Neurocutaneous Disorders
David H. Viskochil
Neurofibromatosis types 1 and 2 (NF1 and NF2), tuberous sclerosis complex (TSC1 and TSC2), and von Hipple-Lindau disease (VHL) are neurocutaneous disorders that are loosely classified as phakomatoses. Neurocutaneous conditions are also discussed in Chapter 578.
The phakomatoses are generally autosomal dominant conditions that show a consistent pattern of abnormal growth of various tissues, and each affected individual has unique and unpredictable manifestations. The variability of clinical expression of cutaneous manifestations and tumors distinguishes each of these disorders, and this variability has multiple causes, including modifier loci, somatic mutation, and simple stoichiometry in cells with haploinsufficiency of the respective neurocutaneous gene. Somatic mutation leading to inactivation of the normal neurocutaneous gene allele, termed second hits or loss of heterozygosity (LOH), in individuals who have a constitutional mutation is a common theme and suggests that genes causing neurocutaneous disorders fit the paradigm of tumor suppressors. Characterization of these genes has led to the identification of biochemical pathways involved in intracellular growth signaling pathways; this information led to the development of novel therapeutic regimens strategically targeted to the regulation of growth of benign tumors associated with these conditions.
NEUROFIBROMATOSIS 1
CLINICAL ASPECTS
Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disorder, affecting approximately 1 in 3000 people worldwide. The hallmark features of NF1, café au lait spots and benign cutaneous neurofibromas, typically arise in early childhood and adolescence, respectively. Approximately two thirds of individuals with NF1 have manifestations that generally do not require clinical intervention, whereas the remaining one third display myriad medical complications which are unpredictable, both in timing and severity.
Even though NF1 has been recognized as von Recklinghausen disease by the medical community since the 19th century, both its variability and age dependence of clinical manifestations made it essential to develop a well-accepted set of clinical criteria to establish the diagnosis (eTable 182.1 
).1-3 The typical clinical manifestations allow the diagnosis to be established in children by 10 years.4 By virtue of full penetrance in the adult population, diagnosis of NF1 is more straightforward in familial cases because it requires only one physical manifestation in addition to an affected first-degree relative. In sporadic cases, NF1-related associations that are not part of the diagnostic criteria sometimes appear prior to the development of a second diagnostic sign.
The typical pattern of clinical presentation in NF1 is age dependent. Usually, multiple café au lait spots (CLS) are identified in the first two years of life (eFig.182.1 
). The observation of more than 5 CLS that are greater than 0.5 cm in diameter and of thoracic location in toddlers is a classical presentation. A number of other conditions include multiple CLS (ie, McCune-Albright syndrome, Noonan syndrome, Bloom syndrome), although other signs and symptoms generally make exclusion of other diagnoses fairly straightforward. Familial multiple café au lait spots without other signs of NF1 is a relatively rare overlap condition, Legius syndrome, and it is caused by mutations in the SPRED1 gene.5
Intertriginous freckling, which usually involves the axillae and groin areas, occurs in approximately three quarters of individuals with NF1 who present with multiple CLS, and this sign develops by late childhood.5 Lisch nodules (iris hamartomas) can be identified by slit lamp examination of the eyes in over 75% of preadolescents.
Neurofibromas are benign tumors that are a collection of Schwann cells, fibroblasts, mast cells, and extracellular matrix. Cutaneous neurofibromas tend to appear at the time of puberty and progress in number throughout life. They can be difficult to detect at their outset, and they are often most easily palpated along the flanks and lower abdomen as slight depressions rather than protruding bumps. Cutaneous neurofibromas may itch but are not painful and never lead to malignancy. Plexiform neurofibromas are very different from cutaneous neurofibromas and arise in sites associated with the peripheral nerve sheath. They affect about one fourth of the NF1 population and arise at variable ages, including infancy.7 Actively growing plexiform neurofibromas in infancy require a significant amount of medical attention, as these tumors are diffuse and may extensively entwine internal organs. Plexiform neurofibromas have a propensity to undergo malignant transformation to sarcoma (malignant peripheral nerve sheath tumor), but this is rare in the pediatric population.
Optic nerve pathway tumors (gliomas) are benign pilocytic astrocytomas that affect approximately 15% of individuals with NF1, but only half of these are symptomatic. Symptomatic tumors tend to arise in the toddler and early childhood years, and rarely develop after puberty. Pediatric ophthalmologists are adept at identifying optic nerve pallor or visual symptoms associated with these tumors, and they are extremely helpful in deciding which children should undergo brain and orbit MRI. Routine brain MRI is generally not required in the absence of clinical indications.8 Like plexiform neurofibromas, optic pathway gliomas are unpredictable in their growth patterns; however, NF1-related optic nerve pathway gliomas (OPGs) have a slower proliferation rate and are less likely to cause visual impairment than similar tumors that arise in non-NF1 individuals. Other low-grade intracranial gliomas behave in similar fashion; in the context of NF1, they grow slower and are less likely to require treatment than their non-NF1 counterparts.
