Genomics in general practice

Disease specific topics

Neurofibromatosis type 1

Neurofibromatosis type 1


The diagnosis of neurofibromatosis type 1 (NF1) is usually made on clinical grounds. While genetic testing is not needed to confirm a diagnosis, confirmation of a gene variant Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people. .  Gene variants can be useful information for family members and family planning.

What do I need to know?

NF1 is a condition that follows an autosomal dominant inheritance When a condition follows an autosomal dominant pattern of inheritance, the family tree will usually reveal multiple affected members in multiple generations on the same side of the family. Dominant conditions or traits are expressed when only a single gene variant is inherited. Wide variability in clinical expression is common in many autosomal dominant conditions, even within the same family. Early onset of conditions, such as cancer, can be indicative of autosomal dominant inheritance within a family. Not all dominant conditions show 100% penetrance eg BRCA1 gene mutations). pattern and affects nerve cell tissue, causing the growth of small tumours throughout the nervous system.

Features are present from childhood and may become more pronounced during puberty, pregnancy and when hormonal changes take place. The severity of the condition can vary greatly, even within a family.

NF1 may be inherited, but up to 50% of cases are caused by a de novo A de novo variant is a new genetic variation that usually arises in the ova or sperm from which the individual is conceived (ie is not present in either parent).  mutation; therefore, a family history of NF1 may not be present.

The diagnosis of NF1 is made on the basis of presence of specific physical findings.

Characteristic features of NF1 include:

  • multiple café-au-lait spots
  • inguinal and/or axillary freckling
  • multiple neurofibromas 

Additional features can include:

  • optic nerve glioma
  • Lisch nodules (iris hamartomas)
  • osseous lesions (eg sphenoid wing dysplasia, tibial pseudoarthrosis)
  • increased risk of various cancers
  • precocious puberty or delayed sexual development
  • specific learning disabilities
  • short stature
  • macrocephaly
  • scoliosis
  • hypertension that can be due to renal artery stenosis or phaeochromocytoma but is most often idiopathic.

Genetic testing

Genetic testing can be helpful to make a diagnosis of NF1 where there are insufficient features present to make a clinical diagnosis. An example is a child with multiple café au lait spots and no other clinical features and no family history of NF1. It is also necessary for prenatal diagnosis and pre-implantation genetic testing Pre-implantation genetic testing is testing performed on embryos produced by IVF. Prenatal testing of successful pregnancies may be undertaken as pre-implantation genetic testing is less than 100% accurate. .

When should I refer?

Patients with NF1 (or a relevant family history) should be referred to genetics, paediatrics and/or neurology services.

Further reading

  • Douglas R.Stewart, Bruce R.Korf, Katherine L.Nathanson, David A .Stevenson, KalebYohay. Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine 20(7), July 2018, Pages 671-682.

Resource for general practitioners

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