Neurofibromatosis type 1 (NF1) is a genetic disorder caused by the dysfunction of a gene called NF1, leading to the development of tumors and various symptoms primarily affecting the skin, bones, and nervous system.

A characteristic feature of NF1 is the appearance of café-au-lait spots—light brown, round to oval patches on the skin—during infancy. If six or more of these spots are present, the likelihood of NF1 is high.

During childhood, attention deficit hyperactivity disorder (ADHD) and learning disabilities may be observed. Additionally, skeletal abnormalities, such as limb length differences and spinal curvature (scoliosis), may develop with growth.

From adolescence onwards, soft tumors known as neurofibromas appear on the skin and gradually increase in number.

While NF1 is associated with various complications and tumors, not all patients experience the same symptoms. The severity of symptoms and the types of tumors that develop vary significantly from person to person, making NF1 a highly diverse condition.

NF1 is diagnosed based on clinical diagnostic criteria, which involve assessing a combination of presenting symptoms.

However, in children under eight years old, all the diagnostic criteria may not yet be present, making early diagnosis difficult.

In 2024, genetic testing was added to the diagnostic criteria and is now available as a covered medical test under Japan’s health insurance system. However, not all patients with NF1-related symptoms will have a detectable genetic mutation through testing.

NF1 is caused by mutations in the NF1 gene and follows an autosomal dominant inheritance pattern. If one parent has NF1, their child has a 50% chance of inheriting the condition.

However, about 50% of NF1 cases occur spontaneously (de novo mutations), meaning they appear in individuals with no family history of the disease. The estimated frequency of new cases is 1 in 3,000 births.

Because NF1 is a genetic disorder, it can be diagnosed through genetic testing.

However, the NF1 gene is exceptionally large and contains a highly variable sequence, meaning mutations can occur at multiple locations rather than a single fixed site.

As of 2024, genetic testing has become part of the diagnostic criteria and is now covered by insurance for cases where clinical diagnosis is difficult.

At Fukuoka University Hospital’s Department of Dermatology, we conduct genetic testing as part of research under the approval of the Ethics Review Board using a technique called whole-exome sequencing.

Testing requires an in-person consultation, and details can be discussed directly with your physician. Genetic counseling by a clinical genetics specialist is also available.

There have been many reports on the use of laser treatment for café-au-lait spots. However, there is no currently recommended treatment due to the high recurrence rate and risk of excessive depigmentation.

At Fukuoka University Hospital, we do not perform laser treatment for café-au-lait spots.

There are three main types of neurofibromas associated with NF1:

1. Cutaneous Neurofibromas: Small to large dome-shaped growths on the skin, found in almost all NF1 patients.
2. Plexiform Neurofibromas: Lumps under the skin that may extend into fat, muscle, and deeper tissues, present in about 30% of NF1 patients.
3. Diffuse Neurofibromas: Soft, ill-defined, raised areas. Both plexiform and diffuse neurofibromas are classified as plexiform neurofibromas.

Surgical Treatment for Neurofibromas

For cutaneous neurofibromas, surgical removal is the primary treatment. Small tumors (one or two) can be removed under local anesthesia in an outpatient setting, while multiple tumors may require inpatient surgery under general anesthesia.

For plexiform neurofibromas, surgical removal is considered first, but these tumors present more challenges than cutaneous neurofibromas. Post-surgical nerve damage, pain, and sensory or motor impairments are possible risks. Diffuse neurofibromas tend to be highly vascular, making complete removal difficult and regrowth common. Thorough preoperative planning, imaging, and hospitalization are required.

Medication: Selumetinib (MEK Inhibitor)

For patients with inoperable plexiform neurofibromas, the MEK inhibitor selumetinib (Koselugo®) is available under insurance coverage.

After extensive clinical trials overseas, selumetinib was approved in Japan in 2022. It is a high-cost medication with potential serious side effects, so patients must fully understand the risks and benefits before starting treatment. Please consult for details.

Future Treatments

Topical medications for neurofibromas and MEK inhibitor trials for adults with plexiform neurofibromas are currently being researched. At present, these trials are not conducted at our hospital.

NF1 is classified as a designated intractable disease by the Japanese government.

Patients with severe neurofibromas (over 1,000 tumors larger than 1 cm), paralysis, pain, or moderate to severe bone deformities (Stage 3 or higher) may be eligible for medical expense subsidies if they meet specific criteria and apply through their local government.

More information can be found on the Nanbyo Information Center (Rare Disease Center) website.

Japan Intractable Diseases Information Center｜Neurofibromatosis Type 1

NF1 is also classified as a Pediatric Chronic Specific Disease, which has different severity criteria than the intractable disease designation.

Information Center for Specific Pediatric Chronic Diseases, Japan｜Recklinghausen Disease

NF1 patient support groups are available, including:

Rares Disease Association – Fukusei Asebi-kai

Fukuoka University Hospital does not currently conduct patient group activities.

Because NF1 affects multiple organ systems, its treatment requires collaboration among various specialists, including dermatologists, internal medicine specialists, pediatricians, plastic surgeons, orthopedic surgeons, neurosurgeons, ophthalmologists, and genetic specialists.

The Japan Neurofibromatosis Society holds annual conferences, bringing together medical professionals from different fields to share knowledge and advance research.

Fukuoka University Hospital is recognized as an NF1 treatment center (NF1-JNET) by the Japan Neurofibromatosis Society, ensuring multidisciplinary care for NF1 patients.

The Japanese Society of Recklinghausen Disease

At Fukuoka University Hospital, we conduct epidemiological research on NF1 to better understand the challenges faced by patients.

We may ask patients to participate in surveys to help improve medical care and treatment strategies.

Your cooperation in this research is highly appreciated.