Neurofibromatosis Type 1 (NF1)

Neurofibromatosis type 1 (NF1) is a common genetic condition that causes tumours to grow along nerves and can affect multiple parts of the body, including the skin, nervous system, eyes, and bones. It is one of the most common genetic conditions worldwide, affecting approximately 1 in 2,500 to 3,000 people.

NF1 was previously known as von Recklinghausen’s disease, named after the German physician who first described it in the 19th century. Today, it is understood to be caused by a mutation in the NF1 gene, which plays a critical role in regulating cell growth.

Although NF1 is present from birth, its features vary enormously from person to person and change throughout life. Many of the tumours associated with NF1 are benign (non-cancerous). However, NF1 also significantly increases the risk of developing certain cancers, including neuroendocrine tumours such as phaeochromocytoma and duodenal neuroendocrine tumours, as well as malignant peripheral nerve sheath tumours, breast cancer, and gastrointestinal tumours.

Because NF1 is associated with these neuroendocrine and tumour-related risks, it falls within the scope of neuroendocrine cancer care. NeuroEndocrine Cancer Australia (NECA) supports people living with NF1 and their families through education, resources, advocacy, and access to the NET Nurse service.

Understanding NF1

NF1 is caused by a mutation in the NF1 gene, located on chromosome 17. This gene produces a protein called neurofibromin, which acts as a brake on cell growth, a function known as tumour suppression.

When the NF1 gene is mutated, neurofibromin is absent or non-functional. Without this break, certain cells (particularly Schwann cells and other cells that surround peripheral nerves ) can grow in an uncontrolled way, forming benign tumours called neurofibromas.

The same loss of growth control increases the risk of certain cancers developing over time. This is why ongoing surveillance for tumour development is an important part of NF1 management throughout life.

NF1 affects multiple body systems. While some people live with mild symptoms that have little impact on daily life, others experience significant complications that require ongoing specialist care. The range and severity of symptoms cannot always be predicted, even within the same family.

Causes and inheritance

The NF1 gene

NF1 is caused by a pathogenic variant (mutation) in the NF1 gene on chromosome 17. This mutation leads to absent or non-functional neurofibromin protein, disrupting normal cell growth regulation.

Autosomal dominant inheritance

NF1 follows an autosomal dominant pattern of inheritance. This means that only one copy of the mutated NF1 gene is needed to cause the condition. A person with NF1 has a 50 per cent chance of passing the condition to each of their children.

De novo mutations

Approximately 50 per cent of NF1 cases arise from a de novo (new, spontaneous) mutation, meaning the person affected has no family history of NF1 and the mutation has occurred for the first time in that individual. The other 50 per cent of cases are inherited from an affected parent.

Because of this, a family history of NF1 is not always present, and its absence does not rule out the diagnosis.

Signs and symptoms of NF1

NF1 can affect many parts of the body. Signs typically appear in early childhood and may change or worsen over time, particularly during puberty, pregnancy, and other hormonal transitions.

Skin signs

Café-au-lait spots: Flat, light brown patches on the skin are usually the earliest sign of NF1, often appearing within the first year of life. Six or more café-au-lait spots (larger than 5mm before puberty or larger than 15mm after puberty) are one of the key diagnostic features.

Axillary and inguinal freckling: Unusual freckling in areas not normally exposed to the sun, particularly the armpits (axillary) or groin (inguinal), is another characteristic feature of NF1. It typically develops between the ages of three and five.

Neurofibromas

Cutaneous neurofibromas: Soft, benign lumps on or just under the skin. They arise from the cells that surround peripheral nerves (particularly Schwann cells) together with other supporting cells within the nerve sheath. . Cutaneous neurofibromas typically begin to appear around puberty and may increase in number significantly with age. In some people they can number in the hundreds or thousands.

Plexiform neurofibromas: Larger tumours that grow deeper inside the body along major nerve pathways. Plexiform neurofibromas may be present from birth, although they are not always detectable early in life. They can grow slowly over time, and in some cases cause pain, disfigurement, or functional impairment depending on their location. A small proportion of plexiform neurofibromas can transform into malignant tumours over time.

