Neurofibromatosis Type 1

Handbook of Clinical Neurology, Vol. 132 (3rd series) Neurocutaneous Syndromes M.P. Islam and E.S. Roach, Editors © 2015 Elsevier B.V. All rights reserved Chapter 4 Neurofibromatosis type 1 JACQUELINE L. ANDERSON AND DAVID H. GUTMANN* Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA INTRODUCTION background (Huson et al., 1989; Rasmussen and Friedman, 2000; Johnson et al., 2013). While NF1 is an History autosomal dominant condition, only 50% of people have Neurofibromatosis type 1 (NF1), previously known as an affected family member with NF1 (familial cases). As von Recklinghausen disease, is a common neurogenetic such, 50% of patients will be the first person in their fam- condition affecting 1:2500 people worldwide. NF1 prob- ily with NF1, arising from a sporadic NF1 gene mutation ably existed in ancient times, with art and literature from (De Luca et al., 2004; Evans et al., 2010). Life expectancy the 3rd century BCE documenting descriptions consistent is reduced by 8–15 years relative to the general popula- with the disease (Zanca, 1980). In 1849, an Irish surgeon tion, with malignancy constituting the major reason named Robert W. Smith differentiated patients with for death prior to the age of 30 (Rasmussen et al., traumatic neuromas from those with cases of multiple, 2001; Evans et al., 2011). With the establishment of an idiopathic neuromas (Smith, 1849). However, it was not online worldwide registry for patients with NF1, new until 1882 that the disease entity was fully recognized: the insights into the epidemiology of this common condition German pathologist Frederick von Recklinghausen first will likely emerge (Johnson et al., 2013). published a classic monograph, in which he described the disease as well as the pathologic basis of neurofibromas CLINICAL MANIFESTATIONS (von Recklinghausen, 1882). Iris hamartomas, or Lisch nodules, were first described in patients with NF1 by Hallmark signs and symptoms the Austrian ophthalmologist Karl Lisch in 1937 (Lisch, The diagnostic criteria for NF1 were first established 1937). Later, Frank Crowe and his colleagues (1956) were by the NIH Consensus Development panel in 1987 the first to recognize NF1 as a hereditary disease, affect- (National Institutes of Health Consensus Development ing 50% of offspring. In 1964, Dr. Crowe then described Conference, 1988) and updated in 1997 (Gutmann skinfold freckling (Crowe, 1964). With the recognition et al., 1997). To make the diagnosis of NF1, two of the that NF1 was a genetic condition, the US National following clinical features are required: Institutes of Health (NIH) convened a consensus devel- ● opment conference to establish consistent diagnostic six or more cafe´-au-lait macules with diameters criteria to enable the identification of people with NF1 greater than 5 mm in a prepubertal patient and (National Institutes of Health Consensus Development greater than 15 mm in a postpubertal patient ● Conference, 1988). This landmark conference laid the two or more neurofibromas or one plexiform foundations for the genetic analysis of families with neurofibroma ● NF1, culminating in the discovery of the NF1 gene in skinfold (axillary or inguinal) freckling ● 1990 (Viskochil et al., 1990; Wallace et al., 1990). optic pathway tumor ● two or more iris hamartomas ● characteristic bony lesion Epidemiology ● first-degree relative with neurofibromatosis type 1. The prevalence of NF1 is approximately 1:2500 to 1:3500 In most cases, the diagnosis of NF1 can be made on clini- in individuals, regardless of ethnic and racial cal grounds; however, only in rare circumstances is it *Correspondence to: David H. Gutmann, MD, PhD, Department of Neurology, Washington University School of Medicine, Box 8111, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Tel: +1-314-362-7149, Fax: +1-314-362-9462, E-mail: [email protected] 76 J.L. ANDERSON AND D.H. GUTMANN Fig. 4.1. Non-neoplastic features of NF1. (A) Typical cafe´-au-lait macule in a child with NF1. (B) Skinfold freckling in the axilla of an adult with NF1. (C) Lisch nodules in an adult with NF1. (D) Tibial pseudarthrosis and fracture in a child with NF1. necessary to pursue genetic testing. When employed, as well as other types of tumors and malignancies NF1 mutation analysis is 95% sensitive (Messiaen (e.g., breast cancer and malignant brain tumors). et al., 2000; Valero et al., 2011). The features that are typically evident from birth or early infancy include a pos- Cutaneous manifestations itive family history and cafe´-au-lait macules. Cafe´- Cafe´-au-lait macules occur in at least 95% of patients au-lait macules grow in size and number during the first with NF1 (Johnson et al., 2013). A child with NF1 usually 2 years of life (Fig. 4.1A). Skinfold freckling, most com- has at least one cafe´-au-lait macule present at birth, and monly observed in the axillary and inguinal regions, there will be an increase in number of macules as well as begins to appear in early childhood, most commonly