Definition

Neurofibromatosis (NF) is a common genetic condition that runs in families. Children inherit this condition from their parents, and it causes tumours to form on nerve tissue. This condition is called phacomatosis and comes in two different forms: NF-1 and NF-2, each with its own set of characteristics. Both types lead to multiple skin lesions (abnormal areas of skin) and growths in the nervous system, both in the brain and along the nerves throughout the body.¹

Symptoms of neurofibromatosis

NF1

Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting about 1 in every 3500 people. It's often first noticed by certain skin marks called café-au-lait macules (CALMs), which are light brown spots usually seen in childhood. Another common sign is freckling in the armpits or groin areas. NF1 can also cause growths called neurofibromas to develop on or around nerves, which can sometimes cause disfigurement or other problems.¹

These growths can be either under the skin or deeper within the body, and in rare cases, they can become cancerous. mall dark spots on the iris, known as Lisch nodules, can also appear. Overall, NF1 can lead to many complications, including nerve dysfunction and disfigurement.^2,3

NF2

Although the first signs of NF2 were noticed in the late 1800s, it wasn't until much later that it was recognised as a separate condition from NF1. NF2 is much rarer than NF1, occurring in about 1 in every 25,000 people.² The first sign of NF2 is often sudden hearing loss, caused by tumours called vestibular schwannomas growing on the nerves responsible for hearing and balance.

Unlike in NF1, these tumours are usually non-cancerous but can still cause problems by pressing on nearby nerves, leading to pain, nerve issues, and pressure inside the skull.^1,6 Other symptoms of NF2 may include ringing in the ears, imbalance, and the development of other types of nervous system tumours like meningiomas or gliomas.⁶

Neurofibromatosis type-1 (NF1)

Non-malignant clinical features

Pigmentary abnormalities

In neurofibromatosis type 1 (NF1), the first signs often appear as light brown spots on the skin called café-au-lait macules, usually showing up within the first couple of years of life.² If there are more than five of these spots and they're bigger than a half-inch before puberty, or bigger than 1.5 inches after puberty, it's a sign of NF1.^2,3

These spots don't turn into cancer and may darken in the sun but fade as you get older. Freckles in the armpits and groin areas are also common in NF1, usually appearing between ages 5 and 8, after the café-au-lait spots.² Also, Lisch nodules, small harmless bumps on the iris of the eye, are usually seen in older kids and adults but don't tend to affect vision or cause any health issues.³

Neurofibromas

Neurofibromas are non-cancerous tumours, made up of Schwann cells, fibroblasts, mast cells, and other cell types. There are four types: cutaneous, subcutaneous, nodular or diffuse plexiform, and spinal. 

Cutaneous neurofibromas appear on the skin in late childhood or early adolescence and don't turn cancerous. They may cause itching due to an abundance of mast cells.^4,5 When many cutaneous neurofibromas are present, they can cause discomfort or disfigurement and may be removed by a plastic surgeon. 

Spinal neurofibromas can affect single or multiple nerve roots and may lead to sensory and motor problems.⁴

Plexiform neurofibromas

Plexiform neurofibromas, which occur in individuals with neurofibromatosis type 1, differ from cutaneous neurofibromas as they arise from multiple nerve bundles and can grow along a nerve's length.² These tumours can also spread into nearby structures, causing significant pain and bone damage. Importantly, there's a risk that plexiform neurofibromas could turn cancerous over a person's lifetime.

Surgical removal is the preferred treatment for symptomatic tumours, but it's not always possible.³ Chemotherapy is being explored as an alternative treatment option. Plexiform neurofibromas often appear at birth but can keep growing into adolescence and early adulthood. They usually grow the most during the first ten years of life.

Skeletal deformities

People with neurofibromatosis type 1 (NF1) may develop various skeletal problems, including osteopenia (low bone density), scoliosis (sideways curvature of the spine), sphenoid wing dysplasia (abnormalities in the bones around the eye), congenital tibial dysplasia (abnormal development of the shin bone), and pseudarthrosis (failure of bones to heal after a fracture properly).² They may also be shorter than expected for their age and have weaker bones. NF1 increases the risk of fractures, especially in older adults and children. 

Lifestyle changes, including exercise and vitamin D supplements, may help improve bone health. Scoliosis affects up to a quarter of NF1 patients and may need bracing or surgery. Sphenoid wing dysplasia can cause facial asymmetry and requires careful examination.⁴ Congenital tibial dysplasia leads to leg bowing and may need early evaluation to prevent complications like repeated fractures and limb amputation.³

Cardiovascular abnormalities

Individuals with neurofibromatosis type 1 (NF1) may also experience cardiovascular issues, ranging from heart defects to problems with blood vessels and high blood pressure.⁴ Studies have found that up to 27% of NF1 patients have heart abnormalities, with pulmonary artery stenosis being the most common.

