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Clinical Updates

Lu Q Le, MD, PhD

Neurofibromatosis Type 1

Lu Le

Thursday, April 14, 2011

Neurofibromatosis type 1 (NF1) - one of the most common tumor-predisposition human genetic diseases - was first described in detail by the German pathologist, Friedrich Daniel von Recklinghausen, in 1882. Fifty years later, the Viennese ophthalmologist, Lisch, described the presence of iris nodules that are now an important criterion for the clinical diagnosis of NF1.1 It has a de novo incidence of one in 3000-4000 individuals and affects males and females equally across all races.2,3 Although it is inherited as an autosomal dominant trait with 100% penetrance, spontaneous mutations occur in 50% of cases.4 This means that the disease is likely to remain in the human population worldwide. Patients with NF1 have a mutation in the NF1 tumor suppressor gene, which encodes a GTPase-activating protein that negatively regulates p21-ras signaling. This mutation causes defects in neural-crest-derived tissues, leading to a wide spectrum of clinical presentations, including developmental, pigmental and neoplastic aberrations.5,6 The cardinal features of NF1 are café au lait macules (CALMs) and skin-fold freckling, combined with multiple peripheral and central nerve tumors (see Figure 1). Patients also exhibit less penetrant pathologies of the skin, nervous system, bones, endocrine organs, blood vessels and eyes (see Table 1).7 

 

Figure 1. Cutaneous manifestations of NF1. (A) CALMs are hyperpigmented lesions that vary in color from light to dark brown. They are observed in 95% of patients with NF1. Axillary freckling (B) and inguinal freckling (C) are akin to CALMs except that they are smaller, approximately 1-3 mm in size, and occur in clusters. The development of freckles often follows the development of CALMs, but this precedes the development of dermal neurofibromas. (D) Dermal neurofibromas are well-circumscribed, solid cutaneous tumors. (E) Subcutaneous neurofibromas are discrete, small tumors under the skin, which can sometimes be tender. (F) Plexiform neurofibromas are often non-circumscribed, thick and irregular. They can cause disfigurement by entwining important supportive structures and impairing organ or neural functions. Images courtesy of author.



Table 1. Key clinical features of NF1.

Reproduced with permission from reference 6.

Cutaneous Manifestations

CALMs are often the first presenting signs of NF1. The majority of patients with NF1 have multiple CALMs scattered predominantly on the trunk, buttocks and extremities, although they can occur anywhere.8 They increase in size proportionally to the growth of the child, but there is no association between the number of CALMs and the severity of NF1. However, when Crowe and Schull published the first report of an association between CALMs and NF1 in the English literature,9 they noted that the fewer the number of CALMs the more marked was the central involvement, ie a greater prevalence of internal tumors was seen. It should be noted here that Crowe's study population may also have included patients with NF2, schwannomatosis and segmental NF1. It was also Crowe who first recognized the association between axillary and inguinal freckling and NF1, which is also known as the 'Crowe's sign'. This freckling can also occur at the posterior neck and in inframammary and perioral regions. This skin-fold freckling was considered pathognomonic for NF1. However, Legius syndrome,10 the newly identified genetic disease whose main clinical features include CALMs and skin-fold freckling, should be included in the differential diagnoses for patients with CALMs and axillary and/or inguinal freckling, but without other stigmata of NF1.

Neurofibromas are the most common tumor seen in NF1 and are classified into three subtypes: dermal, subcutaneous and plexiform. Dermal and subcutaneous forms appear at puberty and these increase in number with age and during pregnancy. They occur as a result of proliferation of all supporting elements of the nerve fibers, including Schwann cells, perineurial cells, fibroblasts and blood vessels, as well as from infiltration of mast cells. Plexiform neurofibromas occur in approximately 30% of NF1 patients and are considered pathognomonic of the disease. They are congenital and progressively enlarge throughout life. Although dermal neurofibromas are mostly benign, patients with plexiform neurofibromas have a 10% lifetime risk of developing malignant peripheral nerve sheath tumors (MPNSTs), which can metastasize widely and are often fatal.11,12 In addition, owing to their unusual capacity for growth, plexiform neurofibromas can be life threatening through their physical impairment of organ or neural functions. Furthermore, they can also occur in deep tissues. The majority of internal plexiform neurofibromas manifest in the paraspinal region at the neural foramina of the vertebral column associated with dorsal root ganglia, and are commonly asymptomatic; however, they can transform into MPNSTs. Identifying those patients who are most likely to harbor paraspinal neurofibromas, and who are, therefore, at higher risk for malignancy, is clinically very difficult. Recently, Sbidian et al. used univariate and multivariate analyses to identify four independent, quantitative variables that are associated with NF1 patients with a higher likelihood of having internal paraspinal neurofibromas.13 These factors include age and three easily recognizable cutaneous features: absence of dermal neurofibromas, presence of subcutaneous neurofibromas and scarcity of CALMs. Each variable is weighted according to its predictive value on the NF1 score, which is conveniently charted alongside the percentage likelihood that an individual assigned a given score has paraspinal neurofibromas. Although the resulting score cannot predict an individual's status with 100% accuracy, it does provide compelling justification for increased scrutiny of NF1 patients with high scores.

The non-Langerhans cell histiocytosis, juvenile xanthogranuloma (JXG) - a benign, usually self-healing disorder - has a higher occurrence in NF1 patients than in the general population. A number of cases presenting with the triple association of JXG, NF1 and juvenile chronic myelogenous leukemia (JCML) have been reported.14,15 Therefore, although reliable data on the association of JXG, NF1 and the incidence of JCML in the NF1 population are lacking, it is recommended that the presence of JXG in children with NF1 should alert physicians to the possible onset of JCML.

