Neurofibromatosis Type 1 in Genetic Counseling Practice: Recommendations of the National Society of Genetic Counselors

Café-au-lait spots (CALS) are pigmentary lesions proportionately darker than one’s skin color with uniform pigmentation and smooth borders. The presence of multiple CALS is one of the most well-recognized features of NF1. Ninety-nine percent of individuals with NF1 meet the CALS diagnostic criteria by 1 year of age (DeBella et al. 2000). In the newborn, typical CALS are oval-shaped lesions between 1 and 4 cm in diameter (Alper and Holmes 1983). As the child ages, the number and size of CALS may increase. In adults, CALS tend to fade and may be more difficult to identify.

Another characteristic but innocuous finding of NF1 is freckling, which is present in over 90% of patients by 7 years of age (DeBella et al. 2000). The freckles are similar in color to café-au-lait spots but are much smaller and often occur in clusters (Friedman and Riccardi 1999). They are most commonly found in the axillary and inguinal regions, but they can also occur in other areas of skin-to-skin contact, such as the underside of the breast in female patients, between skin folds in obese patients, and on the back of the neck.

Lisch nodules are a common feature of NF1. Lisch nodules are pigmented hamartomas of the iris that do not affect vision. They are typically not present at birth, but they develop during childhood. More than 95% of individuals with NF1 have Lisch nodules by the age of 20 (Flueler et al. 1986; Huson et al. 1987; Lubs et al. 1991). Slit lamp examination by an ophthalmologist is necessary to determine the presence or absence of Lisch nodules as well as the distinction between these and iris nevi, which are not associated with NF1 (Friedman and Riccardi 1999).

Optic pathway gliomas (OPG), or pilocytic astrocytomas of the optic nerve, are the most common central nervous system tumors seen in NF1 and typically present in early childhood (less than 6 years of age) (Listernick et al. 1999; Singhal et al. 2002). It has been estimated that up to 70% of all OPGs are related to NF1 (Listernick et al. 1999). OPGs may be either unilateral or bilateral and may involve the optic nerve, the chiasm, or both. Approximately 15% of NF1 patients will develop an OPG, half of whom have no clinical symptoms (Korf 2000; Listernick et al. 1994; Singhal et al. 2002). Most NF1-related OPGs do not progress or metastasize. If progression does occur, presenting symptoms often include proptosis, precocious puberty or increased growth velocity. Other symptoms include loss of visual acuity, abnormal color vision, optic atrophy, and afferent pupillary defect. Some optic nerve tumors may spontaneously regress (Korf 2000).

Scoliosis is the most common skeletal finding in NF1 with an estimated frequency ranging from 10 to approximately 25% (Akbarnia et al. 1992; Crawford and Schorry 1999; Friedman and Birch 1997; Riccardi 1999b; Vitale et al. 2002). The scoliosis can be either dystrophic or non-dystrophic (Alwan et al. 2005). The dystrophic type of scoliosis is associated with bony abnormalities evident on radiographic films and tends to be more severe with rapid progression. This form of scoliosis typically presents between 6 and 10 years of age, and, if not present by 10 years, is unlikely to develop (Riccardi 1999b). The non-dystrophic form of scoliosis has no apparent bony abnormalities and has findings similar to idiopathic scoliosis in individuals without NF1; it presents during adolescence and tends to be less severe. Kyphoscoliosis may also develop (Alwan et al. 2005). Occasionally, these spinal abnormalities may be caused by an underlying neurofibroma.

Sphenoid dysplasia is present in 3–7% of NF1 patients and typically presents as a unilateral defect (Riccardi 1999b; Alwan et al. 2005). Over 50% of cases of sphenoid dysplasia are associated with NF1. The lesions are usually asymptomatic and are diagnosed by skull radiographs or CT scans (Alwan et al. 2005). In rare instances, progression of a lesion may lead to medical complications such as enophthalmos and herniation of the brain into the orbit (Riccardi 1999b).

