Neurofibromatosis 1 (von Recklinghausen Disease)
Article ID: 2023-0013-IR
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Article ID: 2023-0013-IR
Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.
Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common autosomal dominant genetic diseases that affects multiple organs.1 NF1 is caused by heterozygous pathogenic variants in the NF1 gene on chromosome 17q11.2, resulting in RAS pathway activation.2 The prevalence of NF1 has been estimated to be approximately 1 in 3000 individuals with no relation to race.3 NF1 is characterized by cutaneous manifestations, including café-au-lait spots, freckling, and various types of neurofibromas, neurological manifestations, and osseous abnormalities.4 However, clinical manifestations are variable even in members of the same family. Mosaic NF1 is characterized by a regionally limited distribution of the features of NF1.5 Mosaic NF1 is caused by a postzygotic somatic mutation of the NF1 gene in the affected region.6 It has been reported that the estimated incidence of mosaic NF1 is approximately 1 in 36,000–40,000 individuals (0.003%).7
Patients with NF1 have an increased risk of malignancies. The overall risk of malignancies in patients with NF1 is about 2.7 times higher than that in the general population.8 In addition, the average life expectancy in patients with NF1 is about 15 years shorter than that in healthy individuals.9 It has been reported that the health-related quality of life (QOL) is impaired in patients with NF1 in Japan.10
NF1 has usually been diagnosed on the basis of clinical criteria that were proposed by the National Institutes of Health in 1988.11 Because most of the features of NF1 are age-dependent, it is necessary to follow suspected cases for several years before a diagnosis can be made.12 Using the criteria, the diagnosis of NF1 is made in 97% of patients by the age of 8 years.13 Molecular testing for NF1 after genetic counseling has recently become available in Japan, although the cost is not covered by National Health Insurance. In Japan, if a heterozygous pathogenic NF1 variant is found in a patient, a diagnosis of NF1 is made. However, because of medical progress, including genetic diagnosis technology, revised diagnostic criteria for NF1 were proposed in 2021.14 Diagnostic criteria for mosaic NF1 are also included in the revised criteria. Although it was difficult for infant patients without a family history to fulfill the previous criteria, it has been reported that the use of the revised diagnostic criteria for NF1 decreased the time to diagnosis.15 Therefore, the Japanese version of the diagnostic criteria for NF1 should be updated in the near future by the NF1 research group with support from the Ministry of Health, Labour, and Welfare.
Differential diagnosis includes Legius syndrome, Noonan syndrome, Costello syndrome, Cardiofaciocutaneous syndrome, and LEOPARD syndrome related to the RAS signaling pathways (RASopathies).16 Patients with Legius syndrome caused by mutations in the SPRED1 gene have multiple café-au-lait spots and freckling but lack other typical features of NF1.17 Diagnostic criteria for Legius syndrome have also been proposed in the revised criteria.14 Patients with the other diseases have a few café-au-lait spots (<6) or congenital heart diseases, whereas neurofibromas, one of the characteristic features of NF1, are not usually observed. Each of these diseases can be distinguished from NF1 by genetic testing.
Although the pathogenesis of NF1-associated features has not been fully elucidated, loss of heterozygosity or biallelic inactivation of the NF1 gene in different cell lineages has been shown to be related to several manifestions.18 Café-au-lait spots are well circumscribed, appearing as light to dark brown macules with smooth borders. They are usually present at birth or become apparent in early childhood and grow proportionately to body growth. The halo phenomenon is sometimes observed with Mongolian spots in Asian infant patients.19 Freckling is a small brown macule typically seen on the axillae and groin from 3 years of age.
Neurofibroma can be classified into cutaneous neurofibroma and plexiform neurofibroma (PNF) (nodular or diffuse PNF). Cutaneous neurofibromas are soft, dome-shaped, skin-colored nodules of 1–2 cm in diameter. They are detectable in most patients at puberty and increase in number and size with age.20 In contrast, PNF is thought to be a congenital tumor and is seen in about 30% of patients.21 At present, there is no agreement on the definition of PNF.22NF1 haploinsufficiency plays an important role in the development of neurofibromas.23 It has been suggested that abnormally differentiated Remak bundles are the cells of origin for PNF.24 Nodular PNF develops along multiple branches of nerve plexuses and can also be seen within diffuse PNF. Diffuse PNF often develops on an overlying hyperpigmented region (giant café-au-lait spot) and grows rapidly in childhood,25 resulting in disfiguration or significant morbidity. It has been reported that whole-body magnetic resonance imaging (MRI) is useful for detection of an internal PNF.26 Because PNF has potential for malignant transformation (malignant peripheral nerve sheath tumor, MPNST), fluorine-18-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography (CT) is useful for identifying malignant change in a preexisting PNF when a patient complains of pain or rapid growth of the tumor.27
MRI is useful for the diagnosis of optic glioma if there are visual and neurological problems. Lisch nodules are small, pigmented nodules in the iris that are detectable from 3 years of age and are found in most adult patients.28
The typical osseous abnormalities associated with NF1 include sphenoid wing dysplasia, long bone dysplasia, and scoliosis.29 Sphenoid wing dysplasia and long bone dysplasia are usually identified in infancy in approximately 2% of patients. Scoliosis (not included in the diagnostic criteria) is found in up to 10% of NF1 patients.30
Genotype–phenotype correlations have been identified in some cases of NF1.31 It is known that a large gene deletion of NF1 shows a severe phenotype.32
