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Tuberous sclerosis complex (TSC) and neurofibromatosis type 1 (NF1) are autosomal dominant disorders. They are the prototypes of the neurocutaneous diseases. The involvement of multiple tissues and organs, the similar locations of the macular skin lesions of TSC and NF1, the variable clinical expressivity, and similarities in their biochemical pathologic findings cause these two disorders to be considered more closely related than the other neurocutaneous syndromes. Clinically, however, the two disorders are easily differentiated. Other disorders classically considered as neurocutaneous diseases include neurofibromatosis type 2 (NF2) [
], ataxia telangiectasia, von Hippel Lindau syndrome, and Sturge-Weber syndrome. This article focuses on TSC and NF1, particularly with regard to salient clinical aspects of childhood presentation and genetic aspects.
Tuberous sclerosis complex
TSC is an autosomal dominant disorder that involves multiple organs and tissues. The major impact of the disorder is on the brain, skin, and kidneys, but it also affects the eyes and heart. The prevalence of TSC is 1:10,000. Lesions are caused by hamartomas and hamartias [
]. A major point regarding symptoms and signs of TSC is the variable clinical expression of the disorder, even among patients from families with multiple affected generations. The major manifestations of TSC include skin lesions in more than 95%, mental retardation in approximately 50%, autism, seizures in approximately 85%, kidney disease in approximately 60% or more, and uncommon cerebral giant cell astrocytomas, but the severity ranges from asymptomatic patients to severe disability. Although the neurologic symptoms most often raise suspicion for the diagnosis of TSC, the relatively unique skin lesions and cranial MRI characteristics are the most helpful for confirming the diagnosis. Diagnosis requires the presence of two or more hamartomas.
Neurologic symptoms of tuberous sclerosis complex
The neurologic symptoms of TSC are the ones that often call attention to the diagnosis but are not adequate to confirm the diagnosis. TSC patients may have epilepsy, mental retardation, and autism as well as learning disorders. Although neurologic symptoms provide much of the morbidity, TSC patients do not demonstrate unique manifestations of these neurologic problems. For example, even though TSC is one of the major diagnosable causes of infantile spasms, there are many other causes. By contrast, cutaneous symptoms are more helpful for diagnosis but cause no significant morbidity, with the exception of occasional disfigurement.
Seizures
Typical absence seizures do not occur more frequently in TSC patients than in the general population, but all other seizure types are more common in TSC patients. The most common seizure types are infantile spasms or partial seizures, often with rapid secondary generalization. Seizures are the most common neurologic symptom of TSC, occurring in approximately 85% of patients [
]. The prevalence of seizures and mental retardation is not related to subependymal nodules, but the prevalence of both is higher in patients with more cortical tubers.
The most serious seizures for TSC patients are infantile spasms [
], which peak between 4 and 6 months of age. Neonatal onset of seizures in TSC is uncommon. The diagnosis of TSC should be considered in all infants who have infantile spasms. The more common features that raise suspicion for TSC in patients who have infantile spasms include hypomelanotic macules of the skin, cortical tubers on cranial MRI, and cardiac rhabdomyomas by echocardiography. For older children who have seizures, the suspicion for TSC is raised by additional dermatologic manifestations. If there is no family history for TSC and no cranial MRI or skin findings for TSC, further evaluation for TSC in an epileptic patient is usually unnecessary.
Seizures are evaluated and treated medically in TSC patients in the same manner as in other patients with epilepsy; that is, electroencephalograms (EEGs) are performed as part of seizure diagnosis and are repeated as indicated by the course of the seizures. Some antiepileptic agents have been specifically tested in TSC and found to have similar utility as in non-TSC patients. For example, lamotrigine is a useful antiepileptic medication for TSC patients and is more likely to decrease seizures in those TSC patients who have partial seizures only and no history of infantile spasms [
]. Infantile spasms are typically treated with corticotropin or prednisone. In general, antiepileptic medications for TSC patients are chosen based on seizure type [
]. Evidence has indicated that vigabatrin is especially effective for the infantile spasms of TSC, leading to rapid cessation of infantile spasms in 95% of TSC patients [
]. This is a success rate that is arguably not achieved by the more standard treatments of corticotropin or prednisone or by alternative antiepileptic agents, such as topiramate, zonisamide, lamotrigine, divalproex sodium, or others. As yet, no randomized trial has confirmed the superiority of vigabatrin. Evidence of side effects of vigabatrin, such as constriction of visual fields in human beings and vacuolation of cerebral white matter in animals, has derailed efforts for US Food and Drug Administration (FDA) approval of vigabatrin in the United States and has raised serious concerns regarding the safety of vigabatrin [
]. Therefore, if parents in the United States desire that their infants receive vigabatrin treatment for infantile spasms, they must obtain it from foreign countries.