Lesions of the long bones are another feature of NF1 with a prevalence of 1–4% (Crawford and Schorry 1999; Friedman and Birch 1997; Vitale et al. 2002). The tibia is most frequently involved, although other long bones may also be affected (Ali and Hooper 1982; Alldred 1963; Floyd and Percy-Lancaster 1987; Gregg et al. 1982; Keret et al. 2000; Riccardi 1999b). Congenital pseudarthrosis, or “false joint” abnormality, occurs in 1–2% of NF1 patients (Friedman and Birch 1997; Riccardi 1999b). These lesions are often detected during infancy or early childhood and present as bowing or fracturing of the affected bone (Alwan et al. 2005). Other potential abnormalities of the long bones include changes associated with a plexiform neurofibroma or localized lytic defects (Riccardi 1999b).

NF1 patients also have an increased risk for osteoporosis and osteopenia. (Kuorilehto et al. 2005). Other skeletal anomalies found in NF1 patients may include pectus deformities, genu varum, and genu valgum (Riccardi 1999b).

Neurofibromas (NFs) are benign tumors that can occur anywhere in the body. They most commonly develop along peripheral nerves or less frequently in the deep nerves. Neurofibromas are typically multicellular in origin, composed of Schwann cells, axons, fibroblasts, mast cells, endothelial cells and perineurial cells (Peltonen et al. 1988). Pruritis, or itching, is a somewhat common feature of NF1 and when localized, often precedes the development of cutaneous neurofibromas.

NFs can be classified into different types (Friedman and Riccardi 1999; Korf and Rubenstein 2005):

Discrete NFs are benign tumors that arise from a single site on a peripheral nerve. They are rarely present at birth, often appearing just before the time of puberty (Dugoff and Sujansky 1996; Korf and Rubenstein 2005). The number of dermal neurofibromas tends to increase with age and varies widely between individuals. They may increase in size and number during pregnancy. Discrete NFs are encapsulated; they may grow in size and press on other tissues, but will not invade them.

Plexiform NFs (PNFs) grow along the length of a peripheral nerve sheath. They are non-encapsulated and therefore may grow into healthy tissue and interfere with normal development of tissue or bone. These tumors tend to be supported by a network of blood vessels and therefore are usually difficult to surgically remove. Most PNFs are benign, but there is a risk for transformation to malignant peripheral nerve sheath tumors (MPNST) (See ‘Tumors and Malignancy’).

Although not common, there are some studies that suggest an increased frequency of seizures (range 3.5–7.3%) in NF1 (Friedman and Riccardi 1999; North 1993). The seizures that are suggested to be associated with NF1 do not differ from those seen in the general population. When not associated with an intracranial lesion or stenosis, these seizures are generally well-controlled with routine antiepileptic drugs (Gutmann 1999).

Individuals with NF1 have an increased frequency of headaches. These range from a mild “tension” headache to a true migraine (Riccardi 1981). Although common, a new onset of headaches or ones that are atypical for the patient and/or accompanied by neurologic deficits, may warrant investigations for other causes including brain tumors, pheochromocytomas or cerebrovascular etiologies (Friedman and Riccardi 1999; Riccardi 1981).

Cranial MRI scans in NF1 patients often show focal areas of high signal intensity on T2 or FLAIR weighted images. They are typically referred to as Unidentified Bright Objects (UBOs) or “NF spots.” They exert no mass effect and are not observed on CT scan. They often resolve with time and are rarely seen in NF1 patients over the age of 20 (Aoki et al. 1989). Some researchers have suggested a connection between the presence of UBOs and lower IQ, language skills, visuospatial functioning and academic achievement (Denckla et al. 1996), although this has not been found in other studies (Friedman and Riccardi 1999).

Individuals with NF1 tend to be below average in height and true short stature (<10th percentile) occurs in more than 40% of adults with NF1 (Carmi et al. 1999). One study found growth hormone deficiency in 3 of 122 children, although this does not appear to be the cause of short stature in most patients with NF1 (Cnossen et al. 1997).

