Clinical Manifestations and Diagnosis

NF-1 is the most prevalent type, with an incidence of 1/3,000, and is diagnosed when any 2 of the following 7 features are present: (1) Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals. Café-au-lait spots are the hallmark of neurofibromatosis and are present in almost 100% of patients. They are present at birth but increase in size, number, and pigmentation, especially during the first few yrs of life (Fig. 589-1). The spots are scattered over the body surface, with predilection for the trunk and extremities but sparing the face. (2) Axillary or inguinal freckling consisting of multiple hyperpigmented areas 2-3 mm in diameter. Skinfold freckling usually appears between 3 and 5 yr of age. The frequency of axillary and inguinal freckling has been reported to be greater than 80% by 6 yr of age. (3) Two or more iris Lisch nodules. Lisch nodules are hamartomas located within the iris and are best identified by a slit-lamp examination (Fig. 589-2). They are present in >74% of patients with NF-1 but are not a component of NF-2. The prevalence of Lisch nodules increases with age, from only 5% of children <3 yr of age, to 42% among children 3-4 yr of age, and virtually 100% of adults ≥21 yr of age. (4) Two or more neurofibromas or 1 plexiform neurofibroma. Neurofibromas typically involve the skin, but they may be situated along peripheral nerves and blood vessels and within viscera including the gastrointestinal tract. These lesions appear characteristically during adolescence or pregnancy, suggesting a hormonal influence. They are usually small, rubbery lesions with a slight purplish discoloration of the overlying skin. Plexiform neurofibromas are usually evident at birth and result from diffuse thickening of nerve trunks that are frequently located in the orbital or temporal region of the face. The skin overlying a plexiform neurofibroma may be hyperpigmented to a greater degree than a café-au-lait spot. Plexiform neurofibromas may produce overgrowth of an extremity and a deformity of the corresponding bone. (5) A distinctive osseous lesion such as sphenoid dysplasia (which may cause pulsating exophthalmos) or cortical thinning of long bones (e.g., of the tibia) with or without pseudoarthrosis. (6) Optic gliomas are present in approximately 15% of patients with NF-1 and represent mostly low-grade astrocytomas. They are the main CNS tumor with a marked increased frequency in NF-1. Because of their growth, it is recommended that all children age 10 yr or younger with NF-1 undergo annual ophthalmologic examinations. When they progress, visual symptoms are produced because the tumors enlarge and put pressure on the optic nerves and chiasm resulting in impaired visual acuity and visual fields. Extension into the hypothalamus can lead to endocrine deficiencies or failure to thrive. The MRI findings of an optic glioma include diffuse thickening, localized enlargement, or a distinct focal mass originating from the optic nerve or chiasm (Fig. 589-3). (7) A first-degree relative with NF-1 whose diagnosis was based on the aforementioned criteria.

Figure 589-1 A and B, Multiple café-au-lait spots over the back. Note the dermal neurofibromas below the right scapula and right side of the lower back.

(From Hersh JH, Committee on Genetics: Health supervision for children with neurofibromatosis, Pediatrics 121:633–642, 2008, Fig 1.)

Figure 589-2 Neurofibromatosis 1. Pigmented hamartomas of the iris (Lisch nodules).

(From Zitelli BJ, Davis HW: Atlas of pediatric physical diagnosis, ed 4, St Louis, 2002, Mosby, p 507.)

Figure 589-3 Optic glioma. Sagittal T1-weighted MRI scan of a patient with neurofibromatosis 1 shows thickening of the optic nerve (arrow).

Children with NF-1 are susceptible to neurologic complications. MRI studies of selected children have shown abnormal hyperintense T2 weighted signals in the optic tracts, brainstem, globus pallidus, thalamus, internal capsule, and cerebellum (Fig. 589-4). These signals, “unidentified bright objects (UBOs),” tend to disappear with age; most have disappeared by 30 yr of age. It is unclear what the UBOs represent pathologically, and there is disagreement as to the presence and number of UBOs and their relationship to learning disabilities, attention deficit disorders, behavioral and psychosocial problems, and abnormalities of speech among affected children. Therefore, imaging studies such as brain MRIs should be reserved only for patients with clinical symptoms.

