What is Neurofibromatosis type 1?

Neurofibromatosis type 1 (NF1) is a genetic condition that can affect the brain, spinal cord, nerves and skin.

It is characterised by skin changes and the growth of tumours along the nerves in the body. These tumours are usually not cancerous.

How common is NF1?

It is estimated that one in 3,000 people have NF1. This condition has been observed in all racial groups and affects both genders.

What are the features of NF1 and how is it diagnosed?

NF1 is generally diagnosed through a physical examination by a doctor with experience in managing NF1, who will assess if the clinical diagnostic criteria of NF1 is met.

Although NF1 is a hereditary condition that one is born with, some symptoms develop gradually over a number of years. The severity of symptoms varies from person to person. Almost all individuals with NF1 are diagnosed by adulthood.

People may be diagnosed with NF1 by their doctors when they meet two or more of the following features:

1) 6 or more café-au-lait spots

• Multiple flat, coffee-coloured patches on the skin
• These spots must be more than 5 mm in diameter in young children and more than 15 mm in diameter after puberty
• About 10-25% of the general population has café-au-lait spots

2) Freckling around the armpits or groin

3) 2 or more neurofibromas or 1 plexiform neurofibroma

• Neurofibromas are pea-sized bumps that can grow on the nerve tissue or under the skin. They may appear just before puberty and tend to increase in number throughout life. The number of neurofibromas in individuals with NF1 can vary greatly, from just a few to hundreds.
• Plexiform neurofibromasare larger and deeper tumours around the nerves. Sometimes, they cannot be seen or felt, and may be present from early childhood. They usually do not cause problems, but a few may grow quite large and cause local effects or develop into cancer.

4) Optic pathway glioma

• A tumour along the main nerve of the eye that is responsible for sight
• Occurs in 15-20% of children with NF1

5) 2 or more Lisch nodules

• The appearance of tiny tan clumps of pigment within the iris of the eyes, that do not affect vision

6) Specific skeletal changes

• The enlargement or malformation of bones in the skeletal system such as tibial dysplasia (curved lower leg bone) or sphenoid dysplasia (abnormally shaped bone around the eye)

7) Family history

• A parent, sibling (brother or sister), or child with NF1

8) A fault (i.e., mutation) in the NF1 gene

Some children under 8 years of age may have café-au-lait spots, but no other signs of NF1. These children should be monitored carefully to see if other signs of the condition develop

Other medical concerns related to NF1

The following problems are more common in individuals with NF1 and need to be watched for and treated if necessary:

• Learning difficulties
• Attention deficit disorder (ADD/ADHD)
• Larger head size than average
• Shorter stature/height than average
• Scoliosis (curvature of the spine)
• Early puberty
• High blood pressure
• Headaches
• Increased risk of cancer

The features of NF1 can be very different even among members of the same family.

Most people with NF1 do not have many of the health problems listed above, and live long, healthy lives.

What causes NF1?

NF1 is caused by a fault (i.e., mutation) in the NF1 gene. Genes are instructions for cells to make proteins in the body. The NF1 gene is a tumour suppressor gene which normally produces a protein that blocks the development of tumours and cancer. When faulty, it leads to a diagnosis of NF1 and an increased risk of tumours/cancer.

You can undergo genetic testing to understand if you have a faulty NF1 gene. As genes are shared among family, if you have a faulty NF1 gene, it may indicate that other family members may have inherited the faulty gene too and may also be at increased risk of tumours/cancer.

How is NF1 inherited?

NF1 follows a dominant inheritance pattern. This means that having one faulty copy can cause features of NF1.

About half of all people with NF1 have inherited the faulty gene from a parent. The other half have it because of a new and spontaneous change (mutation) in their gene.

Everyone has 2 copies of each gene in their body’s cells:

• 1 copy comes from our father
• 1 copy comes from our mother

A parent with a faulty gene(s) has a 50% chance of passing down their faulty gene(s) to their children. A child, sibling or parent of a family member with a faulty gene(s) has a 50% chance of also inheriting the same faulty gene(s). Extended relatives may also inherit the faulty gene(s).