Macrocephaly, either relative or absolute, is present in 29–45% of individuals with NF1 and usually develops during childhood (Clementi et al. 1999; Friedman and Riccardi 1999; Riccardi 1999b; Szudek et al. 2000). Rarely, underlying hydrocephalus is identified (Friedman and Riccardi 1999).

Most individuals with NF1 undergo normal pubertal development (Friedman and Riccardi 1999). However, in approximately 1–4% of patients, puberty may be premature or delayed (Friedman and Birch 1997). Precocious puberty typically results from an optic chiasm glioma or other tumor proximal to the region of the hypothalamus (Friedman and Riccardi 1999; Habiby et al. 1995).

Although NF1 appears to have no intrinsic effect on fertility, negative pregnancy outcome has been reported (Friedman and Riccardi 1999). Early reports suggest a significant increase in complications including intrauterine growth retardation, preterm labor, and stillbirth (Belton et al. 1984; Edwards et al. 1983; Weissman et al. 1993). However, these findings are controversial, and more recent studies suggest that most pregnancy outcomes for healthy women with NF1 are normal, although there appears to be an increased need for cesarean-sections (Dugoff and Sujansky 1996). Pregnancy is frequently associated with an exacerbation of existing maternal symptoms as well as the new presentation or rapid increase in tumors and hypertension (Ansari and Nagamani 1976; Dugoff and Sujansky 1996; Swapp and Main 1973). A subsequent decrease in the size of the exacerbated neurofibromas in the postpartum period is sometimes seen (Dugoff and Sujansky 1996).

Hypertension is a common finding in individuals with NF1. The incidence of hypertension increases with age and can lead to heart attack, stroke, kidney failure, and other medical problems. In most cases, the hypertension is essential. However, less common causes of hypertension include renal artery abnormalities, pheochromocytomas, and, in rarer instances, aortic coarctations or brain tumors (Friedman 1999a).

Congenital heart defects have been reported in patients with NF1 with an estimated frequency between 0.4 and 6.4% (Carey et al. 1979; Crowe et al. 1956; Lin et al. 2000; Schorry et al. 1989). The most common cardiac abnormality is valvar pulmonic stenosis (Friedman and Birch 1997; Lin et al. 2000). This abnormality has been described in individuals with the Watson and the NF1-Noonan phenotypes as well as individuals with a large gene deletion (See “Variants of NF1”); however, the incidence of pulmonic stenosis is also increased in patients with NF1 without these variant phenotypes. Coarctation of the aorta and other heart defects have also been reported (Friedman and Birch 1997; Lin et al. 2000). Several reports have identified NF1 patients with hypertrophic cardiomyopathy. Current evidence is insufficient to determine whether these reflect manifestations of NF1 or are simply coincidental.

Vasculopathies are a well-recognized cardiovascular complication of NF1 (Friedman 1999a). They may be peripheral or cerebrovascular. The specific types of lesions include stenoses, dilations, aneurysms, and fistulas (Friedman et al. 2002). Arterial involvement is most common, although venous involvement has also been reported (Lehrnbecher et al. 1994). These lesions frequently occur in the renal arteries, but may also occur in the cerebral or visceral arteries (Criado et al. 2002; Serleth et al. 1998; Westenend et al. 1994). The exact frequency of vasculopathy in patients with NF1 is unknown and many patients with vasculopathy remain asymptomatic throughout their lives (Friedman et al. 2002). Symptomatic vascular lesions are most commonly detected in childhood or early adulthood and may be identified during a pregnancy (Friedman et al. 2002; Pilmore et al. 1997). A study by Rosser et al. (2005) identified a cerebrovascular abnormality in 2.5% of patients with NF1. These abnormalities may present with neurological symptoms secondary to cerebral ischemia (Friedman et al. 2002).

Pruritis, or chronic itching, is a relatively common feature of NF1. It may be generalized or restricted to a certain area of the body. When localized, the itching may precede the development of cutaneous neurofibromas. The itching is thought to be related to the large amount of mast cells in neurofibromas and is often relieved by anti-histamines (Korf and Rubenstein 2005; Riccardi 1981).