Eye features

Lisch nodules: Tiny, harmless brown or tan spots on the iris (the coloured part of the eye). They do not affect vision but are a useful diagnostic marker, typically identified on slit-lamp examination by an ophthalmologist. They are present in the majority of adults with NF1.

Optic pathway gliomas: Low-grade tumours on the optic nerve or optic pathways connecting the eyes to the brain. They occur in approximately 15 per cent of people with NF1, most often in young children. Many optic pathway gliomas cause no symptoms and are managed with observation. Some can affect vision and require treatment.

Bone abnormalities

• Scoliosis: A progressive curvature of the spine that may require monitoring or treatment
• Tibial dysplasia: Bowing or abnormal development of the lower leg bones, which can increase the risk of fractures
• Sphenoid wing dysplasia: Abnormal development of a bone in the skull near the eye socket
• Reduced bone mineral density: May contribute to osteoporosis in some individuals and is associated with an increased risk of fractures.

Learning and developmental differences

Up to 50 per cent of children with NF1 experience learning difficulties.  Most learning difficulties in children with NF1 occur in the absence of intellectual disability and are related to differences in attention, processing speed, executive function, and organisation.

Common learning and developmental features include:

• Reading difficulties and dyslexia
• Attention deficit hyperactivity disorder (ADHD)
• Autism spectrum characteristics or social communication difficulties
• Difficulties with memory, spatial reasoning, and executive function
• Anxiety and social challenges

Early assessment and educational support can make a significant difference for children with these difficulties.

Diagnosing NF1

NF1 is usually diagnosed based on clinical findings. According to international diagnostic guidelines, a diagnosis of NF1 is confirmed when two or more of the following criteria are present:

1. Six or more café-au-lait spots (>5mm in children before puberty; >15mm after puberty)
2. Freckling in the armpit or groin
3. Two or more neurofibromas of any type, or one plexiform neurofibroma
4. An optic pathway glioma
5. Two or more Lisch nodules, or two or more choroidal abnormalities on specialist eye examination
6. A distinctive bone lesion such as tibial bowing or sphenoid wing dysplasia
7. A first-degree relative (parent, sibling, or child) with a confirmed NF1 diagnosis, or a pathogenic NF1 gene variant identified through molecular genetic testing

In children under two years of age who do not yet meet the full clinical criteria, molecular genetic testing can confirm the diagnosis. Genetic testing may also be helpful when the clinical picture is uncertain or when family planning is being considered.

Cancer risks associated with NF1

One of the most significant aspects of NF1 is the increased lifetime risk of developing certain cancers. Regular surveillance is therefore an essential part of NF1 management.

Malignant peripheral nerve sheath tumours (MPNSTs)

MPNSTs are one of the most serious cancer risks in NF1. They are aggressive soft tissue sarcomas that often develop from pre-existing plexiform neurofibromas, although they can also arise from other peripheral nerve sheath lesions. People with NF1 have an estimated lifetime risk of developing an MPNST of approximately 8 to 13 per cent.

Warning signs that a plexiform neurofibroma may be undergoing malignant change are described in the Red flag symptoms section below.

Phaeochromocytoma

NF1 increases the risk of phaeochromocytoma, a neuroendocrine tumour of the adrenal gland that produces excess stress hormones (catecholamines). Phaeochromocytoma can cause hypertension, headaches, palpitations, sweating and anxiety

Because phaeochromocytoma can cause dangerous blood pressure surges (particularly during surgery or anaesthesia), assessment for phaeochromocytoma is important in people with NF1 who have symptoms, or other risk factors before planned procedures.

Duodenal neuroendocrine tumours

People with NF1 have an elevated risk of developing neuroendocrine tumours in the duodenum (the first part of the small bowel). These are a specific type of neuroendocrine tumour that may secrete somatostatin and are typically found in the region around the pancreatic duct.