Figure 589-4 T2-weighted MRI scan of a patient with neurofibromatosis 1. Note the high-signal areas (unidentified bright objects) in the basal ganglia (arrows).

One of the most common complications is learning disability affecting approximately 30% of NF-1 children. Seizures are observed in approximately 8% of NF-1 patients. The cerebral vessels may develop aneurysms, or stenosis resulting in moyamoya disease (Chapter 594.1). Neurologic sequelae of these vascular abnormalities include transient cerebrovascular ischemic attacks, hemiparesis, and cognitive defects. Precocious puberty may become evident in the presence or absence of lesions of the optic chiasm and hypothalamus. Malignant neoplasms are also a significant problem in patients with NF-1, affecting approximately 3% of patients. A neurofibroma occasionally differentiates into a malignant peripheral nerve sheath tumor (MPNST). The incidence of pheochromocytoma, rhabdomyosarcoma, leukemia, and Wilms tumor is higher than in the general population. Scoliosis is a common complication found in about 10% of the patients. Patients with NF-1 are at risk for hypertension, which may result from renal vascular stenosis or a pheochromocytoma.

NF-2 is a rarer condition, with an incidence of 1/25,000, and may be diagnosed when 1 of the following 4 features is present: (1) bilateral vestibular schwannomas; (2) a parent, sibling, or child with NF-2 and either unilateral vestibular schwannoma or any 2 of the following: meningioma, schwannoma, glioma, neurofibroma, or posterior subcapsular lenticular opacities; (3) unilateral vestibular schwannoma and any 2 of the following: meningioma, schwannoma, glioma, neurofibroma, or posterior subcapsular lenticular opacities; (4) multiple meningiomas (2 or more) and unilateral vestibular schwannoma or any 2 of the following: schwannoma, glioma, neurofibroma, or cataract. Symptoms of tinnitus, hearing loss, facial weakness, headache, or unsteadiness may appear during childhood, although signs of a cerebellopontine angle mass are more commonly present in the 2nd and 3rd decades of life. Although café-au-lait spots and skin neurofibromas are classic findings in NF-1, they are much less common in NF-2. Posterior subcapsular lens opacities are identified in about 50% of patients with NF-2. The NF2 gene (also known as merlin or schwannomin) is located on chromosome 22q1.11. The frequency of lesions associated with NF-2 is noted in Table 589-1.

Table 589-1 FREQUENCY OF LESIONS ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 2

From Asthagiri AR, Parry DM, Butman JA, et al: Neurofibromatosis type 2, Lancet 373:1974–1984, 2009, Table 1.)

Management

Because of the diverse and unpredictable complications associated with NF-1, close multidisciplinary follow-up is necessary. Patients with NF-1 should have regular clinical assessments at least yearly, focusing the history and examination on the potential problems for which they are at increased risk. These assessments include yearly ophthalmologic examination, neurologic assessment, blood pressure monitoring, and scoliosis evaluation. Neuropsychologic and educational testing should be considered as needed. The NIH Consensus Development Conference has advised against routine imaging studies of the brain and optic tracts because treatment in these asymptomatic NF-1 children is rarely required. All symptomatic cases (i.e., those with visual disturbance, proptosis, or increased intracranial pressure) must be studied without delay.

Genetic Counseling

While NF-1 is an autosomal dominant disorder, over half the cases are sporadic, representing de novo mutations. The NF1 gene on chromosome region 17q11.2 encodes a protein also known as neurofibromin. Neurofibromin acts as an inhibitor of the oncogene ras. The diagnosis of NF-1 is based on the clinical features. However, molecular testing for the NF1 gene is available and can be useful in a number of cases. Scenarios in which genetic testing is helpful include patients who have only 1 of the criteria for clinical diagnosis, those with unusually severe disease, and those seeking prenatal/pre-implantation diagnosis.