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May 15, 2018

Disease summary:

Neurofibromatoses (NF) are a group of disorders characterized by the development of tumors in the nervous system. These benign tumors develop on the nerves heath and are known as neurofibromas. Other findings include skin and bone abnormalities. The severity of the disease varies considerably even within the same family. Neurofibromatosis 1 (NF1) is the main type accounting for 95% of the cases but other subtypes such as Neurofibromatosis 2 (NF2), schwannomatosis and Legius syndrome have been described.1  Heterozygous loss of function pathogenic variants in the NF1, NF2, SPRED1 and SMARCB1 genes are associated with the different forms of neurofibromatosis and related syndromes.

Autosomal dominant

1/3,000 1, 2, 3

Major clinical symptoms for Neurofibromatosis type 1 1:

  • Café-au-lait macules
  • Multiple neurofibromas and plexiform neurofibroma
  • Freckling in the axillary or inguinal regions
  • Optic glioma
  • Lisch nodules (iris hamartomas)
  • Osseous lesion (sphenoid dysplasia or tibial pseudarthrosis)

Major clinical symptoms for Neurofibromatosis type 2 7:

  • Bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction
  • Presence of multiple meningioma, schwannoma, glioma, and/or neurofibroma
  • Posterior subcapsular lenticular opacities
  • Cataract

Diagnosis of NF1 should be suspected in individuals who have any of the following findings 1:

  • Six or more café-au-lait macules
  • Two or more neurofibromas or one plexiform neurofibroma
  • Freckling in the axillary or inguinal regions
  • Optic glioma
  • Two or more Lisch nodules (iris hamartomas)
  • A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis
  • A first-degree relative with a pathogenic variant in the NF1

Diagnosis of NF2 is established in individuals with one of the following 7:

  • Bilateral vestibular schwannomas
  • Presence of any of the following: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
  • A first-degree relative with a pathogenic variant in NF2

There is no cure for NF, but many treatments are available that can result in prevention of complications or to increase the quality of life for the affected patients1:

  • Surgical tumor removal
  • Additional cancer treatments and other symptomatic approaches.
  • Radiofrequency therapy has shown promise for treatment of facial diffuse plexiform neurofibromas and café-au-lait spots.
  • Preliminary studies of numerous clinical trials suggest that sirolimus (mTOR inhibitor), may be useful in treating pain associated with plexiform neurofibromas.
  • Several therapeutic approaches for malignant peripheral nerve sheath tumors are available.
  • Piebald trait associated with pathogenic variants in KIT and SNAI2
  • Meningiomas associated with pathogenic variants in SMARCB1, PTEN, NF2, SMARCE1, MN1, PDGFB and other genes
  • McCune-Albright syndrome (Fibrous dysplasia) caused by pathogenic variants in GNAS
  • Noonan syndrome with multiple lentigines, LEOPARD syndrome, caused by heterozygous pathogenic variant in one of four genes (PTPN11, RAF1, BRAF, and MAP2K1)
  • Proteus syndrome, caused by pathogenic variants in AKT1

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Neurofibromatosis using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Neurofibromatosis panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified in Step 1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

  • Individuals with a positive family history of Neurofibromatosis
  • Individuals with most common symptoms of Neurofibromatosis (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of Neurofibromatosis can allow for genetic counseling and may direct medical management.

Table 1. Overview of the genes in CENTOGENE´s Neurofibromatosis panel

Gene (OMIM) Frequency of pathogenic variants Associated/allelic disorders (OMIM)

>95% for NF1 4, 5

NF1 (162200)
NF2(607379) 22q12.2 72%-92% for NF2 6 NF2 (101000); Schwannomatosis (162091); Meningeoma (607174)
SMARCB1(601607) 22q11.23 7% for Coffin-Siris syndrome 10
35% (35/100) for rhabdoid tumors 11
Coffin-Siris syndrome 3 (614608); Rhabdoid tumors, somatic (609322) Schwannomatosis-1 (162091)
SPRED1(609291) 15q14 1%-2% 12

3%-25% for NF1 13

98% for Legius syndrome 13
Legius syndrome (611431)