The malignancy rates in individuals with NF1 are higher than the general population risk, though precise risk estimates vary. Literature reports suggest that the risk for malignancy in individuals with NF1 is 5–15% higher than the general population risk (Walker et al. 2006). On average, the onset of malignancy in NF1 patients appears to be earlier than the general population (Kim et al. 2002; Walker et al. 2006). A prospective study by Walker et al. suggests that the increased malignancy rate comes primarily from a higher incidence of central nervous system and connective tissue malignancies (Walker et al. 2006).

Approximately 4–13% of patients with NF1 will develop a malignant peripheral nerve sheath tumor (MPNST), also called malignant schwannoma or neurofibrosarcoma (Evans et al. 2002; Korf 2000; Levy et al. 2005). The most common locations of these tumors in NF1 patients are the abdominal paraspinal region, the extremities, and the head and neck regions (Levy et al. 2005). Approximately 20–50% of patients with MPNSTs also have NF1 (Evans et al. 2002; Korf 2000; Levy et al. 2005). Compared to individuals without NF1, individuals with NF1 tend to be diagnosed with an MPNST at a younger age and have a poorer prognosis. Most of the time, MPNSTs in NF1 are associated with an underlying plexiform neurofibroma (Evans et al. 2002; Levy et al. 2005; Korf 2000). While plexiform neurofibromas may be very large tumors, the malignant component of the tumor may be very small and can easily be missed by a single biopsy. Symptoms commonly reported by patients with an MPNST include pain, enlarging tumor mass, and neurologic symptoms (Korf 2000).

Pheochromocytomas are catecholamine-secreting tumors that occur most often in the adrenal gland They occur in approximately 0.1–5.7% of NF1 patients. In the majority of cases, the NF1-related pheochromocytoma will be a single, unilateral tumor (84%). Roughly 10% of patients will have a bilateral pheochromocytoma and a small percentage (6%) will have an extra-adrenal pheochromocytoma (Walther et al. 1999). Pheochromocytomas often lead to increased production of adrenaline which may cause hypertension and a variety of other associated symptoms such as headaches, cardiac palpitations, diaphoresis and tremors. They may become metastatic. (Walther et al. 1999).

There is a wide spectrum and diverse nature of tumors that occur along the gastrointestinal (GI) tract in NF1 patients. Neurofibromas are the most common tumor of the gastrointestinal tract in patients with NF1, however most of these are benign and asymptomatic. When symptomatic, abdominal pain, constipation and bleeding are the most common presenting symptoms. The incidence of gastrointestinal carcinoids is higher in NF1 patients than in the general population; however, the malignancy rate is comparable between the two groups (Levy et al. 2005). Gastrointestinal stromal tumors (GIST) are associated with NF1. Contrary to non-NF1 patients, NF1-related GIST occur primarily in the small intestine and typically present as either multiple tumors or are associated with other GI neoplasms (Levy et al. 2004).

There have been several reports suggesting an increased risk for acute lymphoblastic leukemia, non-Hodgkin lymphoma and juvenile myelomonocytic leukemia (JMML) in NF1 (Stiller et al. 1994; Zvulunov et al. 1995). As many as 14% of individuals with JMML have NF1 (Niemeyer et al. 1997). However, the risk of an individual with NF1 developing JMML is low. (Gutmann and Gurney 1999). An association between leukemia and the cutaneous finding of juvenile xanthogranulomas (JXG) has been suggested, but this association has not been well-established (Cambiaghi et al. 2004; Morier et al. 1990).

Optic gliomas are seldom malignant and are discussed earlier in this document. Other than optic gliomas, individuals with NF1 are at risk for other types of gliomas, including cerebellar astrocytomas, ependymomas, third ventricle astrocytomas, cerebral astrocytomas, brain stem gliomas, and spinal cord tumors. The risk of malignant transformation in these tumors in NF1 patients was found to be higher than in those without NF1 (Ilgren et al. 1985).

