Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1 -related schwannomatosis

Abstract

The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation.

Schwannomatosis: a genetic and epidemiological study

“…The present report confirms the previously described overlap between NF2 and schwannomatosis that is mainly due to VS occurring in LZTR1 -associated schwannomatosis and mosaic NF2 mimicking schwannomatosis 13. Although there is a single case report of an apparent unilateral VS in a SMARCB1 family, this potential association has not yet been validated 20.…”

Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager

“…In contrast, the patient reported here did not meet diagnostic criteria for schwannomatosis and presented with a vestibular schwannoma at young age (14 years). Three additional patients with constitutional LZTR1 mutations and vestibular schwannoma identified at age 37 or older led to a review of the diagnostic criteria for NF2, requiring exclusion of an LZTR1 mutation if a unilateral vestibular schwannoma occurs in the context of two or more nonintradermal schwannomas. Bilateral vestibular schwannomas occurred in one individual with an LZTR1 mutation at age 45 and 46 years, respectively.…”

Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population

“…Adults are often mildly affected, which can occur if the new mutation is not present in all cells, having occurred at a later stage of development. Due to the high proportion of affected adults with no mutation identified in blood, robust diagnostic criteria (box 1)12 are essential to clarify affected status. In contrast, patients presenting at age ≤16 would typically fulfil the diagnostic criteria through identification of an NF2 mutation, emphasising the need for improved understanding of the initial presenting features of affected children, to allow earlier referral for genetic testing.

Revised Manchester criteria for NF212

Bilateral VS <70, or

FDR family history of NF2 and unilateral VS <70, or

FDR family history of NF2 or unilateral VS, and 2 of* meningioma, cataract, glioma, neurofibroma, schwannoma and cerebral calcification (if UVS + ≥2 non-intradermal schwannomas need negative LZTR1 test), or

Multiple meningiomas (2 or more) and 2 of unilateral VS, cataract, glioma, neurofibroma schwannoma and cerebral calcification, or

Constitutional or mosaic pathogenic NF2 gene mutation in blood or identical mutations in two distinct tumours.

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