Although the overall degree of severity and complications in each patient are not predictable, age-specific annual monitoring and patient education are important for the management of NF1.33 The DNB classification (dermatological, neurological, and bone manifestations) proposed by NF1 experts has been used for assessment of the severity of NF1 in Japan (Table 1).34
| Stage | Manifestations | |||
| D | N | B | ||
| 1 | 1 | 0 | 0 | No problems in daily life and social activity |
| 2 | 1, 2 | 0 | 1 | Mild problems in daily life and social activity |
| 1, 2 | 1 | 0, 1 | Mild problems in daily life and social activity | |
| 3 | 3 | 0 | 0 | Mild problems in daily life and severe problems in social activity |
| 4 | 3 | 0 | 1 | Moderate problems in daily life and severe problems in social activity |
| 1 | 0, 1 | Moderate problems in daily life and severe problems in social activity | ||
| 5 | 4 | Any | Any | Severe problems in daily life and social activity |
| Any | 2 | Any | Severe problems in daily life and social activity | |
| Any | Any | 2 | Severe problems in daily life and social activity | |
| Dermatological manifestations (D) | ||||
| 1 | Pigmented macules and a few neurofibromas | |||
| 2 | Pigmented macules and many neurofibromas | |||
| 3 | Numerous neurofibromas (>1000, >1 cm in size) | |||
| 4 | Large plexiform neurofibroma with severe secondary problems or malignant peripheral nerve sheath tumor | |||
| Neurological manifestations (N) | ||||
| 0 | No neurological symptoms | |||
| 1 | Neurological symptoms (paralysis or pain) or/and abnormal neurological findings | |||
| 2 | Severe or progressive neurological symptoms (intellectual disability or brain tumor) | |||
| Bone manifestations (B) | ||||
| 0 | No bone lesions | |||
| 1 | Mild or moderate bone lesions (deformity of spine or limbs) not requiring treatment | |||
| 2 | Severe bone lesions (dystrophic scoliosis, pseudoarthrosis or defect of skull or facial bone) requiring treatment | |||
From Ehara et al.34
Café-au-lait spots and freckling can be treated with various types of laser therapy equipment.35,36 However, it is difficult to treat numerous lesions distributed over the entire body and the results are not always satisfactory because re-pigmentation or more pigmentation might be observed after treatment in some cases.
Cutaneous neurofibromas have a negative impact on the QOL of NF1 patients37 and they can be removed by surgery to improve cosmetic and social problems if they are symptomatic.38 Carbon dioxide laser treatment is also useful for the removal of small lesions.39
Symptomatic nodular PNF can also be surgically treated, but removal may result in a neurological deficit. PNF (diffuse PNF) sometimes causes life-threatening massive intratumor hemorrhage after minor trauma.22 Although it is preferable to treat PNF,40 resection is a therapeutic challenge, especially if it is located on the head and neck or in an internal region.
It is well known that NF1 acts as a tumor suppressor gene. Mutation of the NF1 gene increases signaling through the intracellular Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/mammalian target of the rapamycin (mTOR) pathway.18 Recent targeted strategies have revealed several interesting molecular therapies for PNF in patients with NF1.41 Until 2020, there was no approved therapy for inoperable PNF in patients with NF1, but it has been revealed that treatment with selumetinib, an MEK inhibitor, was beneficial for NF1 children with PNF.42 In Japan, selumetinib was approved in 2022 for pediatric patients (aged 3–18 years) with symptomatic, inoperable PNF. For 74 children enrolled in a trial of selumetinib treatment (median age, 10.3 years), the overall partial response rate (≥20% decrease) was 70% (52/74) during the treatment period (median duration of 57.5 cycles).43 In addition, improvement in pain was sustained with continuous treatment. The most common adverse events were gastrointestinal symptoms, asymptomatic creatinine phosphokinase increase, paronychia, and acneiform rash. With up to 5 years of follow-up, it has been shown that treatment with selumetinib in children is relatively safe and tolerable.
It is important for physicians to be aware of malignancies in patients with NF1. The most common associated malignancies in NF1 are MPNST (in approximately 13% of patients). In addition to loss of NF1 function, other gene mutations, such as mutations in CDKN2A and PRC2 (SUZ12 and EED), are related to the development of MPNST from PNF.44 The standard care for MPNST is wide surgical excision, but an understanding of the genomic drivers of MPNST might improve therapeutic strategies in the future. Guidelines for the management of PNF and MPNST are currently being prepared by NF1 specialists in Japan.
Treatment is not always required for asymptomatic optic glioma. Chemotherapy with vincristine and cisplatinum is usually used in symptomatic cases for management of optic glioma. It has been reported that 6 of 25 patients (24%) had a partial response in a phase II trial with selumetinib (median duration of 26 cycles).45 Osseous abnormalities are rarely found, but early referral to an orthopedist or neurosurgeon is desirable because management is often difficult. In general, it is important that patients with NF1 be referred to appropriate specialists for management of various complications.
Age-specific annual assessment and treatment of complications by a multidisciplinary team are important for management of NF1.46 Various drugs blocking the RAS-MAPK or mTOR pathways are under investigation for several symptoms of NF1 (see www.clinicaltrials.com). In the future, these novel medical therapies may be useful for treatment of a variety of manifestations related to NF1. Construction of a registry for NF1 patients is underway by the NF1 research group with support from the Ministry of Health, Labour, and Welfare of Japan.
This work was supported by a Health Labour Science Research Grant (20FC1043) from the Ministry of Health, Labour, and Welfare of Japan.
The author has received service honoraria from Alexion Pharmaceuticals Inc.
