A 6 month old infant female is seen in your office as a new patient for a well-baby visit. Her family moved here from Asia recently, where she was born. There were no prenatal or postnatal complications, and she has had no significant medical problems since birth. Her family history is significant for her father having a condition in which his body is covered with fleshy small growths, similar to skin tags, and on the paternal side, there are several family members with the same warty growths, seizures, and high blood pressure.

Exam: VS are normal. Her growth parameters are in the 25th to 50th percentiles. Her examination is otherwise unremarkable except for multiple coffee colored spots on her trunk and abdomen.

You suspect neurofibromatosis based on her cutaneous findings and the family history. You schedule her for a follow up visit tomorrow to discuss this further. You have this night to prepare yourself in initiating a proper evaluation and treatment plan, and in counseling this family.

Neurofibromatosis (NF) is one of the more common types of neurocutaneous syndromes that are well known because of its clinical features. Its hallmark sign is the neurofibroma, which is a tumor of nerve connective tissue. There are two types of neurofibromatosis that are clinically and genetically distinct. The first type is NF-1, also called von Recklinghausen’s NF, which is the more common of the two, and its clinical features include café-au-lait spots and neurofibromas. The second type, NF-2, is much rarer, and its clinical feature is bilateral vestibular schwannomas (or acoustic neuromas), with café-au-lait spots and skin neurofibromas being less common (1). Neurofibromatosis was recognized as a disease for well over a hundred years. In 1882, Friedrich von Recklinghausen published his famous monograph describing this entity, and this disease became known as von Recklinghausen disease, which is NF-1. Other people have also recognized this disease as early as the eighteenth century, such as Tilesius and Akenside. In 1981, Dr. Vincent Riccardi recognized NF-2 as a clinically distinct entity from NF-1 (2).

Today, we know much more about both types of neurofibromatosis. The NF-1 gene is on the long arm of chromosome 17 and is a tumor suppressor gene. It encodes for a protein called neurofibromin which is a GTPase-activating protein which downregulate p21-ras, a cellular proto-oncogene, which is important in cell growth and regulation (3). The NF-2 gene is on the long arm of chromosome 22, and produces merlin (also known as schwannomin), which is a cell membrane-related tumor suppressor protein (4). We do know that both types of neurofibromatosis are autosomal dominant, just like tuberous sclerosis, which is another type of neurocutaneous syndrome. Interestingly, new mutations occur in about 50% of patients with NF-1 (3) and NF-2 (4), making these gene loci one of the highest known mutation sites in humans.

NF-1 is one of the most common types of neurocutaneous syndromes, with a prevalence of 1 in 3000 (3). There is no sex or ethnic predilection. NF-2, on the other hand, is uncommon, having an prevalence of 1 in 25,000. This type of neurofibromatosis usually presents in people in their 20’s, and is therefore seen by internists, rather than pediatricians (4).

The diagnosis of NF-1 is still a clinical one, despite the recognition of the gene causing NF-1 and its gene product. In 1987, the U.S National Institutes of Health Consensus Development Conference developed a list of criteria for the diagnosis of this disease which was updated in 1997.

NF-1 is present if two or more of the following signs are present:

1. Six or more café-au-lait macules greater than 5 mm in greatest diameter in prepubertal individuals or >15 mm in greatest diameter after puberty.

2. Two or more neurofibromas of any type or one or more plexiform neurofibromas (see definition below).

3. Freckling in the axillae or inguinal region (Crowe sign).

4. Optic glioma

5. Two or more Lisch nodules (iris hamartomas).

6. A distinctive osseous lesion, such as sphenoid wing dysplasia or thinning of the cortex of the long bones (with or without pseudoarthrosis).

7. A first degree relative (parent, sibling, or offspring) with NF-1 by the above criteria.

The signs of NF are age-dependent, with more signs appearing at older ages. The clinical order is café-au-lait spots first, then axillary freckling, followed by Lisch nodules, and lastly neurofibromas. Osseous lesions occur after age 1 year, and optic gliomas occur by 3 years of age. Because of this, only 54% of NF-1 patients with no family history were diagnosed using these criteria (3).

Genetic testing is available but is complex due to the large size of the gene and the heterogeneity of mutations. Because of this, it can only detect 95% of mutations, and therefore a negative test cannot rule out this disorder. Children with Legius syndrome can be mistaken for NF-1 since they also have multiple café-au-lait spots and axillary freckling; however, they do have macrocephaly and no neurofibromas nor central nervous system tumors. The gene involved with Legius syndrome is SPRED1. Therefore, in young children where the diagnosis is uncertain, the NF-1 mutation test can be done, and if negative, can then be tested for SPRED1 mutation (3).

