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Establishing the Diagnosis

The diagnosis of NF1 is established in a proband with two or more of the features described in Suggestive Findings [Legius et al 2021].

Note:

1.

About half of individuals with Legius syndrome (see Differential Diagnosis) have skin pigmentary features that meet the diagnostic criteria of NF1 (i.e., ≥6 CALMs and axillary or inguinal freckling), but individuals with Legius syndrome do not have neurofibromas, optic pathway gliomas, Lisch nodules, or typical osseous lesions of NF1 [Legius et al 2021]. Moreover, Legius syndrome is much rarer than NF1, and children with Legius syndrome almost always have an affected parent with only CALMs and intertriginous freckling (see Differential Diagnosis).

2.

CALMs, intertriginous freckling, cutaneous neurofibromas, and Lisch nodules are usually bilateral in NF1. A diagnosis of mosaic NF1 should be considered if such lesions are present only on one side or in one segment of the body.

3.

Sphenoid wing dysplasia is not a separate criterion in those with ipsilateral orbital plexiform neurofibromas.

4.

A germline NF1 pathogenic variant must be identified for genetic testing to serve as a criterion for diagnosis [Legius et al 2021]. The criterion is not met by identification of an NF1 variant only in tumor tissue or identification of a germline likely pathogenic variant or variant of uncertain significance.

5.

Negative NF1 molecular testing does not rule out a diagnosis of NF1 [Accetturo et al 2020]. Some individuals diagnosed with NF1 based on clinical criteria do not have a pathogenic variant detectable by current technology. Many clinical features of NF1 increase in frequency with age, and some individuals who have unequivocal NF1 as adults cannot be diagnosed in early childhood, before these features become apparent.

If the phenotypic findings suggest the diagnosis of NF1, single-gene testing may be considered. Sequence analysis of NF1 genomic DNA (gDNA) and/or cDNA (complementary DNA, copied from mRNA) is performed in association with gene-targeted deletion analysis. Because of the frequency of pathogenic variants that affect splicing (22%-30%, more than 1/3 of which are not detected by gDNA sequencing of protein-coding regions), methods that include cDNA sequencing have higher detection rates than methods based solely on analysis of gDNA (Table 1).

Note:

1.

If an NF1 variant is not detected, sequence analysis and deletion/duplication analysis of SPRED1 (see Differential Diagnosis) may be considered in individuals with only pigmentary features of NF1.

2.

Chromosomal microarray analysis (CMA) may be performed instead of sequence analysis to detect NF1 whole-gene deletions if the NF1 microdeletion phenotype is suspected clinically (see Genotype-Phenotype Correlations).

3.

A karyotype may be considered to look for a translocation or complex cytogenetic abnormality if a clinical diagnosis of NF1 is certain, but no pathogenic variant is found on sequence analysis of NF1 gDNA or cDNA and gene-targeted deletion analysis.

If the phenotype is indistinguishable from other disorders characterized by hyperpigmentation, tumors, and/or other overlapping features, a multigene panel that includes NF1, SPRED1, and other genes of interest (see Differential Diagnosis) may be considered. A rasopathy multigene panel is usually most appropriate. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Many multigene panels include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

If the phenotype is nonspecific (e.g., developmental delay and hypotonia in a young child) comprehensive genomic testing (exome sequencing or genome sequencing) may be considered. Note: Identification of one or more characteristic clinical features (see Suggestive Findings) is required to establish the diagnosis in an individual with an NF1 pathogenic variant.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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