Surgical treatment of intractable seizures in TSC is receiving more attention. Previously, it was argued that the multiple cortical tubers of TSC rendered futile the surgical excision of epileptic foci; that is, removal of one epileptic tuber would probably uncover the epileptogenic activity of another tuber. However, several series have demonstrated the utility of tuberectomy in selected TSC patients whose major seizure activity arises from a single tuber [
]. Localization of epileptogenic tubers can be improved with multimodality imaging, including combinations of positron emission tomography (PET) scanning, single photon emission computed tomography (SPECT) scans, and MRI [
]. When seizures remain medically intractable and tuber resection is not tenable, the ketogenic diet, corpus callosotomy, or vagus nerve stimulation is a viable alternative treatment [
The second most common neurologic symptom of TSC is mental retardation, which occurs in approximately 50% of patients. When generalized seizures, including infantile spasms, start in the first 2 years of life, most TSC patients are mentally retarded, autistic, or both. All mentally retarded children with TSC have seizures. TSC patients who have normal intelligence may or may not have seizures, but the seizures are usually not as severe and usually have later onset (Fig. 1). TSC patients who have the most tubers are more likely to have both mental retardation and seizures [
]. The most disabled are those TSC patients who have both infantile spasms and severe to profound mental retardation. Behavior problems, such as hyperkinesis, attention problems, and aggression, are often associated with mental retardation or autism.
Fig. 1A human figure drawing and printed name by a 5-year-old normally intelligent girl with tuberous sclerosis complex.
Among patients who have autism, the cause is unknown for many. Nevertheless, there are several recognizable causes of infantile autism that stand out, including TSC, Rett syndrome, and fragile X syndrome. As many as 50% to 60% of TSC patients may have autism, but the true prevalence is probably lower. Autism may be more prevalent in TSC patients whose tubers predominate in the temporal lobes or cerebellum. Although autism may occur in TSC patients who have neither seizures or mental retardation, the presence of seizures in an autistic patient increases the likelihood of TSC. Therefore, as with patients who have infantile spasms, it is important to consider and evaluate for the diagnosis of TSC for autism, particularly for autistic patients who have seizures.
Autism is a communication disorder that constitutes a syndrome composed of a triad of features: impairment of reciprocal social interaction, impairment in verbal and nonverbal communication, and a markedly restricted repertoire of activities and interests that may manifest as stereotypic activities. It is important to note that all these features are common in patients who have mental retardation and that they become more common as IQ decreases. Therefore, to make a diagnosis of autism, the impairments must be out of proportion to those that are appropriate for the patient's intellectual level.
In a study using PET scans, compared with TSC patients who were retarded or had normal intelligence, autistic TSC patients were more likely to show glucose hypometabolism in the lateral temporal cortices, increased uptake of α-methyl-tryptophan in caudate nuclei, and glucose hypermetabolism in deep cerebellar nuclei [
]. Either a prior history of infantile spasms or the presence of temporal lobe hypometabolism in TSC patients was associated with a communication disorder [
] and typically finishing its growth by the end of the second decade. The giant cell astrocytoma of the brain characteristically arises at either foramen of Monro from a subependymal nodule and typically enhances after intravenous contrast on CT or MRI [
]. If it grows large enough to obstruct one or both foramina of Monro, the astrocytoma may cause hydrocephalus, which is often unilateral. Baseline cranial MRI is useful to determine if the ventricle was abnormally shaped or enlarged before the giant cell astrocytoma. Indications for surgical removal of this relatively benign mass include progressive enlargement of the giant cell astrocytoma, progressive ventricular enlargement, or symptoms of elevated intracranial pressure. If the giant cell tumor is first diagnosed in an individual near or older than 20 years of age who has hydrocephalus that is not progressive, the risk of surgery may outweigh the benefit. Early symptoms of hydrocephalus typically include morning headache and vomiting, and sometimes sixth cranial nerve palsy. The giant cell astrocytoma can be surgically removed with a minimal chance of recurrence. Chemotherapy or radiation therapy is unnecessary and is not administered.
Dermatologic signs of tuberous sclerosis complex
The skin lesions are most helpful in recognizing TSC. There are multiple skin lesions that are characteristic of TSC. The most common skin lesions are hypomelanotic macules (also called hypopigmented macules or ash-leaf spots).
Hypomelanotic macules
Probably 90% or more of TSC patients have hypomelanotic macules, often 0.5 to 2 cm but sometimes larger, occurring on the face, trunk, and extremities (Fig. 2). The macules do not disturb the contour of the skin; they cannot be detected by an examiner with closed eyes. They are pale but do not totally lack pigment as opposed to vitiligo. Frequently, they have an ash-leaf shape, but equally as often in my experience, they have the shape of a thumb print. Occasionally, the hypomelanosis manifests on the scalp as white hair-poliosis. On sun-exposed skin, particularly in older individuals who have tanned their skin repeatedly, areas of skin atrophy may show a similar decrease of pigment as the hypopigmented macules. These areas should be discounted as providing diagnostic evidence for TSC. Of particular difficulty is the differentiation between small areas of skin atrophy and the confetti lesions of TSC in these sun-exposed individuals; the confetti lesions, as the name suggests, manifest as numerous small hypopigmented spots. Hypomelanotic macules rarely may occur in individuals without TSC, but usually are single or few in number. In TSC, hypomelanotic macules are valuable to suggest the diagnosis because they are usually present at birth, a time when there may be few other manifestations. Because the macules are pale, they can be difficult to detect, especially in pale-skinned individuals. Skin examination with the ultraviolet Wood's light makes the macules easy to detect but is not always necessary in patients with dark complexions.
