Thompson & Thompson Genetics in Medicine, 8th Edition

Case 34. Neurofibromatosis 1 (NF1 Mutation, MIM 162200)

Autosomal Dominant


• Variable expressivity

• Extreme pleiotropy

• Tumor-suppressor gene

• Loss-of-function mutations

• Allelic heterogeneity

• De novo mutations

Major Phenotypic Features

• Age at onset: Prenatal to late childhood

• Café au lait spots

• Axillary and inguinal freckling

• Cutaneous neurofibromas

• Lisch nodules (iris hamartomas)

• Plexiform neurofibromas

• Optic glioma

• Specific osseous lesions

History and Physical Findings

L.M. was a 2-year-old girl referred because of five café au lait spots, of which three measured larger than 5 mm in diameter. She had no axillary or inguinal freckling, no osseous malformations, and no neurofibromas. Physical examination of her parents revealed no stigmata of neurofibromatosis. The consulting geneticist informed the parents and referring pediatrician that L.M. did not meet the clinical criteria for neurofibromatosis type 1.

L.M. returned to the genetics clinic at 5 years of age. She now had Lisch nodules in both eyes and 12 café au lait spots, 8 of which measured at least 5 mm in diameter. She also had axillary freckling bilaterally. She was given the diagnosis of neurofibromatosis 1; her parents were told that she likely had a de novo mutation and the recurrence risk was therefore low, but that gonadal mosaicism could not be excluded.

L.M.'s parents declined both molecular testing in L.M. and prenatal testing during their next pregnancy.


Disease Etiology and Incidence

Neurofibromatosis 1 (NF1, MIM 162200) is a panethnic autosomal dominant condition with symptoms most frequently expressed in the skin, eye, skeleton, and nervous system. NF1 results from mutations in the neurofibromin gene (NF1). The disease has an incidence of 1 in 3500 persons, making it one of the most common autosomal dominant genetic conditions. Approximately half of patients have de novo mutations; the mutation rate for the NF1 gene is one of the highest known for any human gene, at approximately 1 mutation per 10,000 live births. Approximately 80% of the de novo mutations are paternal in origin, but there is no evidence for a paternal age effect increasing the mutation rate (see Chapter 4).


NF1 is a large gene (350 kb and 60 exons) that encodes neurofibromin, a protein widely expressed in almost all tissues but most abundantly in the brain, spinal cord, and peripheral nervous system. Neurofibromin is thought to regulate several intracellular processes, including the activation of Ras GTPase, thereby controlling cellular proliferation and acting as a tumor suppressor.

More than 500 mutations in the NF1 gene have been identified; most are unique to an individual family. The clinical manifestations result from a loss of function of the gene product; 80% of the mutations cause protein truncation. A disease-causing mutation can be identified for more than 95% of individuals diagnosed with NF1.

NF1 is characterized by extreme clinical variability, both between and within families. This variability is probably caused by a combination of genetic, nongenetic, and stochastic factors. No clear genotype-phenotype correlations have been recognized, although large deletions are more common in NF1 patients with neurodevelopmental difficulties.

Phenotype and Natural History

NF1 is a multisystem disorder with neurological, musculoskeletal, ophthalmological, and skin abnormalities and a predisposition to neoplasia (Fig. C-34). A diagnosis of NF1 can be made if an individual meets two or more of the following criteria: six or more café au lait spots measuring at least 5 mm in diameter (if prepubertal) or 15 mm in diameter (if postpubertal); two or more neurofibromas of any type, or one plexiform neurofibroma; axillary or inguinal freckling; optic glioma; two or more Lisch nodules; a distinctive osseous phenotype (sphenoid dysplasia and thinning of the long bone cortex, with or without pseudarthrosis); or a first-degree relative with NF1.


FIGURE C-34 A, Cutaneous manifestations of neurofibromatosis 1, including hundreds of small to medium-sized reddish papular neurofibromas and two large café au lait spots (arrows). B, Iris showing numerous Lisch nodules (one typical nodule is indicated by the arrow). See Sources & Acknowledgments.

Nearly all individuals with NF1 but no family history will meet clinical criteria by the age of 8 years. Children who have inherited NF1 can usually be identified clinically within the first year of life because they require only one other feature of the disease to be present.

Although penetrance is essentially complete, manifestations are extremely variable. Multiple café au lait spots are present in nearly all affected individuals, with freckling seen in 90% of cases. Many individuals with NF1 have only cutaneous manifestations of the disease and iris Lisch nodules. Numerous neurofibromas are usually present in adults. Plexiform neurofibromas are less common. Ocular manifestations include optic gliomas (which may lead to blindness) and iris Lisch nodules. The most serious bone complications are scoliosis, vertebral dysplasia, pseudarthrosis, and overgrowth. Stenosis of pulmonic, renal, and cerebral vessels and hypertension are also frequent. The most common neoplasms for children with NF1 (other than neurofibromas) are optic nerve gliomas, brain tumors, and malignant myeloid disorders. Approximately half of all children with NF1 will have a learning disability or attention deficits, which can persist into adulthood. Pheochromocytoma can also occur.

Individuals with features of NF1 limited to one region of the body, and who have unaffected parents, may be diagnosed with segmental (or regional) NF1. Segmental NF1 may represent an unusual distribution of clinical features by chance or somatic mosaicism for an NF1 gene mutation.


NF1 is a clinical diagnosis. Identification of mutations is not done routinely because of the size of the gene and the extreme allelic heterogeneity but is clinically available and be useful for patients in whom the diagnosis is less obvious.

No curative treatments are available, and therefore treatment focuses on symptomatic management. Ongoing surveillance in an individual with NF1 should include an annual physical examination conducted by someone familiar with NF1, annual ophthalmological evaluation in childhood (less frequent as an adult), regular developmental assessments in childhood, and regular blood pressure measurements.

The deformities caused by NF1 are the most distressing disease manifestation. Discrete cutaneous and subcutaneous neurofibromas can be surgically removed if they are disfiguring or inconveniently located. Plexiform neurofibromas causing disfigurement or impingement can also be surgically managed. However, surgical intervention for these neoplasms can be problematic because they are often intimately involved with nerves and have a tendency to grow back at the site of removal.

Inheritance Risk

Individuals with NF1 have a 50% risk for having a child affected with NF1, although the features may be different in an affected child. Prenatal diagnosis is available for those families in whom a causative NF1gene mutation has been identified. Although prenatal diagnosis is accurate, it will not provide much prognostic information because of the extreme phenotypic variability of the disease. Parents of an affected child who themselves show no signs of the disease are still at some small elevated recurrence risk in the next pregnancy because of the possibility of gonadal mosaicism, which has been documented with NF1.

Questions for Small Group Discussion

1. Why is there such clinical variability in NF1? What factors could be influencing this phenotype?

2. Why is a positive family history of NF1 one of the major diagnostic criteria for this condition and not for other autosomal dominant conditions?

3. Review the major points of discussion with a family that desires prenatal testing for NF1 based on a known mutation in one of the parents.

4. How would a treatment of NF1 need to be targeted at the molecular level to specifically address the loss of function seen with this condition? How is that different from a disease caused by a dominant negative mutation?


Friedman JM. Neurofibromatosis 1. [Available from]

Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014;13:834–843.

Pasmant E, Vidaud M, Vidaud D, et al. Neurofibromatosis type 1: from genotype to phenotype. J Med Genet. 2012;49:483–489.