Diagnosis

The presence of two or more of the following clinical criteria is required for the diagnosis of NF1:

  1. Six or more CALMs (>5 mm in prepubertal or >1.5 cm in postpubertal individuals)
  2. Axillary or inguinal freckling
  3. Two or more neurofibromas or one plexiform neurofibroma
  4. Two or more iris Lisch nodules
  5. An optic glioma
  6. A characteristic bony lesion (eg, pseudarthrosis, hypoplasia of sphenoid wing, severe kyphoscoliosis)
  7. A first-degree relative with NF1

These clinical diagnostic criteria for NF1 were established by the National Institute of Health Consensus Development Conference in 1988 and revised in 1997.16,17 Of note, patients with the recently reported Legius syndrome also present with CALMs and axillary/groin freckling in association with mild cognitive problems and macrocephaly. Therefore, these patients can be misdiagnosed as having NF1 by meeting two of the above criteria. These patients do not have a mutation in the NF1 gene but the syndrome is associated with SPRED1 mutations, a member of the SPROUTY/SPRED family of tumor-suppressor proteins.18 In this case, genetic tests should be undertaken; it is important to diagnose patients with Legius syndrome because they have a milder phenotype and will not require monitoring for widespread disease complications.

Management

Clinical management of patients with NF1 requires a multidisciplinary approach, and the use of a multispecialty NF clinic is desirable, especially to diagnose NF1 in difficult cases and undertake age-specific monitoring of disease manifestations, as well as conduct patient education. Ideally, specialists from the fields of genetics, ophthalmology, neurosurgery, neurology, pediatrics, sarcoma surgery, psychiatry, dermatology, plastic surgery, orthopedics, radiology and pathology who are knowledgeable about NF1 should be represented. However, it is most likely that severe disease complications, such as MPNSTs, will become symptomatic between appointments. MPNSTs are difficult to diagnose because they occur in individuals who are accustomed to developing lumps, and the symptoms can overlap with those of benign tumors. Therefore, a good thorough review of systems should be documented at each visit. Patients should be instructed to call their physician if they have any of the following:

  1. Persistent or nocturnal pain associated with a plexiform/subcutaneous neurofibroma
  2. Rapid increase in the size of a neurofibroma or any change to a hard texture
  3. New or unexplained neurological deficits.

Patients with a personal or family history of cancer and previous treatment with radiotherapy will have an increased risk of developing MPNSTs and should alert physicians for close monitoring.

Conclusions and Future Therapies for NF1

The clinical presentations of NF1, together with the emotional burden of carrying the disease and social stigma, have a significant impact on patients' quality of life. Although the mortality from NF1 is not high , the morbidity is significant. The hope for NF1 patients, therefore, is that new understanding of the molecular pathogenesis will lead to more effective treatment. Advances provided by basic scientific research since the cloning of the NF1 gene have afforded new opportunities for the development of specific targeted therapies, which are now beginning to emerge. Therapeutic approaches aimed at the reduction of Ras-GTP levels in affected neural-crest-derived tissues can be expected to relieve some NF1 symptoms, from learning disabilities to tumor susceptibility. Indeed, clinical trials of several therapies are under way, including lovastatin (for NF1-associated learning disabilities), the Ras inhibitor farnesyl-transferase, and Gleevec® (for plexiform neurofibromas) (http://clinicaltrials.gov). Lessons learned from basic scientific research may provide us with novel therapies that will delay and prevent many complications associated with NF1.

References

  1. Riccardi V. Neurofibromatosis phenotype, natural history and pathogenesis. Baltimore, MD: The Johns Hopkins University Press; 1992.
  2. Szudek J, Birch P, Riccardi VM, Evans DG, Friedman JM. Associations of clinical features in neurofibromatosis 1 (NF1). Genetic Epidemiology 2000;19:429-439.
  3. Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clinical Genetics 2006;70:1-13.
  4. Yohay KH. The genetic and molecular pathogenesis of NF1 and NF2. Seminars in Pediatric Neurology 2006;13:21-26.
  5. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol 2007;6:340-351.
  6. Le LQ, Parada LF. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene 2007;26:4609-4616.
  7. Ward BA, Gutmann DH. Neurofibromatosis 1: from lab bench to clinic. Pediatric Neurology 2005;32:221-228.
  8. Shah KN. The diagnostic and clinical significance of cafe-au-lait macules. Pediatr Clin North Am 2010;57:1131-1153.
  9. Crowe FW, Schull WJ. Diagnostic importance of cafe-au-lait spot in neurofibromatosis. AMA Arch Intern Med 1953;91:758-766.
  10. Brems H, Chmara M, Sahbatou M, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature Genetics 2007;39:1120-1126.
  11. Ferner RE. Neurofibromatosis 1. Eur J Hum Genet 2007;15:131-138.
  12. Lakkis MM, Tennekoon GI. Neurofibromatosis type 1. I. General overview. Journal of Neuroscience Research 2000;62:755-763.
  13. Sbidian E, Wolkenstein P, Valeyrie-Allanore L, et al. NF-1Score: a prediction score for internal neurofibromas in neurofibromatosis-1. J Invest Dermatol 2010;130:2173-2178.
  14. Morier P, Merot Y, Paccaud D, Beck D, Frenk E. Juvenile chronic granulocytic leukemia, juvenile xanthogranulomas, and neurofibromatosis. Case report and review of the literature. J Am Acad Dermatol 1990;22:962-965.
  15. Jang KA, Choi JH, Sung KJ, et al. Juvenile chronic myelogenous leukemia, neurofibromatosis 1, and xanthoma. J Dermatol 1999;26:33-35.
  16. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51-57.
  17. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988;45:575-578.
  18. Wakioka T, Sasaki A, Kato R, et al. Spred is a Sprouty-related suppressor of Ras signalling. Nature 2001;412:647-651.
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