Fig. 2A hypomelanotic macule of tuberous sclerosis complex.
Facial angiofibromas are the classic skin lesions of TSC. Perhaps 50% of TSC patients have facial angiofibromas; in the past, they were misnamed as adenoma sebaceum. The angiofibromas typically do not occur until near puberty, a time when the facial bumps can easily be confused with acne. Angiofibromas do not have comedones (whiteheads or blackheads), however. The facial angiofibromas may occur in a limited distribution when first developing, and there may only be three or four, most often on the cheeks and quite close to the nose or in the depression between the lower lip and chin (Fig. 3), and they may progress near and after puberty. In older people, facial angiofibromas can be misdiagnosed as acne rosacea. In people with lighter complexions, the facial angiofibromas are often flesh colored, but the red angiomatous component may show through, giving the impression of a red papular rash. In younger children destined to develop angiofibromas, a fever may cause excessive reddening of the cheeks. Angiofibromas, even when not numerous, may cause facial disfigurement because of their redness or prominence. They may also be prone to easy bleeding even from such minor trauma as contact with a pillow case, as occurred with the teenager in Figure 4.
Fig. 3A small number of flesh-colored tuberous sclerosis complex angiofibromas on the cheek near the nose and a small number in the depression between the lip and chin.
Fig. 4More extensive tuberous sclerosis complex angiofibromas. These may bleed with mild trauma. In this boy, the angiofibromas are bright red. Note the gingival fibromas.
Other skin lesions: forehead plaques, shagreen patches, ungual fibromas, and gingival fibromas
The forehead plaques and shagreen patches have the same angiofibromatous pathologic appearance as facial angiofibromas but appear less vascular and are most common in other areas. Forehead plaques are often darker than surrounding skin, and their location is implicit in the name. Identical-appearing lesions may be present on the scalp or cheeks, however. The shagreen patches are often in the region of the lower back, either close to the midline or on the sides of the back. Sometimes they are in groups of small papules that are only several millimeters large, or they can give the appearance of the surface of an orange peel, but they are usually flesh colored or slightly darker or redder than surrounding skin. One of my patients had multiple large shagreen patches, including one on his forearm (forearm shagreen). Several patients have had shagreen patches on their thighs or buttocks. In most cases, no treatment is necessary for shagreen patches.
The ungual fibromas have the same pathologic characteristics as the facial angiofibromas and are generally flesh colored. Some have a red core from the angiomatous component (Fig. 5). Rarely, trauma to the nail can cause an ungual fibroma (Fig. 6), or the chronic trauma from tight shoes can cause the appearance of an ungual fibroma, especially on the lateral side of the fifth toe. Gingival fibromas between the teeth are less common (see Fig. 4).
Fig. 5A flesh-colored ungual fibroma with a central red core.
Fig. 6A traumatic ungual fibroma on the great toe of a patient with back pain and no clinical features of tuberous sclerosis complex. His toe was traumatized with a hammer when he was 6 years old, and it was traumatized again years later with a cast iron skillet that removed the nail.
Other clinical findings in tuberous sclerosis complex
Renal involvement is relatively common in TSC and includes renal cysts, angiomyolipomas, and, rarely, renal carcinoma (<2%). The original localization of the TSC2 gene was facilitated by the occurrence of polycystic kidneys in TSC, because it led to the use of DNA probes related to autosomal dominant polycystic kidney disease [
]. A contiguous gene syndrome in which there are deletions of both the TSC2 gene and the adjacent PKD1 gene manifests both TSC and massively enlarged polycystic kidneys at birth [
]. Significant cystic renal disease in TSC more often occurs with the TSC2 gene. Renal cysts occur in approximately 10% to 20% of individuals with TSC. Of patients with angiomyolipomas, approximately 10% have TSC [
]. Angiomyolipomas are more common in women and are a common cause of morbidity in TSC. Angiomyolipomas have fat–easily seen on CT, a feature that differentiates them from renal cell carcinomas. Renal insufficiency can occur with both cysts and angiomyolipomas, and serious hemorrhage may occur with larger angiomyolipomas (>3.5 cm). Renal disease is a leading cause of death in TSC [
Cardiac rhabdomyomas are usually asymptomatic but may cause obstruction of flow through the heart; congestive heart failure; cardiac arrhythmias, including Wolff-Parkinson-White syndrome; and sudden death. Rarely, they are associated with stroke, which is more likely related to associated thrombotic material than to tumor fragments [
]. Although TSC pulmonary disease is rare, it can cause severe lung problems. It occurs in adult women (<1%). Aneurysms of cerebral and other vessels rarely occur, but most have been reported in children or young adults [
] and sometimes helpful for diagnosis, but unless symptomatic, they rarely require clinical attention.
Neuroimaging of tuberous sclerosis complex
Radiologic signs in the brain, such as by MRI, most commonly include cortical tubers in the cerebrum or cerebellum. Other findings include subependymal nodules, dysplastic heterotopic neurons that are seen as “migration lines”, and subependymal giant cell astrocytomas.
