Neurofibromatosis type 1 (NF1): genetics, signs and surveillance

The NHS describes NF1 as a genetic condition where tumours grow on the nerves and skin, with no cure currently but treatment that can help manage symptoms. The symptoms are often mild, and how severe they are usually depends on where the tumours are and how large. Many features are present from birth or appear in early childhood, while others come later.

The NHS lists light brown patches of skin (café-au-lait spots, which may be harder to see on brown and black skin), freckles in the armpits or groin, lumps on or under the skin called neurofibromas that tend to appear in the teenage years or early twenties, yellow-brown raised dots on the iris that do not usually affect vision, eye problems, a large head with below-average height, and learning difficulties.

The NHS Genomics Education Programme adds timing details that can be reassuring: most affected children have six or more café-au-lait macules by age two; Lisch nodules, the iris dots, appear in 50% by age five, 75% by age 15 and 90% by age 25; optic pathway glioma, if it occurs, typically appears before age seven; and dermal neurofibromas appear from adolescence into adulthood.

NF1 is a large gene on chromosome 17 that encodes neurofibromin, a protein that helps restrain cell growth. The NHS Genomics Education Programme says harmful variants take several forms, including nonsense, frameshift, splice site, missense and in-frame deletions, and deletions of the entire gene. Complete deletion of NF1 is linked to a particularly severe picture, with more neurofibromas, an earlier start, a higher risk of malignant peripheral nerve sheath tumour and more frequent cognitive problems.

Some people have features limited to one part of the body, known as localised, segmental or mosaic NF1, because only some of their cells carry the variant. Features may be milder, depending on how many cells and which tissues are involved. If no variant is found in the blood, testing a sample of affected tissue such as a skin lesion may be considered.

A similar-looking condition, Legius syndrome, is caused by SPRED1 and gives café-au-lait patches and freckling without some of NF1's more serious complications. A genetic result can therefore sometimes reassure a family and remove the need for some surveillance.

NF1 is autosomal dominant. A person with NF1 has one working and one altered copy of the gene, and each child has a 50% chance of inheriting the altered copy. The NHS says that if you have NF1 there is a 1 in 2 chance of passing it on to any children.

The NHS Genomics Education Programme explains that in around half of diagnosed cases the variant is inherited and in the other half it arises for the first time in the child, by chance. When parents are tested and neither carries the variant, the recurrence risk in a future pregnancy is less than 1%, a little above the background level because of the small possibility of germline mosaicism. It is also important to examine the parents of an affected child for segmental or mosaic NF1, because the risk to the children of a parent with segmental NF1 depends on how much of the reproductive tissue is involved and may be up to 50%.

NF1 is fully penetrant: everyone who has the variant shows some features. What varies is how much, and nobody can say in advance which complications a particular person will have.

The NHS says NF1 is lifelong and usually gets worse over time, affecting everyone differently, and that a check-up at least once a year helps pick up changes early. Children should have their eyes checked every year (adults every two years) and blood pressure checked yearly. Children with NF1 often have learning difficulties and may need extra help at school.

Complications listed by the NHS include high blood pressure, bone and joint problems such as bowed legs or scoliosis, a tumour on the optic nerve causing vision problems, distress related to large or facial tumours, and a higher risk of certain cancers including breast and brain cancer. The NHS says women with NF1 should have a mammogram each year from age 40. The NHS Genomics Education Programme quotes a lifetime risk of 10% to 15% for malignant peripheral nerve sheath tumour and a two- to four-fold increase in premenopausal breast cancer, and gives scoliosis in 11%, learning disability in 33% and epilepsy in 4.3% of cases.

Treatment depends on symptoms. The NHS lists medicine to stop tumours growing, surgery for tumours at risk of causing problems, and radiotherapy for small tumours or remnants, and notes that if symptoms are not causing problems, doctors may suggest waiting. Persistent or worsening headaches, repeated vomiting, or blurred vision or loss of vision need an urgent GP appointment or NHS 111.

The NHS says pregnancy with NF1 can bring problems such as narrowed arteries and high blood pressure, and tumours can increase or grow, so the care team should be told if pregnancy is planned. The NHS Genomics Education Programme recommends genetic counselling before having children where possible, and describes testing in pregnancy and pre-implantation genetic testing as options when there is a recurrence risk.

Nerve Tumours UK supports adults, teenagers and parents of children with NF1, and the Childhood Tumour Trust supports children, young adults up to 30 and their families, according to the NHS. Care teams pass information to the National Congenital Anomaly and Rare Disease Registration Service, and you can opt out at any time.