Gastrointestinal stromal tumours (GISTs)

NF1-associated GISTs are tumours of the gastrointestinal tract, most commonly occurring in the small intestine. They differ biologically from sporadic GISTs and tend to be multiple rather than single lesions.

Pancreatic tumours

Pancreatic tumours, including pancreatic neuroendocrine tumours, have been reported in people with NF1, although they are rare and less commonly associated with NF1 than duodenal neuroendocrine tumours.

Breast cancer

Women with NF1 have an increased risk of developing breast cancer, particularly under the age of 50. Current clinical guidelines recommend that women with NF1 begin annual breast MRI screening from the age of 30, earlier than the general population screening programme.

Other cancer risks

NF1 also increases the risk of:

• Brain tumours and gliomas
• Leukaemia (particularly in children)
• Soft tissue sarcomas

Cardiovascular complications

The NF1 mutation can affect the structure and function of blood vessels, leading to cardiovascular complications in some people.

Hypertension

High blood pressure is more common in people with NF1 than in the general population. It can occur at a young age and may be caused by:

• Narrowing of the arteries supplying the kidneys (renal artery stenosis)
• Phaeochromocytoma

When hypertension is identified in someone with NF1, investigation for an underlying cause is important.

Moyamoya disease

A rare but serious condition in which the major arteries at the base of the brain progressively narrow, causing the formation of fragile alternative blood vessels. This increases the risk of stroke and requires specialist neurological management.

Psychological and quality of life impacts

The physical manifestations of NF1 can have a profound effect on emotional wellbeing and daily life.

Psychosocial effects

Cutaneous neurofibromas can multiply and become visible across the body over time. This can significantly affect body image, self-esteem, and social confidence. Some people with NF1 experience anxiety, depression, and social withdrawal as a result.

Chronic pain from tumours pressing against nerve pathways, and persistent skin itching from cutaneous neurofibromas, can further affect quality of life and sleep.

Adult cognitive challenges

While learning difficulties are often first identified in childhood, adults with NF1 may continue to experience challenges with executive function, including working memory, organisation, planning, and mental flexibility. These difficulties can affect employment, relationships, and independence.

Psychological support, neuropsychological assessment, and occupational strategies can help people manage these challenges throughout life.

Red flag symptoms

People with NF1 and their families should be aware of warning signs that may indicate a benign tumour is undergoing malignant change. These symptoms require prompt medical assessment:

• Persistent pain that steadily worsens over weeks
• New or intense pain that wakes a person from sleep
• A plexiform neurofibroma that suddenly becomes harder or changes in texture
• Rapid growth of an existing or new tumour
• Unexplained and unintentional weight loss
• Sudden weakness, numbness, or reduced function in a limb
• Significant change in the size or feel of a deep tumour

Early assessment of concerning changes allows timely diagnosis and treatment, which may improve outcomes.

Treatment and management

There is currently no cure for NF1. Management focuses on regular monitoring, early detection of complications, and treating specific problems as they arise.

Regular surveillance

Because NF1 can affect multiple body systems in unpredictable ways, structured annual review by a multidisciplinary team is recommended. This may include:

• Clinical review by a specialist with expertise in NF1
• Annual eye examinations, particularly in young children, to monitor vision and detect complications such as optic pathway gliomas early
•  Assessment for skeletal complications, including scoliosis and bone changes, with referral to orthopaedics if needed.
• Blood pressure monitoring
• MRI assessment and monitoring of plexiform neurofibromas when clinically indicated, such as when symptoms develop
• Neuropsychological and developmental assessment in children and young people

MEK inhibitor therapy: selumetinib

Selumetinib is a targeted therapy that works by blocking a signalling pathway (the MEK pathway) that drives neurofibroma growth. It has been approved for children with NF1 who have symptomatic, inoperable plexiform neurofibromas and has been shown to shrink these tumours in a significant proportion of children.

Eligibility and access to selumetinib should be discussed with a specialist multidisciplinary team.