In infants, the cortical tubers show different signal characteristics; that is, tubers have high T1 signal in infants, whereas the tubers do not begin to show high T2 signal until the child reaches the age of 12 months. Because MRI T2-weighted sequences show the contrast between the hypomyelination often associated with tubers and normal myelination, tubers are more readily imaged by MRI after myelination has matured to a greater extent (ie, from 12–18 months and older). Typical MRI T2-weighted sequences detect many tubers, but MRI more readily detects tubers using fluid-attenuated inversion recovery (FLAIR) sequences. Tubers are typically seen at the gray-white junction in the cerebral cortex (Fig. 7).
Fig. 7Coronal fluid-attenuated inversion recovery MRI demonstrating a cortical tuber with a migration line extending to the edge of the ventricle.
Subependymal nodules are present in more than 80% of TSC patients and are commonly calcified. On MRI, they have relatively high T1 signal (isointense to white matter) and are found throughout the outer walls of the lateral ventricles (Fig. 8), often adjacent to caudate nuclei. On T2-weighted images, subependymal nodules are sometimes isointense to white matter but are often hypointense, particularly if they are calcified (Fig. 9). Calcified subependymal nodules are easy to see on CT, but they are now readily recognized by MRI; therefore, MRI is more commonly used for cranial imaging in TSC because it is superior to CT for detection of cortical tubers and migration lines.
Unique to neurocutaneous diseases, inactivating mutations in either of two distinct TSC genes (TSC1 and TSC2) cause one basic syndrome. Before DNA linkage studies, it was not suspected that TSC could be caused by more than one gene [
]. This contrasts with the situation in neurofibromatosis. Although NF1 and NF2 are caused by two different genes, the two genes cause two distinct disorders, and they were recognized as such before the genes were discovered.
Of the two TSC genes, the TSC1 gene was the first to be localized (in 1987) to chromosome 9, but the gene was not sequenced until 1997 [
Autosomal dominant inheritance occurs with TSC. In TSC families, the cause is almost evenly divided between TSC1 and TSC2 mutations. As many as two thirds of TSC cases occur as a result of sporadic (not inherited) mutations, however, and most sporadic TSC cases are caused by mutations in TSC2. Because of gonadal mosaicism in TSC, a recurrence risk of 2% is quoted to parents who are themselves unaffected but have a child with TSC.
Clinical differences between TSC1 and TSC2 are now being recognized, but they are typically differences of degree and not of character. For example, in one series of 224 patients, the clinical syndrome caused by TSC2 was more severe and more often associated with mental retardation [
Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.
]. Although differences between TSC1 and TSC2 families are recognized, the symptoms of TSC are still highly variable in onset and severity. Even in a TSC1 or TSC2 family in which multiple members have TSC, there may be great variability—one patient may have skin lesions, seizures, and mental retardation, whereas others may have skin lesions or seizures but no other problems. The kidney may have cysts, benign tumors, or, rarely, renal cell carcinoma (<2%).
Part of the variability of TSC manifestations stems from the mode in which the defective genes have their deleterious effect. Although their cellular functions remain to be elucidated, several facts have been discovered. Tuberin and hamartin interact in a protein complex [
], which perhaps explains why a deficiency of either one can produce essentially the same clinical syndrome. Both hamartin from TSC1 and tuberin from TSC2 are thought to function, at least in part, as tumor suppressor genes, by which they regulate cell growth and development. It is thought that both alleles of a TSC gene must be defective for the development of a hamartoma or hamartia. This model seems valid for most manifestations of TSC but has not been proven for cortical tubers. As an example of this model, the TSC2 allele on one member of the chromosome 16 pair may harbor a mutation inherited from one of the parents (ie, germline mutation). At the TSC2 allele on the other chromosome 16, a somatic mutation (eg, deletion) may occur. The absence of both normal alleles produces a lack of tuberin, culminating in one of the manifestations of TSC, such as a renal angiomyolipoma [
Blood tests based on gene analysis are available but have a high false- negative rate. No single sign is present in all patients. The diagnostic features constituting hamartomas or hamartias have been divided into major and minor categories [
]. For diagnosis as definite TSC, the patient should have 2 of 11 major features or 1 major feature plus 2 of 9 minor features. Genetic blood tests for TSC1 and TSC2 are available, but perhaps 30% of patients with TSC have negative results.
Major diagnostic features include the following:
Facial angiofibromas or forehead plaque
Nontraumatic ungual fibroma
Three or more hypomelanotic macules
Shagreen patch
Multiple retinal nodular hamartomas
Cortical tuber (dysplasia plus migration tracts count as one feature)
Subependymal nodule
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma (single or multiple)
Lymphangiomyomatosis
Renal angiomyolipoma (when both lymphangiomyomatosis and renal angiomyolipomas are present, they count as one feature)
Minor diagnostic features include the following:
Multiple dental pits
Hamartomatous rectal polyps (histologic confirmation is suggested)
Bone cysts (radiographic diagnosis is sufficient)
Cerebral white matter radial migration lines
Gingival fibromas
Nonrenal hamartoma
Retinal achromic patch
“Confetti” skin lesions
Multiple renal cysts
Additional diagnostic categories include probable TSC with one major plus one minor feature and possible TSC with one major or two or more minor features.