Neurofibromas are benign Schwann cell tumors arising from fibrous tissue surrounding peripheral nerve sheaths, and are a cardinal feature of neurofibromatosis. They are composed of Schwann cells, fibroblasts, perineural cells, and mast cells, and can affect any organ in the body. There are four different types of neurofibromas: focal or diffuse cutaneous neurofibromas, subcutaneous neurofibromas, deep nodular or diffuse plexiform neurofibromas, and spinal neurofibromas (5). The cutaneous neurofibromas are sessile or pedunculated masses on the skin, which are fleshy and resemble skin tags, and can vary in size. Although non-tender, they can be pruritic and sometimes number in the hundreds. The subcutaneous neurofibromas lie deeper and look like bumps on the skin, which can sometimes be tender. The deep nodular neurofibromas occur along proximal nerve roots and major nerves, and resemble cutaneous and subcutaneous neurofibromas, although they are not palpable. The diffuse plexiform neurofibromas differ from the others in that it has fronds that penetrate normal tissue, making them difficult to remove. These plexiform neurofibromas can vary in severity from no skin involvement to severe disfigurement, sometimes resulting in elephantiasis with limb hypertrophy or severe facial disfigurement. The deep nodular neurofibromas and diffuse plexiform neurofibromas share a common feature in that they can become malignant peripheral nerve sheath tumors. The single most important sign that a tumor has become malignant is persistent, unexplained pain (3). Neurofibromas can occur at any time of life, although the cutaneous, subcutaneous, and deep nodular types usually appear in late childhood to early adolescence, and sometimes later. The number and size of the neurofibromas increase throughout middle and late adulthood. By 16 years of age, all patients will have cutaneous and/or subcutaneous neurofibromas. The ones that occur earlier in life are the diffuse plexiform neurofibromas, which are actually thought to be congenital. An interesting finding is an abnormal hair whorl over the spine, called the Riccardi sign, which represents a congenital paraspinal plexiform neurofibroma, which can lead to dysplastic scoliosis later in life (6,7).

Café-au-lait spots are spots with the color of coffee with milk, being tan colored. They can vary in size from smaller than 10 mm to as big as covering a body part on one side, although the typical lesions are 1-3 cm ovoid spots, which are uniform in color. They can occur anywhere on the body except for the scalp, eyebrows, palms, and soles. Histologically, they are giant melanosomes within melanocytes. Although they are a hallmark feature of NF-1 and occur in almost all individuals with this disease, they can also be seen in normal individuals as well. They are usually one of the first signs that will alert the clinician to the presence of NF-1 since they sometimes appear at the time of birth. To satisfy the criteria for NF-1, there must be 6 or more café-au-lait macules larger than 0.5 cm in diameter before puberty or greater than 1.5 cm after puberty (5).

Axillary freckling is akin to café-au-lait spots except they are smaller, about 1 to 3 mm in size, and occur in clusters. They usually appear in intertriginous areas such as the axillae, inguinal area, upper eyelids, the base of the neck, breast folds in women (5), and skin folds in obese patients.

Lisch nodules are another characteristic finding of NF-1, occurring more frequently as an affected individual ages. In those who are 5 years old, the frequency is 25%, at age 10 years it is 50%, and by age 20 years it is more than 95%. They are pigmented hamartomas appearing as translucent masses with a gray-tan hue due to the melanin-containing cells that are on the iris. They are usually bilateral and do not affect vision. Lisch nodules are diagnostic for NF-1, and they can be seen on slit-lamp examination by an ophthalmologist (8).

Optic gliomas are benign tumors which can form anywhere along the optic tract from the globe all the way to the optic radiations out of the occipital lobe and can cause blindness. Optic gliomas occur in about 15% of patients before 6 years old, and rarely in older individuals. Only 33% of these are symptomatic. These symptoms include decreased visual acuity, visual field deficits, proptosis, strabismus, optic atrophy, headache, nausea, anorexia, hypothalamic dysfunction, and precocious puberty. Otherwise, they can remain stable in size for many years, slowly progressive, or spontaneously regress (3,9). Current recommendations are for patients to have a full ophthalmologic examination when first diagnosed with NF with a full ophthalmologic examination annually up to age 8 years, then every 2 years afterwards until age 18 years. Brain imaging with CT or MRI are controversial since there is lack of specificity of abnormalities, inability to consistently identify UBOs (unidentified bright objects which can be seen in NF-1 and may be associated with learning disabilities and cognitive deficits), benign nature of most optic gliomas, and risks of sedation with imaging. Therefore, the NIH (National Institutes of Health) Consensus Development Conference did not recommend imaging for asymptomatic patients, but rather for symptomatic ones (10). The goal of therapy of optic gliomas is to retain vision with the least amount of side effects. Asymptomatic optic gliomas are observed, and when there is extension to the optic canal or progressive visual problems, chemotherapy is done first. When there is complete blindness with proptosis, surgery can be considered. Radiation therapy is avoided due to the increased risk of secondary malignancy (11).

