Diagnosing Neurofibromatosis

Neurofibromatosis type 1 (NF1)

Diagnosis of NF1 is established if ≥ 2 of the following features are present:

• ≥ 6 café-au-lait macules > 5 mm in greatest diameter in prepubertal patients and > 15 mm in greatest diameter in postpubertal patients

• Freckling in the axillary or inguinal region

• ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma

• Optic pathway glioma

• ≥ 2 Lisch nodules (iris hamartomas) identified by slit-lamp examination or ≥ 2 choroidal abnormalities

• A distinctive osseous lesion (eg, sphenoid dysplasia, anterolateral bowing of the tibia, pseudarthrosis of a long bone)

• A germline NF1 pathogenic variant

NF2-related schwannomatosis (NF2)

One of the following:

• Bilateral vestibular schwannomas

• An identical NF2 pathogenic variant in ≥ 2 anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma)

OR

Major criteria (2 of the following):

• Unilateral vestibular schwannoma

• First-degree relative (other than a sibling) with NF2

• ≥ 2 meningiomas

• NF2 pathogenic variant in an unaffected tissue (eg, blood)

OR

One major criterion and 2 of the following minor criteria:

• Can be counted twice*: Ependymoma, meningioma†, nonvestibular schwannoma

• Can be counted only once‡: Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person < 40 years old, single meningioma

• Pattern of genetic changes in unaffected tissue and in tumor tissue in NF2

Non-NF2 schwannomatosis (schwannomatosis)

SMARCB1- and LZTR1-related schwannomatosis (1 of the following):

• ≥ 1 pathologically confirmed schwannoma or hybrid nerve sheath tumor and an SMARCB1 or LZTR1 pathogenic variant in an unaffected tissue (eg, blood)

• A shared SMARCB1 or LZTR1 pathogenic variant in 2 schwannomas or hybrid nerve sheath tumors

22q-related schwannomatosis (all of the following):

• Patient does not meet criteria for NF2-, SMARCB1-, or LZTR1-related schwannomatosis and does not have a germline DGCR8 pathogenic variant

• Loss of heterozygosity of the same chromosome 22q markers in 2 anatomically distinct schwannomas or hybrid nerve sheath tumors

• A different NF2 pathogenic variant in each tumor, which cannot be detected in unaffected tissue

Schwannomatosis not otherwise specified (both of the following, no genetic testing done):

• ≥ 2 imaging-confirmed nonintradermal schwannomas

• ≥ 1 pathologically confirmed schwannoma or hybrid sheath tumor