When performing the diagnostic workup, a careful history and skin examination are the first steps. If infantile spasms or autism is present, further workup to diagnose TSC includes MRI of the brain. If either skin lesions or brain MRI findings are present but inadequate for a diagnosis of TSC, ophthalmologic examination for retinal hamartomas or renal ultrasonography may provide confirmatory evidence. Echocardiography is usually not helpful past the age of 2 years, because cardiac rhabdomyomas regress with advancing age [
]. When TSC is diagnosed, the following studies are performed if not already completed: neurodevelopmental testing, ophthalmologic examination, electrocardiography, renal ultrasonography, and MRI of the brain [
]. If there are no seizures, EEG is not needed. Neurodevelopmental testing is repeated at school entrance. Giant cell astrocytomas of the brain typically do not grow after the second decade, whereas renal angiomyolipomas often enlarge during early adulthood. Therefore, MRI of the brain is repeated every 1 to 3 years during childhood and adolescence, and renal ultrasonography is repeated every 1 to 3 years. For either brain MRI or renal ultrasonography, symptoms may require more scans. Chest CT is performed at adulthood in women for the rare complication of pulmonary lymphangiomyomatosis and is repeated if pulmonary dysfunction occurs. Other tests, such as EEG, ophthalmologic examination, electrocardiography, and echocardiography, are repeated only if clinical findings suggest the need [
After diagnosis, TSC patients require treatment of seizures, educational treatment for mental retardation and autism, and pharmacologic treatment for behavioral disorders related to mental retardation and autism. The major symptom that can be treated is the epilepsy. Various antiepileptic medications, and sometimes surgical approaches, are used as discussed previously. Facial lesions are treated with laser therapy, and bothersome ungual fibromas can be surgically removed. For patients with learning problems, mental retardation, or autism, educational intervention is helpful, but medications can also be useful, including dextroamphetamine and other psychostimulants for hyperactivity and inattention, fluoxetine for autistic symptoms, clonidine for hyperarousal, and risperidone for aggression. Giant cell astrocytomas of the brain are treated surgically as discussed previously. Renal angiomyolipomas, particularly those larger than 3.5 cm, can often be treated with nephron-sparing surgery. For renal failure, TSC patients may undergo kidney transplantation and do not have excessive risk from immunosuppression.
Neurofibromatosis type 1
NF1 is an autosomal dominant disorder with variable expressivity; patients who have the abnormal NF1 gene may manifest (express) different numbers or intensities of features, even within NF1 families. The prevalence is approximately 1 per 4000, the same order of magnitude as Duchenne muscular dystrophy. In contrast to TSC, mental retardation or seizures are relatively uncommon, but nerve sheath and central nervous system tumors cause the major morbidity. The diagnostic suspicion is usually raised by the presence of multiple café au lait spots. Less commonly, in infants, the diagnosis is suspected because of facial malformations caused by bone dysplasia. Occasionally, children present with impaired vision from optic nerve glioma. Onset with other types of neurologic dysfunction is uncommon. Diagnosis requires two or more of the diagnostic features.
Diagnostic criteria for neurofibromatosis type 1
Two or more of the following criteria are required for diagnosis:
Six or more café au lait spots 1.5 cm or larger in postpubertal individuals and 0.5 cm or larger in prepubertal children
Two or more neurofibromas of any type or one or more plexiform neurofibromas
Freckling in the axillary or inguinal regions
Optic nerve glioma (optic pathway tumor)
Two or more Lisch nodules (iris hamartomas)
A distinctive osseous lesion, such as dysplasia of the sphenoid bone and dysplasia or thinning of long bone cortex (pseudoarthrosis)
A first-degree relative with NF1 according to the preceding criteria
Of note, the absence of café au lait spots, axillary freckling, cutaneous neurofibromas, and Lisch nodules by the age of 5 years excludes the diagnosis of NF1 with greater than 95% certainty. Blood tests based on gene analysis are available but have a high false-negative rate.
Dermatologic features of neurofibromatosis type 1
Café au lait spots and skinfold freckling
The hallmark sign of NF1 is the café au lait spot (Fig. 10), named because of its color, similar to coffee with milk. Most children with NF1 have café au lait spots and axillary freckling, and most adults also have cutaneous neurofibromas and Lisch nodules of the iris. Other than cosmesis, café au lait spots have no clinical consequences and no need for treatment. One or two café au lait spots are common in individuals without NF1, but six or more café au lait spots, occurring in more than 95% of people with NF1, rarely occur in people without NF1. Café au lait spots are macular; are distributed on the trunk, face, and extremities; and are darker in sun-exposed areas. A regular border differentiates café au lait spots of NF1 from the café au lait spots of McCune-Albright syndrome (polyostotic fibrous dysplasia with precocious puberty). Rarely, a child may have isolated autosomal dominant café au lait spots. Café au lait spots are typically present by 2 years of age, but other manifestations of NF1 often do not develop until later. Among children with six or more typical café au lait spots, most (73%) develop other findings for NF1 or segmental NF1 by the age of 5 years [
Axillary freckling occurs in most children with NF1 but may not have developed by the time the café au lait spots are first diagnosed. By 5 years of age, however, as many as 84% of the children with NF1 have axillary freckling, with a smaller proportion (∼50%) having inguinal freckling. Submammary freckling in women with NF1 occurs less commonly. Skinfold freckling is diagnostically helpful because freckling in individuals without NF1 is rare in areas that are not sun exposed.