Neurofibromatosis should be considered a multiorgan disease in that tumors can occur in any part of the body. Other manifestations are hypertension from renal artery stenosis, tumors secreting vasoactive compounds, coarctation of the aorta, seizures, scoliosis, long bone dysplasia, sphenoid bone dysplasia, short stature, and macrocephaly. Mental retardation is not common (4% to 8%), while learning disabilities are more common (40% to 60%) (10).

The diagnosis of NF-2 is based on criteria that were first developed in 1987 by the NIH. Two other criteria, the Manchester criteria, and later, the Baser criteria, were developed that improved sensitivity (4). Criteria of NF-2 can be seen in the table below:

Any ONE of the following criteria required:
1. Bilateral vestibular schwannomas.
2. First-degree relative with NF2 and (a) unilateral vestibular schwannoma, OR (b) any two of the following: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities.
3. Unilateral vestibular schwannoma AND any two of the following: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities.
4. Multiple meningiomas AND (a) unilateral vestibular schwannoma, OR (b) any two of the following: schwannoma, glioma, neurofibroma, cataract.

The vestibular schwannoma, previously known as the acoustic neuroma, is the hallmark tumor of NF-2. This tumor arises from the vestibular branch of cranial nerve VIII, and is universal in patients with this type of neurofibromatosis (12). Vestibular schwannoma are usually bilateral and most occur by 30 years of age. The patient may first present with hearing problems, such as when using the telephone. Onset of hearing loss is gradual, although sometimes it can occur suddenly, and can progress to deafness. Besides hearing loss, tinnitus and balance problems can occur. If left untreated, brainstem compression and hydrocephalus can occur when the schwannoma extends medially (4).

Café-au-lait spots (or macules) can be a sign of neurofibromatosis or a part of other neurocutaneous syndromes. The following is a list of diseases that involve café-au-lait spots that are divided into generalized and localized (13):

Generalized
1. Multiple lentigines (LEOPARD) syndrome
2. Carney complex (NAME/LAMB syndrome)
3. Arterial dissection (aortic, internal carotid, vertebral arteries)
Localized
1. Peutz-Jeghers syndrome
2. Laugier-Hunziker syndrome
3. Cowden disease
4. Bannayan-Riley-Ruvalcaba syndrome
5. Lentiginosis perigenitoaxillaris
6. Centrofacial lentiginosis
7. Inherited patterned lentiginosis
8. Partial unilateral lentiginosis
9. Xeroderma pigmentosus
10. Neurofibromatosis type 1
11. Legius syndrome (neurofibromatosis type 1 like syndrome)

Although there are many diseases in this list, the main one to remember is NF-1. What makes things more complicated is that café-au-lait spots are seen in the healthy, normal population. Solitary spots are common, with 3 or more seen in 0.2% to 0.3% of normal children, and 6 or more seen in less than 0.1% of healthy children. To suspect NF-1, there needs to be six or more café-au-lait spots that are larger than 0.5 cm in prepubertal patients, and larger than 1.5 cm in postpubertal patients. These spots, however, are not a major feature of NF-2, and these patients may have only a few spots present.

The management of a patient with neurofibromatosis should focus on genetic counseling and evaluating for the development of new tumors. The patient should be referred to a neurofibromatosis clinic if one is available because of the multidisciplinary assistance that can be received. The American Academy of Pediatrics published a policy statement on the health supervision of children with NF-1 (14). The skin should be examined for new neurofibromas and progression of lesions. Blood pressure should be checked yearly because of the higher risk for hypertension due to renal artery stenosis, aortic stenosis, and pheochromocytoma (more common in adults). Learning disabilities can occur and the child should be evaluated for this annually in terms of his or her academic performance. Annual eye examinations should be performed annually. Skeletal changes should be monitored, such as scoliosis, vertebral angulation, and limb abnormalities, with referral to an orthopedist should it occur. NF-1 is autosomal dominant, and therefore the unborn child has a 50/50 chance of having this disease. Prenatal diagnosis is available for NF-1 by amniocentesis or chorionic villus sampling, and can be performed if one of the parents has NF and the precise mutation is known. Pre-implantation genetic diagnosis can be used to identify embryos that do not carry a known familial NF-1 mutation (3).