The skeletal features of neurofibromatosis type 1 (NF1) are also age dependent. Sphenoid wing dysplasia, long-bone bowing (ie, tibial dysplasia with or without pseudarthrosis) and dystrophic scoliosis all tend to present either in infancy or childhood. The pathophysiology of the various skeletal features is not understood, and it challenges the paradigm of NF1 being a disorder of neural crest origin. Both dystrophic scoliosis and pseudarthrosis of long bones are primary defects that require significant orthopedic management and do not usually arise in the context of either plexiform or paraspinal neurofibromas. Like cutaneous neurofibromas, paraspinal neurofibromas tend to arise in later childhood and adolescence. In general, these tumors are not symptomatic unless they compress either nerve roots or adjacent spine. A perplexing finding in NF1 is the connection between sphenoid wing dysplasia and orbital-temporal plexiform neurofibromas.9 Sphenoid wing dysplasia affects approximately 1% of NF1 patients and it is almost always unilateral. At least half of those individuals will have an ipsi-lateral orbital-temporal plexiform neurofibroma. These disfiguring tumors tend to be raised and pigmented, and their unchecked growth can obscure vision.
Individuals with NF1 are prone to a number of medical complications that are quite varied, although it is rare that any one individual has more than one major complication. Approximately 40% to 50% have speech and language delays as preschoolers and/or learning problems in school, which are not specific to NF1.10 Early recognition and treatment within the educational environment can effectively deal with NF1-related learning problems, and is one reason to provide a provisional diagnosis of NF1 in sporadic cases who only have multiple café au lait spots. Short stature, macrocephaly, hypertension, constipation and chronic headaches are other NF1-related features. Dystrophic scoliosis, deep plexiform neurofibromas, low-grade astrocytomas of the posterior fossa, spinal neurofibromas, malignant peripheral nerve sheath tumors, pheochromocytomas, rhabdomyosarcomas, and myelogenous leukemia are a few of the more serious medical complications associated with NF1.
MOLECULAR ASPECTS
The NF1 gene spans approximately 335 kilobases of genomic DNA and is ubiquitously expressed. It encodes neurofibromin, a GTPase activating protein that downregulates ras signaling through the mitogen-activated protein kinase (MAPK) pathway. NF1 mutations are generally inactivating, and double inactivation of both alleles in NF1-related tissues classifies this gene as a tumor suppressor.11,12
Approximately half of individuals with neurofibromatosis type 1 (NF1) seen in North American and European clinics are sporadic cases, which indicates that the gene is highly mutable. The high germ-line NF1 mutation rate likely carries over to somatic mutation, which supports the tumor suppressor model for NF1 and provides one explanation for the variable and progressive nature of some clinical features. Random acquisition of somatic mutation that inactivate the normal NF1 allele (second hit) in tissue showing abnormal growth could explain the age-related clinical presentation of many NF1 features, that is, neurofibromas, optic nerve pathway tumors, and tibial dysplasia. Leukemia cells, neurofibromas, malignant peripheral nerve sheath tumors, and pheochromocytomas have all demonstrated double inactivation of NF1.
MANAGEMENT
As a prototype for other neurocutaneous disorders, counseling issues surrounding NF1 relate to its heritability, variable expressivity, age-related penetrance of myriad clinical features, and pleiotropy. Even though there is a high sporadic incidence, once it is established within a family it behaves as any other autosomal dominant condition, whereby there is a 50% risk for occurrence in each child conceived. However, unlike many other dominant conditions, the lack of a genotype–phenotype correlation means that affected family members who have the same NF1 mutation usually have different manifestations. This is one reason clinical mutation analysis on a routine basis is generally not needed. To date, there are only two clear genotype–phenotype correlations. Those with a large, whole-gene deletion (∼5% of all NF1 patients) share a phenotype marked by an unusually large number of neurofibromas that present at an earlier age, distinctive facial features differing from family background, and decreased level of intellectual functioning.13 Those with a specific 3 base-pair deletion leading to loss of a methionine residue generally have multiple café au lait spots without other serious clinical manifestations.14 This group of patients may be indistinguishable from those who have mutations in SPRED1, thus suspicion of Legius syndrome is pretense for NF1/SPRED1 mutation analysis because lack of tumors alters the approach to clinical management.