Neurofibromas
Cutaneous (dermal) neurofibromas
Neurofibromas arise from the peripheral nerve sheath. Neurofibromas of the skin are rare in young children but may develop in preadolescence in up to 14% of children less than 10 years old. When they first appear, the neurofibromas often have a slight irregularity of skin with a combined small elevation and depression, sometimes with reddening of skin caused by dilated or proliferated capillaries. Larger neurofibromas protrude from the skin, are often pink or violaceous, and frequently have an appearance that suggests a hard surface, but they are typically soft, and some even feel velvety. Cutaneous neurofibromas typically enlarge and increase in number at certain times of hormonal change (puberty in boys and girls and pregnancy in girls and women). Although 95% of adults with NF1 who are more than 30 years old have neurofibromas, less than half of adolescents with NF1 have neurofibromas. Typically, an early age at the time of appearance of neurofibromas portends larger and more numerous neurofibromas in adulthood. Some neurofibromas, particularly subcutaneous neurofibromas or nodular neurofibromas on nerve trunks, may be painful or pruritic, and they can be removed surgically.
Plexiform neurofibromas
Compared with dermal neurofibromas, these skin tumors have ill-defined borders and are more diffuse and highly vascular and do not follow tissue planes. The skin overlying the tumor is typically hyperpigmented and often hairy. Associated structures can be hypertrophied. Some feel nodular with palpable nerve trunks. Plexiform neurofibromas that occur in deep structures (eg, mediastinum and retroperitoneal compartment) may be difficult to diagnose and may cause various complications relating to the structures involved. Plexiform neurofibromas occur in approximately 25% of NF1 patients and are present at birth or detected in early childhood; however, they may enlarge, especially near adolescence. They may be disfiguring, particularly when they involve the head (eg, eyelids) or neck. The plexiform neurofibromas are difficult to treat surgically, regrow if not completely removed, and do not respond to radiation therapy. If they are disfiguring or located in areas that cause significant morbidity, they should be removed. The best results occur with early removal, but because of their nature, the surgical morbidity may be substantial, making the decision for surgery difficult.
In contrast to dermal neurofibromas, which have no malignant potential, plexiform neurofibromas may transform in 1% to 4% of individuals into neurofibrosarcomas, rarely before the age of 10 years. Areas of abrasion (eg, the belt line) are more susceptible to malignant transformation. Rapid growth is an indication for biopsy [
Lisch nodules are benign iris hamartomas, often visible only by slit-lamp examination. They cause no clinical problems but are useful for diagnosis. They are uncommon in young children (22% by 5 years of age), but if only café au lait spots are present, the discovery of Lisch nodules can confirm the diagnosis of NF1. They occur in 70% of children by 10 years of age [
] and are present in almost all adults (96%) with NF1.
Neurologic features of neurofibromatosis type 1
Tumors
The most common tumors of the central nervous system in NF1 occur in the optic pathways, and are mostly slow-growing low-grade astrocytomas. Rarely, meningiomas occur in the same location in NF1 patients and may show identical findings. Although imaging studies demonstrate that approximately 15% to 20% of NF1 patients have optic pathway tumors, no more than half of the tumors become symptomatic. In general, the presence of an optic nerve glioma in a child should raise the suspicion for NF1; at least 50% of children with optic nerve gliomas have NF1. Because chiasmatic tumors may involve the hypothalamus, the occurrence of precocious puberty in NF1 children should signal the likelihood of an optic glioma. Most children with symptomatic gliomas develop decreased visual acuity and optic pallor/atrophy, but depending on the location of the tumor in the visual pathways, they may present with visual field defects, restricted eye movements, proptosis, headache, or hypothalamic dysfunction. Tumors that cause symptoms are typically diagnosed by the age of 6 years, and more than 90% show no progression of symptoms after diagnosis. A more recent study of 1893 NF1 patients less than 21 years old found that symptomatic optic gliomas are usually diagnosed by the age of 3 years [
]. Therefore, imaging as a screen for optic pathway tumors in the absence of symptoms has limited value. Treatment for progressive tumors usually includes surgery and chemotherapy [
], cognitive problems, endocrine dysfunction, and the possibility, particularly after radiation therapy, of transformation of low-grade tumors into more malignant tumors. Whether treated initially or not, patients with visual pathway tumors are followed closely for any deterioration of vision or endocrinologic dysfunction.
