Neurofibromatosis type 1 (NF1), Legius syndrome, neurofibromatosis type 2 (NF2), and schwannomatosis can manifest themselves in a so-called "mosaic" form.
These forms are linked to post-zygotic mutations in the genes involved in the same diseases. Thus, heterozygous mutations are not found in 100% of cells but in a variable percentage depending on the tissue removed (ranging from 0 to 100%). These molecular peculiarities are detailed in the page dedicated to genetics.
As a result, clinical involvement is not generalised or systemic but segmental (restricted to only certain cells of the body). These mosaic forms are often not severe.
The diagnostic criteria for mosaic NF1 are met in an individual if any of the following is present:
- A pathogenic heterozygous NF1 variant with a variant allele fraction of significantly less than 50% in apparently normal tissue such as white blood cells AND one other NF1 diagnostic criterion (except a parent fulfilling diagnostic criteria for NF1).
- An identical pathogenic heterozygous NF1 variant in two anatomically independent affected tissues (in the absence of a pathogenic NF1 variant in unaffected tissue)*.
- A clearly segmental distribution of café-au-lait macules or cutaneous neurofibromas
- Another NF1 diagnostic criterion (except a parent fulfilling diagnostic criteria for NF1**.
- Or Child fulfilling diagnostic criteria for NF1.
- Only one NF1 diagnostic criterion from the following list: freckling in the axillary and inguinal region, optic pathway glioma, two or more Lisch nodules or two or more choroidal abnormalities, distinctive osseous lesion typical for NF1, two or more neurofibromas or one plexiform neurofibroma and a child fulfilling the criteria for NF1.
**If only "café-au-lait" macules and freckling are present, the diagnosis is most likely mosaic neurofibromatosis type 1 but rarely might be mosaic Legius syndrome or constitutional mismatch repair deficiency (CMMRD) syndrome.
Diagnosis of NF1 in mosaic is made when any of the following criteria are present:
- A heterozygous pathogenic SPRED1 variant with a variant allele fraction of significantly less than 50% in apparently normal tissue such as white blood cells and six or more "café-au-lait" macules.
- An identical pathogenic heterozygous SPRED1 variant in two independent affected tissues (in the absence of a pathogenic SPRED1 variant inunaffected tissue)*.
- A clearly segmental distribution of café-au-lait macules AND a child fulfilling the criteria for Legius syndrome.
The diagnostic management of these mosaic forms is sometimes more complex and may require additional molecular analyses from other than blood samples, for instance, samples of hair, urine, skin, sperm, etc. The risk of transmission to the offspring of genuine NF1 or Legius syndrome is sometimes difficult to assess and analysing such biological samples may be useful.
Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Do G. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. Published online May 19, 2021. doi:10.1038/s41436-021-01170-5