Neurofibromatosis Type 1

Definition and Clinical Features

presentation image for neurofibromatosis Type 1
Image courtesy of GEN Opens in new window

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant Opens in new window inherited disease characterized by pigmented skin lesions, skin tumors that develop along peripheral nerves, iris hamartomas Opens in new window, café-au-lait spots (light-brown macules of varying size), axillary freckling, scoliosis, and an increased incidence of a variety of neural tumors and associated gliomas, and intracranial meningiomas.


One of the most common inherited syndromes, NF1 carries 100% disease penetrance within families. However, the clinical spectra of the disease vary dramatically even within families. Two or more of the following findings are sufficient for diagnosis:

  1. Six or more café-au-lait-spots Opens in new window.
  2. Two or more Lisch nodules (see here Opens in new window).
  3. Two or more skin or subcutaneous neurofibromas Opens in new window.
  4. A plexiform neurofibromas.
  5. An optic nerve glioma Opens in new window.
  6. Bony defects involving the tibia or sphenoid.
  7. Axillary freckling Opens in new window.

Other findings may include the following:

  • Facial weakness and numbness from 5th and 7th cranial nerve involvement and hemilateral facial atrophy from plexiform neuromas that cause overgrowth of the skin and subcutaneous tissue.
  • Neurologic features of macrocephaly, mental retardation, speech impediment, intracranial tumors, epilepsy, and spinal cord and peripheral nerve tumors.
  • Endocrine abnormalities such as acromegaly, Addison disease, hyperparathyroidism, precocious puberty, gynecomastia, pheochromocytoma, and medullary thyroid carcinomas.
  • Skeletal changes in von Recklinghausen disease include bony overgrowth, fibrous dysplasia, osteomalacia, vertebral anomalies, and pseudoarthrosis of the tibia or radius.
  • Malignant changes (malignant neurofibrosarcoma, Wilm’s tumor, fibrosarcoma, rhabdomyosarcoma, leukemias, and retinoblastoma).

Other findings include renal vascular lesions causing hypertension, cystic lung disease, and gastrointestinal neurofibromas with chronic blood loss.

Skin Features

The various skin features include the following:

  • Nodular cutaneous and subcutaneous neurofibromas develop on the trunk during adolescence in von Recklinghausen disease. They are sessile, dome-shaped, or pedunculated and increase in number throughout life.
  • Café-au-lait spots   Opens in new window appear as sharply defined, light brown patches and occur on the trunk, axilla, and occasionally, face.
  • Smaller freckles of the axilla, Crowe sign , and other intertrginous areas are common and are almost pathognomonic for neurofibromatosis.
  • Subcutaneous plexiform neurons are usually located along the trigeminal nerve or in the peripheral nerves. They have indistinct margins, they feel soft like “a bag of worms,” and the overlying skin is hyperpigmented or is covered by excessive hair.
  • Other skin features include elephantiasis neurofibromata; papillomatous tumors of the palate, buccal mucosa, tongue, and lips; and macroglossia.

Ocular Features

The ocular features include the following:

  • Lid or eyebrow involvement includes hyperpigmentaton, neurofibromas, plexiform neuromas of the upper eyelid, ptosis, trichiasis, and thickened skin (fibroma molluscum), especially temporally. When the eyelid is involved there is often an S configuration to the eyelid margin because of the weight of the plexiform neuroma.
  • Conjunctival hyperpigmentation; thickening; and isolated neurofibromas on the limbus, tarsus, or bulbar conjunctiva.
  • Corneal nodules (neurofibroma) and thickening of the corneal nerves.
  • Pulsatile exophthalmos or orbital asymmetry from sphenoidal bone defect; exophthalmos and evidence of a space-occupying lesion; enlargement of the optic canal; and enophthalmos from bony defects.
  • Lisch nodules and choroidal melanocytic lesions represent uveal tract changes in neurofibromatosis. Lisch nodules are round, dome shaped, brownish-colored iris lesions, measuring less than 1 mm.
  • Benign astrocytic growths of the retina similar to tuberous sclerosis and dense macular pigmentation.
  • Optic nerve involvement at the chiasm, optic pathway, or optic nerve; papilledema and optic atrophy.
  • Other ocular features include neuromas of the ciliary body leading to buphthalmos and glaucoma.
  • Café-au-lait spots in fundus can be seen as well-demarcated, nonelevated areas of localized pigmentation or abnormalities in pigment distribution.

Cause: NF1 Gene Mutation

Neurofibromatosis type 1 results from the mutational inactivation of the NF1 gene on human chromosome 17. The NF1 gene contains 61 exons that give rise to 12kb mRNA and encodes neurofibromin, a protein with a GTPase Activating Protein (GAP) domain. Its major function in acting as tumor suppressor is in stimulation of conversion of the active GTP-bound RAS to the inactive GDP-bound RAS. By rendering RAS inactive, the typical proto-oncogenic signaling of RAS is terminated.

Mutations Opens in new window in RAS genes can lead to the production of permanently activated RAS proteins. As a result, this can cause involuntary and overactive signaling within the cell, even in the absence of incoming signals.

All RAS proteins are part of a group of proteins referred to as small GTPase and when levels of RAS GTP are increased, there occurs the stimulation of the P13 K/AKT/mTOR signaling pathway that protects cells from apoptosis.

Mutations of the germ line cells are common for the NF1 gene; however, there are reports where individuals with somatic NF1 gene mutations develop segmental forms of this clinical entity and have characteristic lesions limited to only a limb.

The germ line mutation rate for the NF1 gene is ten times more common than that observed for most other inherited diseases. Currently, by a combination of different techniques, nearly 95% of germ line mutations can be detected.

There are a lot of phenotypic variations within NF1 gene mutations such that only two firm genotype-phenotype correlations have been reported. Consequently there are patients who are better described as gonadal mosaics, in whom none of the phenotypic variations of neurofibromatosis may be seen but will have descendants who may express the neurofibromatosis type 1 phenotype. This shows that, even within families, the NF1 gene exhibits large variations in expression and there is evidence for regulating the expression of NF1 gene by modifying the NF1 gene loci.

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