Symptomatic parenchymal brain tumors occur infrequently in NF1 (∼1%–2% of patients), and they are usually low-grade astrocytomas. Brain tumors in NF1 generally become symptomatic by the time the patient reaches the age of 20 years. With the exception of brainstem gliomas, the outcome of these tumors is typically the same as in children without NF1. Brainstem gliomas, however, show slower progression or even regression in NF1 and may not need treatment [
]. Hydrocephalus, which may occur with brainstem tumors (eg, tectal gliomas), may require ventriculoperitoneal shunting. Other tumor types are much less common, including ependymomas, meningiomas, medulloblastomas, and primitive neuroectodermal tumors, and these tumor types are treated as they would be in children without NF1.
If brain tumors are symptomatic and they are low-grade hemispheric or cerebellar astrocytomas, they are often removed surgically, particularly if they are not in areas that are critical for nervous system function. Those that are recurrent or not surgically accessible are treated with chemotherapy [
] or radiation therapy. In young children, the morbidity from radiation therapy is high. Similar to optic nerve gliomas in NF1, parenchymal brain tumors are not treated on discovery. They should be monitored before treatment for either lack of progression or the possibility of spontaneous regression [
Spinal nerve root neurofibromas and, less commonly, spinal cord gliomas may cause symptoms and are typically treated surgically. Spinal meningoceles, often thoracic, are caused by dural ectasia and can be confused with neurofibromas. Spinal meningiomas are probably no more common in NF1 than in the normal population; rather, they more commonly complicate NF2.
Cognitive problems
Mental retardation occurs only slightly more commonly in NF1 (4%–8%) than in the normal population (3%). Specific learning disabilities have a major impact, however, and occur in 30% to 60% of children with NF1. Psychologic testing shows visual-spatial problems, language disorders, and memory dysfunction. Some of the children have attention-deficit hyperactivity disorder. It remains unsettled as to whether cranial MRI T2 hyperintensities are correlated significantly with the learning problems of NF1. Awareness of the possibility of learning problems in NF1 children can lead to proper educational treatment.
Other complications of neurofibromatosis type 1
NF1 may cause problems with almost every organ system because it affects both neural crest–derived cells and mesodermal tissues. There is only a slight increase in the prevalence of epilepsy, perhaps 2% to 5%. Somewhat less than half of NF1 children have macrocephaly without hydrocephalus or any definite abnormality. Short stature occurs in approximately one third of such children.
Scoliosis is frequent in NF1 (∼15%). Scoliosis occurs earlier, and it more commonly needs surgical correction than does idiopathic scoliosis. Although it may have a long length similar to idiopathic scoliosis, vertebral dysplasia is often related to the NF1 scoliosis and then may show an acute angulation. Causes of scoliosis include spinal meningoceles and nerve root neurofibromas (often with a dumbbell configuration). Sphenoid wing dysplasia occurs congenitally in less than 1% of children with NF1 but is relatively unique for NF1. Thinning of long bones, especially with medial bowing of the tibia, may predispose to fractures and pseudoarthrosis.
Glaucoma occurs rarely and is usually congenital. It is associated with photophobia and enlargement of the corneal diameter. Neurofibromas can occur in multiple areas, leading to unexpected complications, including constipation and prostate involvement [
]. Some tissues may be enlarged, leading to clitoral enlargement, macrodactyly (with or without a plexiform neurofibroma), and macroglossia. Hypertension may occur in childhood but is more common in adults with NF1. A neurofibroma may compress the renal artery, or the vascular dysplasia of NF1 may cause renovascular hypertension. NF1 may be the most common cause of renovascular hypertension in children [
]. Hypertension may also be caused by a pheochromocytoma. In addition to pheochromocytoma, NF1 is rarely associated with other neoplasms, such as carcinoid of the duodenum, nonlymphocytic leukemia, adenocarcinoma of the ampulla of Vater, and possibly rhabdomyosarcoma.
The vascular dysplasia of NF1 is also associated with stroke in childhood, usually caused by the moyamoya phenomenon associated with occlusion of the supraclinoid carotid artery or proximal vessels of the circle of Willis [
Compared with TSC, neuroimaging in NF1 does not have as much importance for diagnosis of the disorder but is more important for monitoring complications. There are no neuroimaging findings included in the diagnostic criteria for NF1. When the consensus criteria for diagnosis of NF1 were formulated in 1987, there was not much experience with MRI, especially in children. MRI T2 hyperintensities may have diagnostic significance, however. In NF1, most young patients have unidentified bright objects (UBOs) on cranial MRI (Fig. 11), whereas the prevalence of UBOs goes down in older children. The nature of the UBOs remains unclear, and they are postulated to represent hamartomas, dysmyelinated areas, or spongiosis. Most adults with NF1 either do not have UBOs typical for NF1 or have confounding lesions caused by vascular or other disease. DeBella et al [
] used cranial MRI to examine 19 children with NF1 and 19 controls. Of the 19 control children, 11 had UBOs. Of note, the control children all had neurologic disorders. When only the UBOs typical for NF1 were considered (ie, those located in the basal ganglia, cerebellum, and brainstem), their presence was correlated with NF1 to a high degree, yielding a diagnostic sensitivity of 97% and a specificity of 79%. In terms of diagnosis, UBOs are more helpful in young children who have only one criterion for diagnosis (usually multiple café au lait spots). They are less helpful later, because by the age of 5 years, diagnosis can usually be made based on other criteria. Further studies are necessary before typical UBOs can be considered a diagnostic criterion.
