Clinical and Health Affairs
Neurofibromatosis Type 1
Update on a Common Genetic Condition
By Elizabeth Siqveland, M.S., R.N., C.N.P., and Dinel Pond, M.S., C.G.C.
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition affecting the skin, peripheral nervous system, and skeletal system. Half of all cases are inherited from a parent. The disease, which often manifests in childhood, affects an estimated 1 in 3,000 people, making it likely that physicians in Minnesota will encounter a patient with NF1. This article describes the diagnostic criteria for NF1 and the use of genetic testing for diagnosis; it also includes information about resources for diagnosing and treating children with the condition.
At first glance, Robert looks like a normal teenager—a lean, lanky, 13-year-old African-American boy slouched in a chair. He politely answers questions about school, saying he struggles in math and science but is pleased to be passing all of his classes. When asked about pain, he describes chronic backaches and difficulty extending his arms completely, which makes everyday tasks such as carrying bags of groceries and sitting for long periods of time difficult. Robert has special permission to sit on pillows and change positions throughout the school day. He says he often chooses to sit on the floor to make himself comfortable. Robert says he has several friends but describes being teased by peers because of his differences.
On physical exam, Robert meets the diagnostic criteria for neurofibromatosis type 1 (NF1). He has multiple dark brown café-au-lait spots scattered over his torso, axillary freckling, and several subcutaneous nodules on his extremities, including large round lumps near each antecubital fossa. Radiographs of his spine taken a few years ago revealed a bilobed soft-tissue mass. Follow-up MRI revealed extensive plexiform neurofibromas spread diffusely throughout his spine, pelvis, and thighs. These large, benign lesions have grown over time, and he complains of back pain daily. Robert is currently participating in a clinical trial, with the hope that the medication being tested will halt tumor growth or decrease tumor volume.
A Variable Condition
Neurofibromatosis type 1 is an autosomal dominant genetic condition affecting the skin, peripheral nervous system, and skeletal system. Half of all cases are inherited from a parent, while the other half are caused by a spontaneous mutation. The incidence of NF1 is estimated at 1 in 3,000 people,1 but actual numbers may be higher because the disorder is underrecognized. The condition is widely variable among affected people, even within the same family. It is not uncommon to diagnose a mildly affected parent at the same time a child is newly diagnosed. Nearly 100,000 people in the United States, including approximately 500 children in Minnesota, are affected by NF1. Given those numbers, clinicians are likely to encounter at least 1 patient with the condition in their practice.2
People with NF1 have a mutation in 1 of the 2 copies of the NF1 gene, which produces the protein neurofibromin. The current understanding of neurofibromin’s function is primarily that of tumor suppression. Neurofibromin is part of the Ras signaling pathway, which controls cell growth and differentiation. Depending on the severity of the mutation, the gene either produces poorly functioning or nonfunctioning neurofibromin, produces an amount of functional neurofibromin that’s less than normal, or fails to produce neurofibromin at all. Consistent with Knudson’s 2-hit hypothesis of tumorigenesis, loss of heterozygosity for the NF1 gene leads to an overgrowth of cells along the peripheral nerve sheath, resulting in the development of neurofibromas and other tumors.3 Many details about the function of neurofibromin remain unknown, making this an area of interest for researchers.
Diagnosing NF1
Hallmark features of NF1 are café-au-lait spots and neurofibromas. Other features may include relative macrocephaly, short stature, precocious or delayed puberty, headaches, learning disabilities, and ADHD. Criteria used to make a clinical diagnosis of NF1 are described in Table 1. For younger children with no family history, diagnosing the condition can be difficult and is often delayed. Patients with neurofibromatosis are not typically born with full manifestations of the disorder. For example, an infant may be born with multiple café-au-lait spots and not develop other signs of NF1 until later in life. Although the condition may be suspected, a diagnosis cannot be made based on the presence of café-au-lait spots alone. Many of the signs or features of NF1 are age-dependent, requiring clinicians to conservatively follow most infants with café-au-lait spots over time before they are able to confirm the diagnosis. In one study of 1,893 people with NF1, 95% met the diagnostic criteria by age 8, with 100% meeting the criteria by age 20.4 In families with a known history of NF1, a clinical diagnosis can be more easily made because a family history of the condition is considered a major diagnostic criterion. Molecular gene analysis can be used as an adjunct for diagnosis.