size of the existing macules over the first 1–2 years of life between 5 and 8 years of age (Fig. 4.1B). Optic pathway (Nunley et al., 2009). These macules range in color from gliomas develop almost entirely in the pediatric popula- light to dark brown, depending on the background skin tion, usually prior to the age of 7 years old, with a median pigmentation. Typically, cafe´-au-lait macules are homo- age at presentation of 4 years (Listernick et al., 1994). geneous in color with smooth borders. Pathologic exam- Lisch nodules appear as a function of age, such that ination of these lesions reveals an increased number of 30–50% harbor these iris hamartomas by age 6 years, macromelanosomes (Slater et al., 1986). and 92% are present by adulthood (Fig. 4.1C) (Nichols Skinfold freckling is present in 50% of children with et al., 2003). Characteristic bony abnormalities, such NF1 by 10 years of age (Huson et al., 1988; DeBella et al., as long bone pseudarthrosis and sphenoid wing dyspla- 2000). The freckles are typically 1–3 mm in diameter, sia, when present, are seen in early infancy (Fig. 4.1D). and occur in symmetric clusters in the intertriginous Dermal neurofibromas typically appear in the peripuber- areas of the axillary and inguinal regions as well as under tal years, and increase in number over the ensuing years. the chin and breasts in women. Plexiform neurofibromas are considered congenital, but may not cause problems until later during development Neurofibromas and malignant peripheral or in adulthood. nerve sheath tumors In addition to the classic features of NF1, people with NF1 are prone to developing aqueductal stenosis, pheo- Neurofibromas are the most common tumor type in NF1, chromocytoma, learning and intellectual disabilities, affecting 40–60% of patients with NF1 (Friedman and attention deficit, scoliosis, seizures, and vasculopathy Birch, 1997; McGaughran et al., 1999). Neurofibromas NEUROFIBROMATOSIS TYPE 1 77 are benign tumors of peripheral nerve sheath cells cosmetic impact or cause irritation because of rub- (WHO grade I) and can occur throughout the peripheral bing or clothing irritation. nervous system. Dermal neurofibromas arise from a sin- Between 30% and 50% of patients with NF1 have plex- gle peripheral nerve, whereas plexiform neurofibromas iform neurofibromas (Waggoner et al., 2000; Mautner arise from a bundle of fascicles or a larger nerve plexus et al., 2008). Plexiform neurofibromas are clinically (sacral or brachial plexus). distinct from localized neurofibromas in that they Cutaneous, localized neurofibromas appear on the have potential for malignant transformation. Cutaneous surface and can be pedunculated, subcutaneous, or plexiform neurofibromas are characterized by overly- sessile (Fig. 4.2A). They may show slight overlying ing skin hyperpigmentation and a thickened dermis, skin discoloration, sometimes initially appearing as and have been described as “a bag of worms” on palpa- raised erythematous areas. Dermal neurofibromas tion (Fig. 4.2B). Internal plexiform neurofibromas first appear around the time of puberty, and they can appear as extensive tumors on imaging studies typically increase in number with age. While these (Fig. 4.2C). Plexiform neurofibromas are most likely tumors are benign and do not transform into malig- congenital, and usually grow most rapidly during the nant cancers (Boyd et al., 2009; Jouhilahti et al., first decade of life. Although the majority of plexiform 2011), they are frequently associated with significant neurofibromas remain benign, there is still considerable Fig. 4.2. NF1-associated peripheral nerve sheath tumors. (A) Dermal neurofibromas on the arm of an adult with NF1. (B) Plex- iform neurofibroma on the foot of an adult with NF1. (C) Internal plexiform neurofibroma in the abdomen/pelvis of an adult with NF1. (D) Neck plexiform neurofibroma in an adolescent with NF1. (E, F) Positron emission tomography reveals malignant peripheral nerve sheath tumors in the neck (E) and leg (F) of two different adults with NF1. 78 J.L. ANDERSON AND D.H. GUTMANN morbidity associated with them, including disfigurement These tumors can occur anywhere along the optic path- and local invasion of neighboring structures (e.g., bone), way, including the optic nerves, chiasm, and postchias- leading to pain and bony deformities (stimulation of matic tracts and radiations (Fig. 4.3A–C) (Listernick et bone growth or bony erosion) as well as rare instances al., 1989, 1994, 1995). Up to half of optic pathway gliomas of internal organ, trachea, or vascular compression become symptomatic, but typically only one-third of chil- (Prada et al., 2012)(Fig. 4.2D). dren with NF1-OPG require therapeutic intervention Spinal neurofibromas may cause neurologic symp- (Lewis et al., 1984; Listernick et al., 1994; Fisher et al., toms by compressing the spinal cord or spinal roots 2012; de Blank et al., 2013). The decision to treat should within the foraminal spaces.

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