Who should undergo genetic testing for NF1?

If you or your family members meet the following criteria, genetic testing should be considered to confirm the diagnosis of NF1.

• Individuals who exhibit features of NF1 and would like to confirm the diagnosis of NF1
• Individuals who have family members with a previously identified faulty NF1 gene
• Individuals with NF1 who are planning for a family and are interested in assisted reproductive technologies

How is genetic testing done?

Genetic testing is typically a one-time blood test. If a blood sample cannot be taken, other sample sources (e.g., skin or saliva) may be explored.

What are the possible results of genetic testing?

There are 3 types of results you may receive:

How can your genetic test result help you?

1. Personalised management
   The genetic test result may help to personalise management options based on one’s tumour/cancer risk.

   
   If you have a cancer diagnosis

   • Can help guide and personalise treatment options
   • Can help understand what other tumours/cancers you are at risk of and how to manage these risks

   
   If you are currently cancer-free

   • Can guide relevant screening options to detect tumours and cancer at their earliest, most treatable stage
   • Can help individuals with NF1 to consider dedicated reproductive options when planning to have children

A genetic test result can also help one to understand if other family members are at risk of NF1. Family members can then consider their own testing (predictive testing) to clarify carrier status and determine their tumour/cancer risks.

Can NF1 be cured?

While it is not possible to cure NF1, much can be done to make sure that you or your child has the best possible outcome.

The multidisciplinary medical team looking after you or your child will be able to address specific medical concerns and routine NF1-related healthcare issues.

What are the medical issues to look out for in childhood and how are they managed?

Sun protection, such as the use of sunscreen, is also recommended.

What can I do to manage my/my child’s increased risk of tumours and cancer?

Screening and management recommendations for individuals below 18 years

• General
  • Annual physical examinations (which include skin and neurological examinations, blood pressure, height, weight and pubertal development)
• Optic nerve pathway gliomas
  • Regular eye examinations
• Malignant peripheral nerve sheath tumours (MPNST)
  • Annual clinical review with an NF1 specialist
  • Further imaging of tumours may be recommended on a case-by-case basis
• Neurofibromas
  • Options for removal (if needed) are surgical excision, laser removal and electrodessication
• Phaeochromocytomas
  • Usually from the age of 10 onwards
  • Annual blood pressure checks
  • Blood tests and/or urine tests (if needed)
• Juvenile myelomonocytic leukaemia
  • Surveillance for children with xanthogranulomas (a type of skin lesion)
  • Blood tests may be ordered if certain features are observed (e.g., prolonged fever, weight loss, loss of appetite)

Screening and management recommendations for individuals 18 years and older

• Optic nerve pathway glioma
  • Regular eye examinations on a case-by-case basis
• Breast cancer
  • Maintain breast awareness
  • Annual breast mammograms and/or breast magnetic resonance imaging (MRI) scans
• Malignant peripheral nerve sheath tumours (MPNST)
  • Annual clinical review and physical examination with an NF1 specialist
  • Encourage early reporting of symptoms
  • Further imaging of tumours may be recommended on a case-by-case basis
• Phaeochromocytomas
  • Annual blood pressure checks
  • Blood tests and/or urine tests (if needed)
• Neurofibromas
  • Options for removal (if needed) are surgical excision, laser removal and electrodessication

Your managing doctor(s) will discuss screening recommendations with you and your child (if needed) in greater detail. The age and onset of screening may depend on the personal and/or family history of NF1. Screening guidelines may change as more information is known.

Other screening and management recommendations

Hypertension

• Further imaging may be recommended to understand the cause of hypertension

Bone problems

• Clinical evaluation of the back
• Management of scoliosis (curved spine) and/or osteoporosis
• Vitamin D supplementation

Neurological or psychiatric conditions and pain

• Screening assessments
• Medications, physical therapy and surgery

These issues may not be encountered by most individuals with NF1. Screening, management or treatment of these problems are offered on a case-by-case basis and will be discussed in greater detail by your managing doctors.