All children with NF1 need to have a thorough heart examination, especially if they have any heart murmurs.^2,4 NF1-related blood vessel problems can include narrowing of the arteries in the kidneys and brain, as well as abnormalities in the aorta. These issues can lead to conditions like cerebrovascular disease or renal artery stenosis.⁸

Neurocognitive deficits

Neurocognitive problems are common in individuals with (NF1). Children should have neuropsychological screenings early on, followed by more detailed tests if needed. These issues can involve spatial awareness, language, and motor skills.²

Additionally, conditions like attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders, behavioural issues, and social challenges are often seen in NF1. A team of specialists, including educators, neuropsychologists, therapists, and occupational therapists, can work together to help children reach their full potential academically and socially.^8,1

Nervous system tumors

Optic pathway and brainstem gliomas

In individuals with NF1, about 15-20% may develop low-grade glial tumours, with approximately 80% of these occurring in the optic pathway and some in the brainstem.² Optic pathway gliomas are often seen in children under 7 years old with NF1 and are linked to reduced vision or early puberty.

Regular eye exams by a pediatric neuro-ophthalmologist are recommended for children under 13 to detect optic gliomas early. Brainstem gliomas, common in NF1, may present with symptoms like cranial nerve problems, lethargy, or headaches.⁷

Glioblastomas

Those with NF1 have a significantly higher risk of developing other types of brain tumours, including grade IV astrocytomas known as glioblastomas. These tumours typically occur in young adults and are associated with a poor prognosis.⁸

Malignant peripheral nerve sheath tumours

Malignant peripheral nerve sheath tumours (MPNSTs), also known as neurofibrosarcomas or neurogenic sarcomas, are a subtype of sarcoma thought to originate from Schwann cells. They account for about 3-10% of all soft-tissue sarcomas, with a significant proportion occurring in individuals with neurofibromatosis type 1 (NF1).⁵

NF1 patients have a much higher risk of developing MPNSTs, as compared to the general population.⁵ MPNSTs can occur anywhere in the body, with their risk increasing profoundly in areas with existing internal plexiform neurofibromas.⁴

Symptoms of MPNSTs may include severe or difficult-to-control pain, the rapid growth of existing neurofibromas, changes in tumour consistency, or new neurological deficits.⁴

Non-nervous system tumour

Gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GISTs) are tumours of mesenchymal origin that can develop anywhere along the gastrointestinal tract. In individuals with neurofibromatosis type 1 (NF1), GISTs tend to occur at a slightly younger age compared to the general population and are often asymptomatic. Patients with NF1 and GISTs are more likely to have multiple tumours.¹⁰

Common symptoms of GISTs include abdominal pain, bleeding, intestinal perforation, and obstruction. These tumours can be discovered incidentally during imaging studies or surgery for other conditions, or they may present with symptoms.¹⁰

Breast cancers

Individuals with NF1 face a fivefold increased risk of developing breast cancer, particularly women under 50 years old. Moreover, mortality rates among women with NF1 and breast cancer surpass those of the general population. Although studies with NF1 patients are limited, their associated risk is comparable to individuals with a family history of breast cancer.^11,12

Neurofibromatosis Type-2

NF2 presents a significant burden in terms of morbidity and mortality compared to other forms of neurofibromatosis. There are two main clinical subtypes: a severe type, often manifesting before age 25, with multiple tumours requiring repeated surgeries and causing a shortened life expectancy, and a milder subtype, typically appearing after age 25 with fewer and slower-growing tumours, allowing for survival past 50 years.^1,2

The latest diagnostic criteria for NF2 distinguish between confirmed (definite) NF2, characterised by specific tumour patterns, and presumptive (probable) NF2, which includes unilateral vestibular schwannoma (VS) and additional tumour types. This classification ensures those needing long-term monitoring for disease progression are identified appropriately. Around 15% of NF2 cases can manifest in early childhood, highlighting the importance of early detection and surveillance.

NF2, characterised by bilateral vestibular schwannomas in 85-90% of cases, exhibits symptoms like hearing loss, tinnitus, vertigo, and facial weakness, typically emerging in late teens or early twenties.⁶ These tumours are often larger and multilobulated compared to sporadic cases, perhaps involving multiple nerves.

Other associated tumours include schwannomas, meningiomas, and glial tumours, each presenting with distinct symptoms. Routine MRI screening aids in early detection. Additionally, asymptomatic lesions like intramedullary schwannomas and ependymal ectopias are common. Management varies depending on tumour growth and symptoms, often requiring a multidisciplinary approach.^6,11

Importance of early detection and multidisciplinary management

To ensure a timely intervention and improved outcomes, detecting the symptoms of neurofibromatosis is vital. Multidisciplinary management, involving specialists enables comprehensive care, prevention of complications, and the enhancement of quality of life for patients. Empowering individuals with knowledge and support enables proactive management of their condition.⁹

Summary

Neurofibromatosis (NF) encompasses NF1 and NF2, genetic conditions causing multiple skin lesions and nervous system growths. NF1 affects 1 in 3500 people, characterised by café-au-lait macules, freckling, and neurofibromas, while NF2, rarer at 1 in 25,000, manifests with vestibular schwannomas and other nervous system tumours.

Surveillance and multidisciplinary management are crucial. NF1 patients face increased breast cancer risk, while NF2 poses significant morbidity and mortality risks, emphasising the need for early detection and intervention in both.^8,9