The management of NF-2 includes genetic counseling, annual hearing screenings, and surgery or radiation therapy for tumors. For those with severe hearing impairment, cochlear or brainstem implants may be considered (4).

The prognosis for NF-1 is not a promising one. Life expectancy is shortened with the cause of death likely being due to a malignant tumor if death occurred before age 30 years (3).

NF-2 patients do not fare well either. The average life expectancy is 36 years with death being due to surgically inoperable tumors according to studies done in 1970s and 80s; however, survival may be longer since then with earlier diagnosis and better treatment. The majority of patients become deaf due to vestibular schwannomas and wheelchair bound due to cranial nerve VIII involvement, vision problems, and muscle weakness (4).

We have now identified the gene and gene products for neurofibromatosis. With new discoveries and technologies, gene therapy may be used to treat and prevent this disease in individuals at risk in the near future.

Questions

1. How many café-au-lait spots are needed to diagnose neurofibromatosis? How big do they need to be in prepubertal and postpubertal patients?

2. What is the hallmark tumor in NF-2? How is it manifested in a patient?

3. If you see a patient with café-au-lait spots who you suspect has NF-1, what tests or evaluations need to be performed?

4. What types of neurofibromas can become malignant peripheral nerve sheath tumors?

5. Put the following in clinical order from the earliest to the latest: axillary freckling, café-au-lait spots, Lisch nodules, neurofibromas.

6. What is the genetic inheritance pattern for neurofibromatosis? What percentage of cases occur without a family history of NF (sporadic)?

7. What are the eye tumors that you can find on the iris of NF-1 patients called?

References

1. Sahin M. Chapter 589. Neurocutaneous Syndromes. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 19th edition. 2011, Philadelphia: W.B. Saunders Company, pp. 2046-2053 e1.

2. Riccardi VM. Chapter 1 - Historical Background and Introduction. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 1-25.

3. Plon SE. Neurofibromatosis type 1. In: Up-to-Date. March 15, 2013, Amsterdam: Wolters Kluwer.

4. Evan DG. Neurofibromatosis type 2. In: Up-to-Date. June 22, 2013, Amsterdam: Wolters Kluwer.

5. Williams VC, et al. Neurofibromatosis Type 1 Revisited. In: Pediatrics. 2009; 123(1): 124-133.

6. Friedman JM, Riccardi VM. Chapter 2 - Clinical and Epidemiological Features. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 29-86.

7. Korf BR. Chapter 6 - Neurofibromas and Malignant Tumors of the Peripheral Nerve Sheath. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 142-161.

8. MacCollin M. Chapter 13 - Clinical Aspects. In: Friedman JM, et al (eds). Neurofibromatosis, 3rd edition. 1999, Baltimore: The Johns Hopkins University Press, pp. 299-326.

9. Friedman JM. Neurofibromatosis 1. 1998 Oct 2 [Updated 2012 May 3]. In: Pagon RA, Adam MP, Bird TD, et al (eds). GeneReviews [Internet]. 1993-2013, Seattle: University of Washington.

10. Hersh JH and Committee on Genetics. Health Supervision for Children with Neurofibromatosis. In: Pediatrics 2008; 121(3): 633-642.

11. Recht LD. Optic pathway glioma. In: Up-To-Date. June 30, 2013, Amsterdam: Wolters Kluwer.

12. Park JK, et al. Vestibular schwannoma (acoustic neuroma). In: Up-To-Date. April 11, 2013, Amsterdam: Wolters Kluwer.

13. Schaeffer JV, Bolognia JL. Benign pigmented skin lesions other than melanocytic nevi (moles). In: Up-To-Date. Dec 8, 2012, Amsterdam: Wolters Kluwer.

14. Hersh JH. Health Supervision for Children with Neurofibromatosis. In: Pediatrics. 2008; 121(3): 633-642.

Answers to questions

1. 6 spots. >5 mm in prepubertal and >15 mm in postpubertal patients.

2. Vestibular schwannoma (acoustic neuroma). It is manifested by hearing problems.

3. Blood pressure measurements due to increased risk of renal artery stenosis, vasoactive secreting tumors and coarctation of the aorta; and eye examinations to look for Lisch nodules. Imaging with CT or MRI is not recommended if asymptomatic.

4. Deep nodular neurofibromas and diffuse plexiform neurofibromas.

5. The clinical order is café-au-lait spots first, then axillary freckling, followed by Lisch nodules, and lastly neurofibromas.

6. Autosomal dominant. 50% occur without a family history (i.e., new mutation).

7. Lisch nodules.