Genotype-phenotype data from a case series of patients with mosaic neurofibromatosis type 1

Dear Editor, Neurofibromatosis type 1 (NF1) arises from NF1 variants and deletions and results in multiple skin and eye manifestations.1 Segmental NF1 is confined to a body segment2 and is thought to be caused by somatic mosaicism, but few cases are confirmed by molecular testing.2,3,4,5 We describe phenotypically eight patients with molecularly confirmed mosaic NF1 (MNF1). We identified patients with a clinical diagnosis of segmental neurofibromatosis by retrospective chart review. We then performed NF1 sequencing and dosage analysis on blood‐ and patient‐derived cultured Schwann cells or melanocytes from affected tissue, as previously described.4 This study was approved by the research ethics board at the Hospital for Sick Children (REB #1000050336). We identified eight patients (six male and two female) with MNF1. The age at biopsy was above 17 years for seven of the eight patients, who were able to give informed consent for genetic testing. Patient 7 (age 6 years) was tested with parental consent. A summarized description of the genotypes and phenotypes is presented in Table 1 (full data are available from the authors). Although most of our patients fit the classic clinical diagnosis of segmental NF1, three patients developed nonlocalized pigmentary changes and one patient had lesions crossing the midline. Most patients (six of eight) had exclusively pigmentary findings, specifically café au lait macules (CALMs) and freckling. Patient 1 had a left orbit plexiform neurofibroma with ipsilateral sphenoid wing dysplasia and cerebral tortuous large intracranial arteries. Patient 3 had a unilateral Lisch nodule identified on eye exam (only five patients had eye exams). No patients had cutaneous neurofibromas or optic gliomas (only four had brain magnetic resonance imaging). Patient 8 had tibial rotation bilaterally. We also describe macrocephaly (four of eight) and attention deficit hyperactivity disorder (three of eight) in our cohort. Genotype–phenotype data from eight patients with mosaic neurofibromatosis type 1 Dx, diagnosis; Bx, biopsy; CALM, café au lait macule; L, left; R, right; LOH, loss of heterozygosity. B1–3 are the three biopsies of CALMs. Case 1 did not have CALMs so B1 was taken from a plexiform neurofibroma and B2 from unpigmented normal skin. Samples from blood lymphocytes were normal in all cases. Where two pathogenic variants were observed, the variant common to all biopsy samples (presumed ‘first hit’) is in bold. Where ‘?’ is included instead of a deletion start point, this means the starting breakpoint was intronic and could not be identified. aNumbers for Dx and Bx are the age in years. Genotype–phenotype data from eight patients with mosaic neurofibromatosis type 1 Dx, diagnosis; Bx, biopsy; CALM, café au lait macule; L, left; R, right; LOH, loss of heterozygosity. B1–3 are the three biopsies of CALMs. Case 1 did not have CALMs so B1 was taken from a plexiform neurofibroma and B2 from unpigmented normal skin. Samples from blood lymphocytes were normal in all cases. Where two pathogenic variants were observed, the variant common to all biopsy samples (presumed ‘first hit’) is in bold. Where ‘?’ is included instead of a deletion start point, this means the starting breakpoint was intronic and could not be identified. aNumbers for Dx and Bx are the age in years. Six patients had a known pathogenic loss‐of‐function variant in NF1 and two patients had NF1 microdeletions. We identified two postzygotic mutations in one or more skin tissue cultures of all of our patients. One genetic variant was common to the three biopsy specimens for each individual patient except patient 1, see Table 1). No mutations were found in the blood lymphocytes of these patients. A meta‐analysis on segmental NF1 identified 320 cases without confirmatory NF1 molecular testing.2 Ruggieri and Huson showed in 124 patients that 65% had unilateral findings and 69% had pigmentary changes alone.6 Lisch nodules, skeletal abnormalities, optic gliomas and learning difficulties were also observed. Listernick et al. focused on 39 paediatric patients, showing that 77% had isolated pigmentary changes, but some had plexiform neurofibromas, pseudoarthroses and optic pathway tumours.7 This meta‐analysis included 157 case reports, and pseudoatrophic plaques, hypertension, learning disabilities, seizures and scoliosis were also described. The terms mosaic and segmental NF1 are often used interchangeably, but only 15 published cases have undergone NF1 molecular testing. An NF1 gene deletion was found in the fibroblast tissue culture but was not identified in leucocyte DNA in one published case.3 This patient showed CALMs and freckles localized to the left side of the neck, the upper part of the trunk, axilla and arm. Two patients with segmental NF1 with an NF1 deletion in melanocytes4 and one patient with an NF1 deletion in Schwann cells5 have also been reported. Our case series of NF1 mosaicism phenotypes demonstrates phenotypic variability including patients presenting with plexiform neurofibromas, sphenoid dysplasia, vasculopathy and Lisch nodules, with a predominance of localized lesions and pigmentary changes only (Table 1). MNF1 occurs when there is a postzygotic mutation in NF1. Somatic mosaicism can result from an NF1 mutation at an early postzygotic stage, as indicated by two sets of discordant monozygotic twin pairs.8 The Knudson two‐hit hypothesis for the aetiology of NF1 suggests that there is biallelic inactivation of the NF1 gene, with a ‘second hit’ in one cell type that clonally expands to give rise to CALMs, neurofibromas and glomus tumours.1 We support this hypothesis as our patients have at least two postzygotic mutations. Individuals with MNF1 may have gonadal mosaicism, meaning that they could have up to a 50% chance of having a child affected by classical NF1, with at least 12 cases reported.2 A major advantage of identifying the precise NF1 mutation in MNF1 is the ability to provide accurate reproductive genetic counselling and offer the option of molecular‐based prenatal testing via chorionic villus sampling or preimplantation genetic diagnosis. Due to the reproductive counselling advantages, we suggest that paired blood and tissue genetic testing should be offered to adolescents in all cases of suspected segmental neurofibromatosis. Funding sources: none. Conflicts of interest: none to declare.

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