS is inherited in an autosomal dominant manner. Approximately 50% of affected individuals harbour a de novo pathogenic NF1 variant, while the remainder have inherited the variant from an affected parent. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Main differential diagnoses include:

• : short stature, congenital heart defect (most often pulmonic stenosis), neck webbing, and characteristic facies, without cutaneous neurofibromas, café au lait macule burden, or Lisch nodules.
• : multiple café au lait macules with intertriginous freckling but without neurofibromas, Lisch nodules, or optic pathway gliomas; additional features include lipomas, macrocephaly, and learning disabilities.
• (formerly LEOPARD syndrome): multiple lentigines, ocular hypertelorism, sensorineural deafness, and congenital heart disease, with lentigines rather than café au lait macules

• Establishing the molecular genetic diagnosis confirms the clinical suspicion and provides the basis for genetic counselling.
• Confirmation of the molecular diagnosis enables specific and individualised surveillance for known disease manifestations, planned and coordinated by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive and carrier testing of at-risk relatives becomes possible, allowing informed reproductive and family-planning decisions.

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• Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat. 2020;41(1):299-315. doi:10.1002/humu.23929. PMID:; PMCID:PMC6973139.
• D’Amico A, Rosano C, Pannone L, Pinna V, Assunto A, Motta M, et al. Clinical variability of neurofibromatosis 1: a modifying role of cooccurring PTPN11 variants and atypical brain MRI findings. Clin Genet. 2021;100(5):563-72. doi:10.1111/cge.14040. PMID:.