Rhabdomyosarcomas are seen with disproportionately high frequency in individuals with NF1. An association of NF1 with neuroblastoma and Wilms tumor has been suggested but has not been confirmed (Korf 2000; Levy et al. 2005).

Questions have been raised regarding a potentially increased risk for breast cancer in individuals with NF1 due to the possible role of neurofibromin in some breast cancers (Guran and Safali 2005). This concern has been further supported by a prospective study suggesting an increased risk for early onset-breast cancer among women with NF1 (Walker et al. 2006). Additional data and larger studies are necessary to determine whether the breast cancer risk in individuals with NF1 is truly increased.

A variety of other tumors occur in NF1 including leiomyosarcomas, ganglioneuromas and adenocarcinomas (Levy et al. 2005).

The vast majority of individuals with NF1 have intelligence within the normal range. However, there is a documented leftward shift in the IQ curve, as well as an increased incidence of both mental retardation (MR) and learning disabilities as compared to the general population (Barton and North 2004; Eliason 1986; Ferner et al. 1996; Mazzocco et al. 1995).

The incidence of MR in the NF1 population is estimated to be between 4.8 and 11% (Dilts et al. 1996; Ferner et al. 1996; Hyman et al. 2005; North et al. 1995; Wadsby et al. 1989). Large NF1 gene deletions are a frequent finding in patients with MR, and patients with such deletions tend to exhibit a more severe phenotype overall (Ainsworth et al. 1997) (See “Variants of NF1”). Accordingly, MR is not typically expected in individuals without the deletion. The occurrence of MR in a patient with NF1 without a full gene deletion may warrant further evaluations to rule out other more common causes of MR, such as chromosomal duplications/deletions, and fragile X syndrome.

Learning disabilities are a much more common occurrence in NF1. Historically, most studies have estimated the incidence of learning disabilities to be between 40 and 60%, although the criteria for defining a “learning disability” have varied (Hyman et al. 2005; Kayl and Moore 1995; North 1999; Ozonoff 1999; Samuelsson and Axelsson 1981; Stine and Adams 1989; Wadsby et al. 1989). The Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV) defines a specific learning disability as “the achievement on standardized tests that is more than two standard deviations below that expected for the individual’s level of intelligence” (American Psychiatric Association 2000). Using this definition, a study by Hyman et al. (2005) examined a cohort of 81 children with NF1, in which 81% of individuals showed some sort of cognitive impairment, but only 25% of individuals met the DSM IV diagnostic criteria for learning disabilities when controlling for IQ. Thus, some individuals with NF1 do not qualify for a formal diagnosis of a learning disability but will still require intervention for other neuropsychological deficits. These deficits can include but are not limited to visuospatial skills, executive function, expressive and receptive language, social skills and motor coordination (Barton and North 2004; Chapman et al. 1996; Dilts et al. 1996; Ferner et al. 1996; Hyman et al. 2005; Johnson et al. 1999; Mazzocco et al. 1995; North et al. 1994, 1995, 2002; Varnhagen et al. 1988; Zoller et al. 1997).

Several studies have suggested a frequency of attention deficit disorder (ADD) with or without hyperactivity in approximately 30–40% of the NF1 population (Bawden et al. 1996; Cutting et al. 2000; DeWinter et al. 1999; Hyman et al. 2005; Kayl and Moore 1995).

In summary, the cognitive phenotype of NF1 is complex, variable, and unpredictable, and can include a wide range of learning disabilities, other neuropsychological deficits, and less often, mental retardation. Formal neuropsychological evaluation can help elucidate the specific challenges of an individual with NF1 to allow for appropriate intervention. Intervention is based on the presenting cognitive features, and these are managed in the same way as they would be in the non-NF1 population.

Risk for siblings of proband is low (thought to be less than 1%), but remains increased due to the possibility of germline mosaicism (see “Special Considerations”).

Apply principles of autosomal dominant inheritance to pedigree. All offspring of an affected parent have a 50% risk to inherit the mutation. As indicated, identify nearest genetics/NF clinic for affected relatives not living in the area.