Neurofibromatosis Type 1 and the NF1 gene

Neurofibromatosis Type 1 and the NF1 gene

Neurofibromatosis Type 1, also known as von Recklinghausen Disease, is a hereditary cancer syndrome caused by germline mutations in the NF1 gene. It is not rare, affecting 1 in 3,000 to 1 in 4,000 people.

NF1 is characterised by growths affecting the covering of peripheral nerves (neurofibromas) that can be seen as lumps on the skin.

Although there are a broad range of health problems associated with NF1, not everyone is affected, even within the same family.

Neurofibromatosis Type 1 does NOT cause "elephant man" syndrome. Although Joseph Merrick, the person who was known as the Elephant Man, died in 1890, in 1986, geneticists Tibbles and Cohen published a paper in the British Medical Journal diagnosing Merrick with Proteus syndrome. This is a much rarer condition. Proteus syndrome results from a mutation in the AKT1 gene that occurs early on in the growing baby, after fertisation of the egg by the sperm. This genetic change is not inherited and is not passed on. (Inherited mistakes in the AKT1 gene are, in fact, lethal and the baby doesn't grow).

Unlike many hereditary cancer syndromes, in which a mistake in a gene has been passed down over many generations, in NF1 around half of the cases are caused by a new mistake (a "de novo" mutation) that occurred just in that particular sperm or egg or in the first few divisions are fertilisation.

NF1 is usually diagnosed clinically at a young age. Almost all children will meet the clinical criteria by age 8 and half by age 1.

The clinical criteria include two or more of the following:

  • six or more café-au-lait macules (each measuring 5 mm if prepuberty and 15 mm post puberty).
  • two or more neurofibromas.
  • one plexiform neurofibroma.
  • freckling in the armpits or groin.
  • optic glioma.
  • two or more Lisch nodules (benign growths in the eye).
  • an osseous lesion such as sphenoid dysplasia or tibial pseudoarthrosis.

Neurofibromatois Type 1 is associated with growths that can cause problems by compressing other structures. The growths can also become cancers and this may happen at a young age. Most children and adults with NF1 are seen via special clinics to manage the screening and deal with any problems that may arise promptly. Individuals with NF1 should avoid unnecessary radiation, including unnecessary CT scans.

Here are some of the common features of Neurofibromatois Type 1 and what to do about them.

Some features of NF1 are characteristic but don't cause problems. Almost all people with neurofibromatosis type 1 have multiple café-au-lait spots (often called birth marks, although they can appear after birth and after puberty).

During childhood, benign growths called Lisch nodules often appear in the colored part of the eye (the iris). Lisch nodules do not interfere with vision and do not need treatment.

Optic nerve glioma

Optic nerve glioma are growths that arise in or around the optic nerve. They mainly occur between ages 3 and 5 and do not usually require any intervention. Sometimes, they can compress the optic nerve, affecting sight. Screening by an ophthalmologist is done every 6 months to age 4 and then annually to age 16.

Breast cancer

Women with NF1 are at higher risk for breast cancer than the average woman. This risk is "moderate" (15 to 30% lifetime compared to the average risk of 10 to 15%). Risk reducing mastectomies are not usually recommended at this level of risk.

Screening usually starts at age 35 and includes annual breast MRIs to age 50 when screening is done every 2 years usually with mammograms.

Malignant peripheral nerve sheath tumours.

Malignant peripheral nerve sheath tumours (MPNST) usually arise in a plexiform neurofibroma. They may present with a hard lump felt under the skin and, because they are associated with a nerve, can cause pain, weakness or numbness. Screening starts at age 10 with an annual physical examination.


Pheochromocytoma are rare affecting perhaps 1 in 2000 people. They are usually small growth in the adrenal glands, which sits above the kidneys. They cause problems by secreting the "fight or flight" hormone adrenalin. In NF1, they become cancerous 20% of the time, so it is important to detect them early.

Screening starts at age 10, measuring blood pressure and checking the blood for breakdown products of adrenalin.

Genetic testing

The diagnosis of NF1 is usually based on clinical diagnostic criteria and genetic testing does not alter the management.

NF1 genetic testing could be considered in the following circumstances:

  • Individuals who fulfil clinical criteria for NF1 and are considering prenatal or preimplantation genetic diagnosis.
  • Children who do not yet meet clinical criteria for NF1 and a genetic diagnosis is considered important to inform management decisions.
  • Adults who do not meet clinical criteria for NF1 and an atypical phenotype is suspected (e.g. spinal NF1).

Does this sound like you or your family?
Has an NF2 mutation been detected in a blood relative or has a clinical diagnosis of NF2 been made in you or your family?
Make an appointment with Dr Hilda High at Sydney Cancer Genetics. It is a confidential opportunity to discuss your personal and family history of cancer and genetic testing can be organised, if needed.

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