Surgery

Surgery may be considered when:

• A tumour causes significant pain, nerve compression, or functional impairment
• There is concern about malignant transformation
• Cosmetic or reconstructive intervention is appropriate

Surgery for plexiform neurofibromas is complex and is generally performed at specialist centres.

Managing associated cancers

When cancers such as MPNSTs, phaeochromocytoma, breast cancer, or GISTs develop, treatment follows the approach for that specific cancer type and is guided by a specialist multidisciplinary team.

Developmental and educational support

For children with learning difficulties, ADHD, or developmental differences, early intervention and ongoing support are important. This may include:

• Educational support plans and school-based accommodations
• Speech and language therapy
• Occupational therapy
• Psychological support and behavioural strategies

Hormonal changes and life stages

Puberty

The onset of puberty often triggers an increase in the number and size of cutaneous neurofibromas. Regular assessment is particularly important during adolescence.

Pregnancy

Most women with NF1 have healthy pregnancies. However, hormonal changes during pregnancy may increase the size and number of neurofibromas, and there is also an increased risk of high blood pressure. Specialist obstetric care with awareness of NF1 is recommended for pregnant women with the condition.

Menopause

Some women report changes in their neurofibromas around menopause, though the evidence for this is less consistent than for puberty and pregnancy.

Genetic counselling and family planning

Because NF1 is autosomal dominant with 50 per cent inheritance risk or chance of passing the condition on, genetic counselling is an important part of care for people with NF1 and their families.

Genetic counselling can help with:

• Understanding the inheritance pattern and risk to future children
• Options for family planning, including prenatal testing and preimplantation genetic diagnosis
• Cascade testing for other family members
• Understanding the variability and unpredictability of the condition

Even when NF1 arises as a de novo mutation, the risk of passing it to future children is still 50 per cent.

Living with NF1

NF1 is a lifelong condition that affects people differently at each stage of life. Many people with NF1 live full and active lives with appropriate monitoring and support. Others face more significant challenges due to complications such as plexiform neurofibromas, malignancy, learning difficulties, or cardiovascular disease.

Regular specialist review, early identification of complications, access to appropriate therapies, and strong psychological and social support all contribute to better outcomes.

Living with a condition that is visible on the body, variable in its course, and carries a risk of cancer can be emotionally demanding. Connecting with specialist care teams and peer support can make a meaningful difference for people with NF1 and their families.

Follow-up and surveillance

Lifelong follow-up is recommended for all people with NF1. The frequency and content of surveillance depends on age, current complications, and individual risk factors.

Research and future directions

Research into NF1 is advancing rapidly, with growing understanding of the molecular mechanisms underlying tumour development and expanding targeted treatment options.

Important areas of research include:

• Further development of MEK inhibitors and other targeted therapies for plexiform neurofibromas
• Identifying biomarkers to predict which plexiform neurofibromas are at highest risk of malignant transformation
• Better strategies for treating MPNSTs, which remain difficult to manage
• Understanding the cognitive and neurodevelopmental aspects of NF1
• Trials of combination therapies targeting the NF1 molecular pathway
• Improved imaging techniques for early detection of malignant change
• Management strategies for NF1-associated cardiovascular complications

Clinical trials may be available for some people with NF1, particularly those with plexiform neurofibromas or MPNST. The treating specialist team can advise on relevant trial opportunities.

Support available through NeuroEndocrine Cancer Australia

Living with NF1 involves navigating a complex, multisystem condition with lifelong implications for health, learning, and wellbeing. NeuroEndocrine Cancer Australia provides support for people affected by NF1 and their families, including:

• Access to the NET Nurse service
• Specialist NET dietitian and counsellor
• Patient and carer information and resources
• Support for navigating rare cancer and tumour care
• Education about neuroendocrine cancer and related conditions
• Guidance on questions to ask the treating team
• Connection to specialist information and support pathways

For support, information, and guidance after an NF1 diagnosis, contact NeuroEndocrine Cancer Australia.

References

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