Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation
ABSTRACT:
Purpose: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct
tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology,
neuropathology, and neuroimaging.
Methods: We used a multistep process, beginning with a Delphi method involving global
disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and
foundations/patient advocacy groups.
Results: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2
and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we
recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and
to minimize misdiagnosis with neurofibromatosis type 1.
Conclusion: The updated criteria for NF2 and SWN incorporate clinical features and genetic
testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that
continued refinement of these new criteria will be necessary as investigators study the diagnostic
properties of the revised criteria and identify new genes associated with SWN. In the revised
nomenclature, the term “neurofibromatosis 2” has been retired to improve diagnostic specificity
The UAB Medical Genomics Lab Obtains California Licensure
Genotype-phenotype correlation in NF1 patients: evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848
Authors Koczkowska M. et al, American Journal of Human Genetics
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Abstract
Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2000-3000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons Leu844, Cys845, Ala846, Leu847 and Gly848, located in the Cysteine-Serine-Rich Domain (CSRD). Collectively, these recurrent missense mutations affect ~0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1 cohorts (both p<0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1 population (p=0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.
The Medical Genomics Laboratory is pleased to offer new next generation sequencing testing options for NF1/SPRED1 and other Rasopathy related conditions.
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