♦ Café-au-lait Spots and Freckling
Café-au-lait spots are the primary feature of NF1 and should raise a red flag for medical providers. As the name suggests, café-au-lait spots are the color of coffee with milk in fair-skinned individuals and dark brown in individuals with darker skin coloring. Café-au-lait spots typically present between birth and early childhood, but they may develop through age 12.5 Typically, café-au-lait spots are 4mm in diameter or larger. Having 1 or 2 café-au-lait spots is common in the general population; however, the vast majority of children with 6 or more spots will eventually fulfill the diagnostic criteria for NF1.6
Axillary and inguinal freckling develops in approximately 85% of people with NF1, although usually not until they are 3 years of age.5 Freckles are the same color as café-au-lait spots but are only 1 mm to 3 mm in diameter.7 Young children may have only a few freckles in the axillae or inguinal area, while older children and adults often have clusters of freckles. Patients with NF1 may have freckling in other areas with skin folds including the base of neck and the underside of the breasts in women—areas that experience little-to-no sun exposure.
♦ Tumors
Development of cutaneous and subcutaneous neurofibromas typically begins just prior to puberty and continues throughout adulthood, with the number of tumors increasing with age. Cutaneous neurofibromas develop from cellular overgrowth along a nerve in the uppermost layers of the skin. They may resemble mosquito bites or grow larger and protrude from the skin. Some cutaneous neurofibromas are pink or purple in color and feel like a small divot or indentation. Subcutaneous neurofibromas develop around nerves just below the skin. Some are barely detectable, while others are clearly visible and are palpable (firm and rubbery). Neurofibromas may itch or cause discomfort, especially if they are in an area that is frequently irritated (ie, under a waistband or shirt collar). They may be large enough or numerous enough to be of cosmetic concern. Removal is an option, but there is a risk for regrowth, local nerve damage, and residual scarring. There is no way to predict how many neurofibromas an individual will have or where lesions will develop.
Plexiform neurofibromas are potentially much more problematic than cutaneous or subcutaneous neurofibromas. These larger tumors develop along the length of peripheral nerves and can be disfiguring or painful, or infringe on vital structures. Complete resection of these tumors is often difficult because of their infiltrative nature. Although plexiform neurofibromas are seen in 20% to 44% of people with NF1,8 most patients’ tumors will never become symptomatic. The lifetime risk of malignant transformation is 10%.9 Patients with known plexiform neurofibromas should have them evaluated regularly for rapid growth, changes in consistency (firmness), or pain.7 Research is underway to learn more about the natural history of and effective treatments for plexiform neurofibromas.10
♦ Ophthalmologic Features
Optic pathway tumors (optic gliomas) are recognized in approximately 15% of people with NF1, generally by 6 or 7 years of age. Optic pathway tumors may be the presenting feature for a patient, as 70% of children with optic pathway tumors meet the diagnostic criteria for NF1.11 Optic pathway tumors originate from astrocytes surrounding the optic nerves and are typically low-grade gliomas. These tumors remain indolent in most people with NF1. For that reason, treatment is reserved for the small subset of individuals with optic pathway gliomas that become symptomatic and create either visual impairment or pituitary dysfunction.12 A baseline brain MRI to screen for optic pathway tumors in asymptomatic individuals with NF1 is no longer recommended because it detected a large number of optic gliomas that never became symptomatic. Therefore, screening was not shown to positively affect outcomes.13 Instead, children should have an annual eye exam by a pediatric ophthalmologist who is knowledgeable about NF1, with MRI reserved for the evaluation of children with clinical concerns. In cases where optic gliomas are causing symptoms, chemotherapy can be used to halt tumor growth.
A Resource for Minnesota Children
Physicians who encounter a child whom they suspect may have NF1 can refer them to a clinic specializing in neurocutaneous syndromes for initial diagnosis, genetic testing and counseling, treatment, long-term follow-up, and care coordination.
One clinic that provides such services is the Neurocutaneous Syndromes Clinic Without Walls. Created in 2005 by Children’s Hospitals and Clinics of Minnesota, Gillette Children’s Specialty Healthcare, and the Minnesota Epilepsy Group, it brings together a network of providers who offer coordinated care for children and families with NF1 and similar disorders. The clinic also is a member of the Minnesota Clinic Without Walls, an affiliate of the Children’s Tumor Foundation Neurofibromatosis Clinic Network. For information or to schedule an appointment at the Neurocutaneous Syndromes Clinic Without Walls, call 612/813-7076.
To learn more about NF1, go to the Children’s Tumor Foundation website, www.CTF.org, or the Neurofibromatosis, Inc. website, www.NFINC.org. |
Lisch nodules (iris hamartomas) are a primary diagnostic feature of NF1; these nodules do not cause vision problems. The presence of Lisch nodules is age-dependent, with only 40% of affected children having them by 6 years of age.
4 By late adulthood, more than 95% of people with NF1 have Lisch nodules, making them a useful screening criterion when evaluating other family members. It is important for an experienced ophthalmologist to examine for Lisch nodules, as they may be difficult to distinguish from ordinary iris freckles or other causes of irregularity or discoloration of the iris.
