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14 | InTouch AUGUST 2022 Neurofibromatoses are a group of genetic disorders that cause tumors to form on nerve tissue. These tumors can develop anywhere in the nervous system, including the brain, spinal cord and nerves. What is Neurofibromatosis Type1? Neurofibromatosis type 1 (NF1) is a genetic condition that can cause tumours on nerve tissue anywhere in the body and a variety of other effects. It occurs in 1 in 3000 births and affects boys and girls equally. In 1882 a German pathologist called Freidrich Daniel von Recklinghausen first characterised the benign tumours, which consist of the mingling of nerve cells and fibrous tissue, as neurofibromas. NF1 is sometimes referred to as von Recklinghausen syndrome. The main features of NF1 include multiple café au lait (CAL) spots on the skin, freckling in the armpits or groin area, pigmented spots on the irises (Lisch nodules) and lumps under the skin (neurofibromas). Most manifestations of NF1 are benign and largely cosmetic but occasionally more serious complications can occur, many of which can be effectively treated, especially if detected promptly. Cause of Neurofibromatosis Type 1 Neurofibromatosis type 1 is caused by pathogenic variants in the NF1 gene located on chromosome 17. The NF1 gene encodes a protein called neurofibromin. This protein is expressed in most tissues, predominantly in the central and peripheral nervous system and adrenal glands, and acts as a tumour Neurofibromatosis Type1 YOUR CONDITION IN REVIEW suppressor. When functioning normally, neurofibromin keeps cells from growing and dividing too rapidly or in an uncontrolled way. A pathogenic variant in the NF1 gene results in the production of a non- functional version of neurofibromin that cannot regulate cell growth and division, and thus increases the risk of benign and (less commonly) malignant tumours. It is unclear how pathogenic variants in the NF1 gene lead to the other, non-tumourous, features of NF1, described in more detail below (see Features of Neurofibromatosis Type 1). We each have two copies of the neurofibromin gene in every cell, one from each of our parents. To be affected with NF1 only one copy needs to be defective. Around half of all people diagnosed with NF1 will have one parent who also has the condition. This type of inheritance pattern is called Autosomal Dominance. The other half are thought to have a new (spontaneous) mutation in the gene, primarily in the paternal copy, and are the first person in their family to be affected. This is referred to as a sporadic or de novo case of NF1. Someone with NF1 has a 50% risk of passing on the condition each time they have a child. Symptoms of NF1 vary considerably within, as well as between, families but does not skip generations. This means that children in the same family can have different presentations from each other and these may be different again from another unrelated family’s presentation of the condition. Occasionally in NF1, only one area of the body is involved. This is called mosaic or segmental NF1 and is due to somatic mosaicism, meaning some cells have two fully functional copies of the NF1 gene while other cells contain a pathogenic variant in one copy of the NF1 gene. The incidence of mosaic neurofibromatosis is around 1 in 30,000 to 40,000 and reoccurrence risk will depend on whether the germ cells in the ovaries or testes are involved. Genetic testing is possible and speaking with a clinical geneticist is valuable in these cases. Diagnosis of Neurofibromatosis Type 1 The diagnosis of NF1 is clinical and is made when specific NIH clinical criteria are fulfilled. Ninety-seven percent of people with NF1 meet diagnostic criteria by the age of 8 years. These criteria include the presence of six or more café-au- NF1 is very variable and for many people who have NF1 the problems are largely cosmetic, but in about a third of cases more serious complications can occur.