Neurofibromatosis peripheral Q85.0

Hereditary, autosomal-dominantly inherited neuroectodermal systemic disease, also caused by spontaneous mutation.

Prevalence 1:2,500/3,500; low androtropy

Autosomal dominant inheritance. Mutation of gene locus q11.2 on chromosome 17. This NF1 gene locus comprises three genes: OMPG (encoding a membrane-bound glycoprotein of oligodendrocyte myelin), EVI2A and EVI2B (encoding viral insertion sequences).

The NF1 peptide shows sequence homologies with GTPase-activating protein (GAP) and stimulates Ras GTPase activity.

When GTPases are activated, they hydrolyze GTP to GDP and as such are no longer able to stimulate their effector. Defective GAPs can no longer switch off a mitogenic signal, and the cells proliferate uncontrollably.

The appearance of café-au-lait stains is possible from birth, but mostly in the first months of life until the age of 2. Dermal neurofibromas only develop later between the ages of 10 and 16.

• Pigmented spots:
  • Café-au-lait spots (> 95% of cases): about 80% of pat. show > 6 café-au-lait spots. However, this symptom may also occur in 10% of the unaffected population.
  • Axillary freckling (about 90% of pat.; = Crowe's sign); pigmentation of the oral mucosa.
  • Nevi: Melanocytic nevi (incidence lower than in the average population).
  • Furthermore, the occurrence of hemangiomas, lymphangiomas, lentigines and nevi spili is possible.
  • In >50% of patients with neurofibromatosis type I a n. anaemicus is found gfls. rarely together with a juvenile xanthogranuloma (JXG).
  • JXG occurs more frequently than average (in about 3% of cases) together with type I neurofibromatosis (NF1) (Miraglia E et al. 2022).
• Single or numerous, pea-sized or monstrous, skin-colored to bluish, broad or pedunculated papules or nodules (neurofibromas), possibly with wrinkling or as dewlap-like structures, cutis laxa.
  • Bell button phenomenon: Herniated subcutaneous tumors protruding through the skin can be pushed back with a finger.
  • In addition, deeper subcutaneous neurofibromas, often pressure-dolent, are found as derb palpable nodules.
• Neurology: CNS tumors and neurologic symptoms present as serious problems in NF-1. Tumors of the cranial nerves in particular may require surgical intervention. Acoustic and trigeminal schwannomas especially cause hearing loss but also pain. Optic gliomas can cause unilateral blindness; tumors of the spinal roots can cause paralysis and pain.
• Eyes: Mostly exophthalmos and Lisch nodules.
  • Lisch nodules (Irishamartomas): Small, roundish, sharply defined, and slightly raised changes in the iris. They have a light, yellowish to brownish hue. They are considered an important diagnostic criterion in peripheral neurofibromatosis and occur in almost all patients with neurofibromatosis type I (> 20 years). They do not occur in NFII, NFIII and NFIV.
• Skeleton: Changes occur in 1/3 of patients as thickening and lengthening of long bones, kyphoscoliosis (maldevelopment of vertebral bodies), bone cysts, pathological fractures and habitual dislocations. Furthermore: short stature and cranial deformities.
• All other tumors(spinal and peripheral neurofibromas, schwannomas of peripheral nerves, etc.) are found in less than 5% of patients. About one-third of patients also have nonspecific symptoms such as school problems (30%), short stature (15%), macrocephaly (25%), and scoliosis (30%). Pseudoarthrosis and epilepsies occur in less than 5% of patients. A proportion of patients develop pheochromocytoma.

• Notice. The diagnostic criteria include the symptoms that the vast majority of patients develop during the course of the disease. However, not all patients develop all these symptoms, but only a more or less random combination of them. Doctors make a statistically clever selection of average symptoms and use them as diagnostic criteria to predict whether a person has the particular disease.

Molecular genetic detection of the NF1 mutation. Mutation detection is extremely complex due to the size of the NF1 gene, the presence of pseudogenes, and the wide variety of mutations (Ko JM et al. 2013). For example, a large Korean NF1 population showed 52 different NF1 mutations identified in 60 families. The mutations included 30 single base substitutions (12 missense and 18 nonsense mutations), 11 missplicing mutations, seven small insertions or deletions, and four large deletions. Sixteen (30.8%) mutations were novel; c.1A>G, c.2033_2034insC, c.2540T>C, c.4537C>T, c.5546G>A, c.6792C>A, and c.6792C>G were consistently identified. The mutations were evenly distributed across exon 1 to intron 47 of NF1. No mutation hotspots were found. Genotype-phenotype analysis suggests that there is no clear relationship between specific mutations and clinical features (Ko JM et al. 2013).

At least two of the main criteria should be met (Karaconji T et al. 2019):

• At least 6 pigmentary spots in the form of milk-coffee-colored spots (café-au-lait spots) of at least 5 mm in size.
• At least 2 cutaneous neurofibromas or one plexiform neurofibroma
• Freckling or multiple, inguinal lentigines in the axilla and/or groin area
• Optic glioma
• at least 2 Lisch nodules (pigment accumulations in the iris of the eye)
• Bone malformations (pseudarthrosis, sphenoid wing dysplasia, curvature of the long tubular bones)
• Neurofibromatosis type 1 in the family

Since peripheral neurofibromatosis (NF type I) is a genetic disease, a therapy aimed at curing the underlying disorder is currently not possible.

Therefore, the only treatment option is surgical removal of the cutaneous neurofibromas.

Tumors of the central nervous system may be so localized that surgery is not possible without altering healthy tissue. There is also the possibility that surgery and radiation may promote tumor growth. Therefore, a very careful risk-benefit assessment is required. Usually, only those changes that have the risk of malignant development are removed. Severe neurological or orthopaedic symptoms, serious cosmetic problems and the threat of blindness are also reasons for surgery.

The prognosis is decisively determined by the occurrence of malignant tumors

Because of the autosomal-dominant inheritance, a critical examination of the desire to have children is advised. Fertility disorders seem to occur.

Patients with a detected mutation in the NF1 gene are advised to undergo early screening.

To prevent complications, regular check-ups should be performed as well as preventive imaging examinations if necessary.

1. Ferner RE et al. (2013) Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol 115:939-55.
2. Karaconji T et al (2019) Neurofibromatosis type 1: review and update on emerging therapies. Asia Pac J Ophthalmol (Phila) 8:62-72.
3. Ko JM et al (2013) Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol 48:447-453.
4. Meissner M et al (2011) Rapid and effective treatment of minor neurofibromas. JDDG 9: 167-169
5. Miraglia E et al (2022) Juvenile xanthogranuloma in neurofibromatosis type 1. Prevalence and possible correlation with lymphoproliferative diseases: experience of a single center and review of the literature. Clin Ter 173:353-355.