Fig. 11Axial T2-weighted MRI of unidentified bright object in the cerebellar white matter.
Because of the morbidity of tumors in NF1, the follow-up of optic nerve gliomas, brain tumors, and spinal lesions is the most important use of neuroimaging in NF1. On T2-weighted MRI, optic nerve gliomas either demonstrate an enlarged optic nerve with a core of low signal surrounded by high signal, or there is a tubular enlargement of affected optic nerves. Optic nerve sheath dysplasia occasionally is mistaken for an optic nerve tumor.
As discussed previously, imaging of asymptomatic patients to screen for optic nerve gliomas or brain tumors is rarely useful. Most clinicians obtain a baseline cranial MRI. If asymptomatic lesions are discovered that might represent tumors, they are commonly monitored every year or so. Cranial MRI T2 hyperintensities in the visual pathways, brainstem, or cerebellum often represent benign UBOs. After discovery of MRI T2 hyperintensities, however, it is helpful to perform a study with contrast. An enhancing lesion is more likely to represent an astrocytoma or other tumor. Although lack of enhancement is reassuring, some astrocytomas do not enhance. A follow-up scan is usually indicated to confirm lack of progression.
Genetic aspects of neurofibromatosis type 1
NF1 is an autosomal dominant disorder. For an affected parent, the risk of affected offspring is 50% with each pregnancy. The spontaneous mutation rate is high; thus, perhaps 50% of affected patients represent sporadic cases. Those with a new sporadic mutation then transmit NF1 as an autosomal dominant disorder. The gene for NF1 was initially localized to chromosome 17 in 1987, the same year that TSC1 was localized to chromosome 9. The NF1 gene is large and was described in 1990. There is only one gene that causes NF1. Most NF1 mutations cause premature truncation of the neurofibromin protein. Similar to the TSC1 and TSC2 gene products, the normal NF1 gene product, neurofibromin, is thought to function as a tumor suppressor [
]. Neurofibromas are composed of multiple cellular elements, but the Schwann cell seems to be the target for NF1 gene inactivation. An individual with NF1 inherits an inactivating mutation of one of the NF1 alleles. This mutation is present in all cells. When a somatic inactivating mutation of the NF1 gene occurs in the other allele, a neurofibroma or other tumor may develop. The prevalence of learning problems and other symptoms unrelated to tumor formation has led to the speculation that this large gene may have additional functions that may play a role in the heterozygous state.
Germline mosaicism, documented in only one clinically normal father of two offspring with NF1, is thought to be rare enough that it is not important for genetic counseling [
]. By contrast, some patients have segmental or anatomically limited signs of NF1 consistent with somatic mosaicism. If patients with segmental NF1 have mosaicism of germ cells, they transmit NF1 as an autosomal dominant disorder.
Management of neurofibromatosis type 1
Patients with NF1 have multiple possible complications and need access to multiple specialists. A clinician who has a broad familiarity with NF1, often a neurologist or geneticist, coordinates the care. Patients are seen yearly and are evaluated for complications, such as focal neurologic dysfunction, abnormal puberty, optic pathway tumor, scoliosis, cognitive/learning problems, and hypertension. Counseling includes supportive information, genetic aspects, surveillance of plexiform neurofibromas for malignant transformation, and reassurance that less than half of NF1 patients (40%) develop medical problems from NF1. The similarity of a small portion of the neurofibromin molecule to the GTPase-activating proteins raises the possibility of pharmacologic treatment (eg, farnesyl transferase inhibitors), which might prevent or ameliorate the neoplastic complications of NF1.
Summary
TSC and NF1 are the most common of the neurocutaneous diseases, and both are autosomal dominant with a high spontaneous mutation rate. For diagnosis, two features are necessary for each disease. Skin findings for each are especially helpful for diagnosis, as is neuroimaging in TSC. For NF1, neuroimaging is not yet reliable for diagnosis. In children, brain symptoms cause most of the morbidity in TSC, and nerve sheath and nervous system tumors as well as learning disabilities cause major morbidity in NF1. Renal disease becomes a serious problem for adults with TSC. The TSC1, TSC2, and NF1 genes function as tumor suppressor genes and have other functions that are being investigated. Blood tests for diagnosis have a high false-negative rate. Therapies for TSC and for NF1 are both medical and surgical.
References
MacCollin M.
Mautner V.F.
The diagnosis and management of neurofibromatosis 2 in childhood.
Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.
Dr. Raymond Kandt's article, “Tuberous sclerosis complex and neurofibromatiosis type 1: the two most common neurocutaneous diseases” was originally published in the November 2002 issue of the Neurologic Clinics on “Pediatric Neurology, Part I;” however, the figures were poorly reproduced when printed. Dr. Kandt's article, with the corrected figures, is reprinted in its entirety on the following pages.
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