Trends in phenotype in the English paediatric neurofibromatosis type 2 cohort stratified by genetic severity

Abstract

Childhood onset neurofibromatosis type 2 can be severe and genotype dependent.We present a retrospective phenotypic analysis of all ascertained children in England <age 18 (N = 87; male 61%). Mean age at last review was 13.9 years with mean follow-up 6.5 years. Patients were stratified using a validated score (1A/1B:no NF2 pathogenic_variant in blood; 2A/2B:mild/moderate NF2 constitutional or mosaic pathogenic_variant in blood; 3: constitutional truncating exon 2-13 pathogenic_variant.A total of 91% patients had a constitutional NF2 pathogenic_variant (44% de novo).Mean age at first manifestation was 4.3 and 8.8 years in groups 3 and 2A, respectively.Bilateral vestibular schwannoma, intracranial meningioma and spinal schwannoma occurred in 77%, 52% and 65% of group 3 patients, respectively, and 58%, 26% and 33% in 2A. A total of 43% group 3 and 18% 2A had severe unilateral visual loss (logmar >1.0). Focal cortical dysplasia occurred in 26% group 3 and 4% 2A. A total of 48% of group 3 underwent ≥1 major intervention (intracranial/spinal surgery/Bevacizumab/ radiotherapy) compared to 35% of 2A; with 23% group 3 undergoing spinal surgery (schwannoma/ependymoma/meningioma resection) compared to 4% of 2A. Mean age starting Bevacizumab was 12.7 in group 3 and 14.9 years in 2A. In conclusion, group 3 phenotype manifests earlier with greater tumour load, poorer visual outcomes and more intervention.childhood NF2, NF2, NF2 genetic severity score, paediatric NF2 genotype phenotype D Gareth Evans and Allyson Parry joint contributed for this study.

Brainstem ischemic syndrome in juvenile NF2

“…There have been rare cases in which angiographic narrowing of the internal carotid artery, 6 middle cerebral artery (with middle cerebral artery infarct), 13 vertebral artery, 12 aorta, 12 or renal artery 14 has been seen in NF2, leading those authors to propose a vascular process. Although well known in NF1, vasculopathy is not clearly recognized in young patients with NF2 at this time.…”

“…Although well known in NF1, vasculopathy is not clearly recognized in young patients with NF2 at this time. 1,2,12 Progressive brainstem stroke syndromes have been seen with dolichoectasia of the basilar artery in NF1. 15 Our patient did not meet the criteria for dolichoectasia.…”

“…One had renal artery stenosis and coarctation of the aorta, and a second had vertebral artery stenosis and a 22q microdeletion. 12 Table 2 shows an analysis of the NF2 variants reported in each case. Overall, the similarities between cases are striking.…”

Structural Abnormalities of the Central Retina in Neurofibromatosis Type 2

“…Early diagnosis of NF2 is important to optimize management and allow timely intervention. The diagnosis of NF2 is frequently delayed [32], especially in children with severe de novo NF2, who typically present with symptoms and signs that are not related to a vestibular schwannoma [18][19][20][21]. The heterogeneous presenting clinical features of NF2 highlight the value in developing reliable biomarkers for NF2.…”

“…Symptoms and signs relating to vestibular schwannomas are not always the presenting feature in NF2, even less so in children who more commonly manifest eye, skin, or neurological problems [18][19][20][21]. The detection of ocular features can aid in the clinical diagnosis of NF2 and prompt early genetic testing [21,22].…”