Most tumor-related complications of NF1 are managed surgically; however, there is clearly a role for watchful waiting in this condition, especially with the development of medical therapies targeted to the RAS-MAPK signal transduction pathway. Clinical trials with various RTK (receptor tyrosine kinase), MAPK, and mTORC (mammalian target of rapamycin complexes, see below) pathway inhibitors are underway, thus medical therapies might be available to complement the surgical management of NF1-related tumors. Treatment of symptomatic or progressive optic nerve pathway tumors in NF1 is non-surgical, and biopsies are not needed to begin therapy with either carboplatin or carboplatin plus vincristine chemotherapy protocols. Radiation therapy is generally contraindicated in the treatment of NF1-related central nervous system (CNS) tumors because of significant side effects and heightened risk for secondary, radiation-induced malignancy years after treatment.
Anticipatory guidance for NF1 includes the recognition of the age-related occurrence of many manifestations, some of which are quite rare and not included in the diagnostic criteria (eTable182.2 
). Common issues to be addressed on a regular basis are school performance, tumors, bone abnormalities, and psychosocial adaptation. Annual clinical assessments using a multidisciplinary approach are important to determine appropriate imaging protocols on an individualized basis.
TUBEROUS SCLEROSIS COMPLEX
CLINICAL ASPECTS
Tuberous sclerosis is an autosomal dominant condition that potentially affects as many as 1 in 5700 people worldwide. Tuberous sclerosis complex (TSC) clinically manifests in many ways, as evidenced in the diagnostic criteria outlined in eTable182.3 
.15 The hallmark cutaneous features include ash-leaf-shaped hypo-pigmented macules, shagreen patches, facial angiomas and forehead plaques, and ungual fibromas (see Fig. 182-1 and eFig. 182.2 
). The multisystem involvement of TSC is much broader than the other neurocutaneous disorders, including a higher risk for mental retardation and autism, especially if seizures occur in the first year of life. A difficult diagnostic and counseling issue in TSC is the incomplete penetrance of this condition. Unlike neurofibromatosis type 1 (NF1), in which affected adults can be readily identified, mild cases of TSC have often been diagnosed only when an affected first-degree relative with TSC has prompted an imaging workup that identifies an asymptomatic manifestation. Approximately 90% of individuals with TSC have subependymal glial nodules and 70% have tubers on intracranial imaging.16 The broad variability of clinical expression within individuals and families with multiple affected members is similar to NF1.
The clinical presentation for TSC is unpredictable, although recognition of TSC in its complete form by physical examination in older children and adults is straightforward, with skin being affected in almost all. The diagnosis is often complicated both by the age dependency of many features and incomplete cutaneous manifestations. Extensive imaging to identify hamartomatous involvement of various organs is necessary for both diagnosis and anticipatory guidance. Prenatal cardiac rhabdomyomas identified by fetal ultrasonography may be the earliest sign of TSC, and these tumors typically regress within a few years of birth. The prevalence of these tumors in infancy is more than 50%, which makes echocardiography one of the more reliable diagnostic screening tests in that age group. Cardiac rhabdomyomas are not predictive of other TSC-related features and usually do not cause severe morbidity unless arrhythmias arise. Infantile spasms are not considered in the diagnostic criteria for TSC, but approximately 50% of all infants with this type seizure activity have the condition. The onset of seizures before one year of age predicts more significant mental impairment and greater numbers of cortical tubers on brain imaging studies.17 Regardless of seizure status, both cortical tubers and subependymal nodules become evident by brain imaging in early childhood.
Hypopigmented spots of ash-leaf character can be seen in all ages, even newborns, and, unlike the café au lait macules, enhancement with a Wood’s lamp may be extremely useful in the diagnostic clinical examination. The hypopigmented skin findings of TSC are not specific; however, the manifestation of clustered spots in a confettilike presentation, in addition to the typical ash-leaf spots, may be the only physical features in the childhood years. Fibrous plaques involving the cranium can also occur in infancy, but other cutaneous features such as adenomatous sebaceum and multiple ungual fibromas, and the shagreen patch (firm pale pink areas resembling orange peel texture, usually on the lower back) typically present later in life, even after adolescence.
Brain imaging (CT or MRI) is an important diagnostic procedure, and is needed for ongoing surveillance.18 In the absence of new symptoms, brain MRI is indicated every 2 years. Of the renal manifestations, cysts are common in childhood and may be confused with polycystic kidney disease, whereas angiomyolipomas typically arise in middle age and have been found in approximately two thirds of individuals with TSC.19 Retinal abnormalities, pitted enamel hypoplasia, and rectal polyps are found in over one-half of TSC patients. All these findings can arise in childhood and should be considered in the diagnostic work-up. Finally, pulmonary lymphangioleiomyomatosis, a rare complication of TSC, typically develops in females in the third or fourth decade. The age dependence of the various manifestations of TSC is an important concept that must be considered in the management of pediatric cases of TSC.
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