♦ Skeletal Differences
Bony lesions are more common among children with NF1. Tibial dysplasia and sphenoid wing dysplasia are included in the diagnostic criteria; both involve thinning of the respective bones. Although tibial dysplasia is uncommon among people with NF1 (5%), approximately 50% to 80% of all patients born with tibial dysplasia will eventually meet the diagnostic criteria for NF1.14 Tibial dysplasia may be significant enough to result in fracture and pseudoarthrosis with long-term implications. Although not part of the diagnostic criteria, similar deformities of the radia and ulna have been reported.14 Sphenoid dysplasia, best seen by CT, is found in 1% of patients with NF1 and may present as proptosis or asymmetry of the face. Sphenoid dysplasia consists of remodeling or decalcification of the sphenoid wings with enlargement of the anteroposterior middle cranial fossa.15
Associated Findings
In addition to the diagnostic criteria, there are a number of important medical considerations for individuals who have NF1. Scoliosis occurs in 10% to 30% of people with NF1 compared with 1% to 2% of the general population.13 Onset may be early, with some infants and toddlers having marked asymmetry upon exam. Scoliosis is most commonly nondystrophic and is similar to idiopathic scoliosis seen in the general population. There is a risk for developing dystrophic scoliosis, which is characterized by its sharply angled curves and potential for rapid progression. Vertebral scalloping and kyphosis may also be seen.7
Hypertension is a particularly important clinical indicator, and people with NF1 should have their blood pressure screened annually. In young children, hypertension may indicate renal artery stenosis; in children older than 10 years and adults, this may suggest the presence of a pheochromocytoma.
Rates of malignancy are higher among people with NF1. There is a chance that plexiform neurofibromas may become malignant peripheral nerve sheath tumors, which have a poor prognosis. Other rare complications include pheochromocytoma, juvenile myelomonocytic leukemia, and rhabdomyosarcoma. The overall incidence of these disorders is low, and presymptomatic screening is not routinely recommended.7
Learning disabilities are present in 30% to 60% of individuals with NF1. Learning disabilities may be of any type and may affect children of all ages. Attention deficit hyperactivity disorder has been reported in 38% of children with NF1.16 Mental retardation is slightly more common in the NF1 population (3% to 8% of people with NF1, compared with 3% of the general population).7 Difficulties with motor skills, coordination, and speech are common and may contribute to challenges in school and on the job.
Genetic Testing and Counseling
The diagnosis of NF1 is based on clinical criteria; however, molecular gene analysis may be considered under several circumstances (Table 2). Genetic testing for NF1 is currently quite good, with greater than 95% sensitivity. For patients without a family history and who do not meet the diagnostic criteria, a negative result does not completely rule out NF1. Limited information is available regarding genotype-phenotype correlation, which is evident in the variability seen in various members of the same family. However, there are at least 2 exceptions to this general rule: Patients with a whole-gene deletion of the neurofibromin gene may have a phenotype that includes mild facial differences, more severe cognitive impairment, and a heavier neurofibroma load.17 A mild phenotype consisting of café-au-lait spots and freckling with a paucity of neurofibromas and/or obvious plexiform neurofibromas has also been reported in association with at least one specific mutation.18 A certified genetic counselor should always interpret molecular test results.
Clinical Care Guidelines
Clinical care guidelines have been developed and were recently updated by the American Academy of Pediatrics Committee on Genetics.13 Individuals with NF1 are encouraged to have a thorough exam each year. Although mildly affected patients may be followed in their primary care clinic, those with multi-system involvement also may be seen in a specialty clinic. Treatment plans are individualized for each patient, depending on their symptoms and the severity of the condition. Patients who have an optic glioma and experience visual impairment from progressive tumor growth will usually respond to chemotherapy. For patients with plexiform neurofibromas, there is no definitive treatment to date, but a number of researchers are testing new experimental agents aimed at the Ras pathway. Current clinical trials involve agents such as pirfenidone, tipifarnib, cediranib, sorafenib, and rapamycin.
Conclusion
All physicians, including specialty providers, are encouraged to take a close look at their patients’ skin and address parental concerns regarding multiple birthmarks. A detailed family history can reveal family members who are mildly affected by NF1 or are unaware of the fact that they have the condition. Although NF1 is the primary concern when evaluating a patient with multiple café-au-lait spots, these spots may indicate other disorders including familial café-au-lait spots, segmental neurofibromatosis, McCune Albright syndrome, LEOPARD syndrome, or Noonan syndrome.
With nearly 500 children in Minnesota affected with NF1, most primary care and specialty physicians will encounter a patient with this condition. For that reason all providers need to be aware of the clinical signs and symptoms associated with NF1. MM
Elizabeth Siqveland is a pediatric nurse practitioner who specializes in the diagnosis and care of children with neurocutaneous disorders. Dinel Pond is a genetic counselor who works with families affected by NF1.
References
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18. Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007;80(1):140-51.