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Conditions

Neurofibromatosis type 1

Neurofibromatosis type 1 is a multisystem genetic condition characterised by cafe-au-lait macules, neurofibromas and sometimes learning and/or behavioural problems.

Overview

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition characterised by an early presentation of multiple café-au-lait macules and, later, benign growths known as neurofibromas. Multiple complications can occur secondary to the location of benign growths, and due to the higher risk of malignancy.

Clinical features

Revised diagnostic criteria suggest that a diagnosis of NF1 can be made in a patient without a family history when two or more of the following features are present:

  • six or more café-au-lait macules (over five millimetres in pre-pubertal individuals, over 15 millimetres in post-pubertal individuals);
  • axillary and/or inguinal freckling;
  • two or more neurofibromas or one plexiform neurofibroma;
  • optic pathway glioma;
  • two or more iris Lisch nodules on slit lamp examination, or two or more choroidal anomalies imaged by optical coherence tomography (OCT) or near-infrared reflectance (NIR) imaging;
  • a distinctive osseus lesion such as sphenoid dysplasia, tibial bowing or pseudoarthrosis of a long bone; and
  • a heterozygous pathogenic NF1 variant with an allele fraction of 50%.

Note that the child of a parent who meets diagnostic criteria and has one or more of the diagnostic criteria outlined above also meets the revised diagnosis criteria.

Some features of NF1 show age-dependent expression, which may offer reassurance to some families. Below is a list of features and the age by which they should present.

  • By age two:
    • most will have six or more café-au-lait macules;
    • rarer presentations include:
      • sphenoid wing dysplasia;
      • pseudoarthosis; and
      • plexiform neurofibroma (most clinically disfiguring lesions will have developed by age two).
  • By age five:
    • Lisch nodules (these are not present at birth; 50% of those affected will have them by age five, 75% by age 15 and 90% by age 25).
  • By age seven:
    • Optic glioma (patients typically do not develop these after age seven, if at all).
  • Childhood:
    • axillary and/or groin freckling.
  • Adolescence through to adulthood:
    • dermal neurofibromas and nerve sheath tumours.

Additional complications include:

  • scoliosis (occurs in 11% of cases);
  • hypertension secondary to renal artery stenosis (especially in the second decade of life) or phaeochromocytoma;
  • pulmonary stenosis (occurs in 1%–2% of cases);
  • precocious puberty (usually occurs in association with chiasmal optic glioma);
  • learning disability (occurs in 33% of cases);
  • epilepsy (occurs in 4.3% of cases);
  • increased solid organ and haematological cancer risk (including the following):
    • malignant peripheral nerve sheath tumour (MPNST) (lifetime risk is 10%–15%, with a median age of 26);
    • premenopausal breast cancer (risk is increased between two- and four-fold);
    • gastrointestinal stromal tumour;
    • phaeochromocytoma; and
    • rhabdomyosarcoma;
  • myeloproliferative neoplasia;
  • neurocognitive issues; and
  • autism spectrum disorder.

Genomics

NF1 is caused by pathogenic variants in the NF1 gene, which is found at chromosome position 17q11.2. This gene encodes for the protein neurofibromin, which is a tumour suppressor gene that is found in many types of cells, including nerve cells and those that form part of the myelin sheath.

NF1 is a large gene spanning 350 kilobases of DNA, and pathogenic genetic variants include nonsense, frameshift, splice site, missense and in-frame deletions, and deletions of the entire NF1 gene.

There are several known genotype–phenotype correlations. Deletion of the entire NF1 gene results in a particularly severe phenotype, with an earlier appearance and a larger number of neurofibromas, a higher risk of developing MPNST, and more frequent and severe cognitive anomalies. For other genotype–phenotype correlations, see our resources list below.

Individuals with features of the condition limited to a particular area (or areas) of the body are described as having localised, segmental or mosaic NF1. These individuals have a proportion of cells with two standard copies of the NF1 gene and a proportion of cells with a pathogenic variant in one copy of the gene. Clinical features may be milder, though that will depend on the level of mosaicism and the tissues involved. If no NF1 variant is identified in the blood, testing of affected tissue (for example, via skin biopsy of a lesion) may be considered.

Diagnosis

A clinical diagnosis can be made as per the diagnostic criteria (see ‘Clinical features’ above), which includes the presence of café-au-lait macules. The most common cause of café-au-lait macules is NF1, though other conditions may present with them. See Presentation: Child with multiple café-au-lait macules for information about genomic testing – it also contains information about other conditions that present with café-au-lait macules and other features.

Some presentations of NF1 are very specific, and there is some debate around the necessity of molecular diagnosis in these cases. However, there are some conditions which can present with overlapping features that should be considered. For example Legius syndrome, caused by variants in SPRED1, can present with café-au-lait patches, relative macrocephaly, axillary or inguinal freckling and neurodevelopmental associations, but without some of the more serious complications that can arise in NF1. Therefore, in cases without neurofibromas, a molecular diagnosis may provide reassurance and remove the need for surveillance in some families.

In addition, molecular diagnosis can be useful for young family members seeking predictive (also known as pre-symptomatic) testing prior to the onset of symptoms, or where the diagnosis is uncertain. It can also be useful for prenatal counselling, and to access reproductive options.

Some individuals with NF1 will need additional genomic testing to identify a molecular cause. This may include individuals with mosaic or segmental NF1 who may need deeper sequencing, or testing of a skin biopsy from an affected area. There are also some individuals that have a non-coding variant that affects the expression of the NF1 gene that would not be picked up by standard testing. In these cases analysis of the cDNA or RNA may be required.

In some cases individuals may not have a currently identifiable molecular diagnosis, but strongly fit the clinical criteria. In these cases it is important that the clinical diagnosis is respected and that the patient still accesses screening.

Inheritance and genomic counselling

In around half of all diagnosed cases, the pathogenic variant in the NF1 gene is inherited from a parent. The remaining half arise spontaneously for the first time in the child by chance (de novo).

NF1 is an autosomal dominant condition:

  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with apathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Unlike many autosomal dominant, NF1 is fully penetrant, although expression is variable.

It is important to examine the parents (of an affected child) for segmental NF1 or mosaic NF1: risks to the offspring of an individual with segmental NF1 depends on the degree of gonadal involvement, which cannot be easily defined but may be up to 50%.

Reproductive options, including testing in pregnancy and preimplantation genetic testing, are available where there is a recurrence risk. Patients should be referred for genetic counselling before having children to discuss these options when possible.

If neither parent, when tested, is found to carry the pathogenic NF1 variant, the risk of recurrence for the couple in a future pregnancy would be less than 1%. The risk remains slightly above that of the background population due to the small possibility of germline mosaicism.

Management

Management of children with NF1 is complex and should be delivered via a multidisciplinary team. Detailed suggested approaches have been published by several authors – please see the resources list below.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 25/02/2025
  • Next review due: 25/02/2027
  • Authors: Dr Lianne Gompertz
  • Reviewers: Dr Elaine Clark, Dr Ellie Hay, Dr Terri McVeigh