Cutaneous Features

The cutaneous lesions of TSC include hypomelanotic macules, the shagreen patch, ungual fibromas, and facial angiofibromas. Hypomelanotic macules (ash leaf spots) occur in up to 90% of affected individuals (Fig. 65.1). The lesions usually are present at birth but may be seen in the newborn only with an ultraviolet light. Other pigmentary abnormalities include confetti lesions (areas with stippled hypopigmentation, typically on the extremities) and poliosis (a white patch or forelock) of the scalp, hair, or eyelids (Fig. 65.2, D). Hypomelanotic macules are common in normal individuals (Table 65.1), but three or more hypomelanotic papules is a major diagnostic criterion for TSC.

Fig. 65.1 A hypomelanotic macule (ash leaf spot) (arrow) from the leg of a patient with tuberous sclerosis.

(Reprinted with permission from Weiner, D.M., Ewalt, D.H., Roach, E.S., et al., 1998. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 187, 548-561.)

Fig. 65.2 Classic cutaneous manifestations of tuberous sclerosis include facial angiofibromas (A), shagreen patch (B), ungual fibromata (C), and poliosis (D).

(Reprinted with permission from Roach, E.S., Delgado, M.R., 1995. Tuberous sclerosis. Dermatol Clin 13, 151-161.)

Table 65.1 Frequency of Lesions in Individuals with Tuberous Sclerosis Versus Other Individuals

Facial angiofibromas (adenoma sebaceum) consist of vascular and connective tissue elements. Although considered specific for TSC, they are found in only three-fourths of affected individuals and often appear several years after other means have established the diagnosis. The lesions typically become apparent during the preschool years as a few small red macules on the malar region; they gradually become papular, larger, and more numerous, sometimes extending down the nasolabial folds or onto the chin (see Fig. 65.2, A). Laser therapy may be a useful therapeutic intervention and particularly helpful in early childhood or just prior to puberty, before a time when growth may be rapid and more aggressive interventions warranted.

The shagreen patch most often is found on the back or flank area; it is an irregularly shaped, slightly raised, or textured skin lesion (see Fig. 65.2, B). Only 20% to 30% of patients with TSC have one patch, which may not be seen in young children. Usually considered specific for TSC, ungual fibromas are nodular or fleshy lesions that arise adjacent to (periungual) or underneath (subungual) the nails (see Fig. 65.2, C). These can occur as a single lesion after trauma in normal individuals. Ungual fibromas occur in only 15% to 20% of patients with TSC, more likely in adolescents or adults.

Forehead plaques or fibrous facial plaques resemble angiofibromas histologically, though they are not papular. Angiofibromas have improved with oral rapamycin administered for immunosuppression related to renal transplantation in TSC, and topical application is under consideration for study.

Neurological Features

The predominant neurological manifestations of TSC are mental retardation, seizures, and behavioral abnormalities, although milder forms of the disease with little or no neurological impairment are common. Neurological lesions probably result from impaired cellular interaction resulting in disrupted neuronal migration along radial glial fibers and abnormal proliferation of glial elements. Neuropathological lesions of TSC include subependymal nodules (SENs), cortical and subcortical hamartomas (tubers), areas of focal cortical hypoplasia, and heterotopic gray matter. SENs commonly arise from germinal matrix progenitors in the caudothalamic groove near the foramen of Monro. These lesions can grow over time, but usually only into adolescence, after which time they calcify. These remain asymptomatic unless they enlarge and transform into subependymal giant-cell astrocytomas (SEGAs). Tubers frequently extend from the ventricle wall to the cortical surface, with a linear or wedge-shaped distribution. Similar to normal brain, tubers develop between 14 and 16 weeks gestation, such that the tuber load is established before birth, though they may not be visualized until later childhood, given myelination status. These focal malformations of cortical development most frequently involve one gyrus at a time, but more diffuse involvement such as hemimegalencephaly can occur as well. Histology of these areas demonstrates disorganized cortical lamination and underlying abnormal myelination with indistinct gray/white junction architecture. Calcinosis frequently is present. Dysmorphic neurons can be present, and other abnormal astrocytes similar to those seen in sporadic focal cortical dysplasias are termed balloon cells or giant cells for their abundant cytoplasm.

Seizures of various types occur in 80% to 90% of patients. Most develop during the first year postpartum, which is an indicator for autism and poor cognitive development. TSC is the most common cause of infantile spasms, and one-third of children with TSC develop them. Children with infantile spasms have more cortical lesions demonstrated by magnetic resonance imaging (MRI) and are more likely to exhibit long-term cognitive impairment. For many, vigabatrin has been a more effective treatment option than adrenocorticotropin hormone (ACTH). Occasionally, children can discontinue their antiepileptic medication. Corpus callosotomy is an option in young children. Resective epilepsy surgery is a consideration in individuals with seizures localizing to a single tuber, who can experience seizure freedom or at least significant seizure reduction.

Most patients with mental retardation have epilepsy, but many have seizures and normal intelligence. The number of subependymal lesions does not correlate with the clinical severity of TSC, but patients with MRI evidence of numerous cortical lesions tend to have more cognitive impairment and more difficulty with seizure control. The most abnormal regions seen on MRI tend to coincide with focal abnormalities of the electroencephalogram (EEG). The likelihood of intellectual disability in patients with TSC probably is overestimated, and the severity of intellectual dysfunction ranges from borderline to profound mental retardation. However, in addition to intellectual disability, many children with TSC have serious behavioral disorders. Autistic behavior, hyperkinesis, aggressiveness, and frank psychosis sometimes occur, either as isolated problems or in combination with epilepsy or intellectual deficit. The prevalence of autistic spectrum disorders is 25% to 50% and equal between boys and girls. Behavioral problems are frequent and independent of intellectual ability (de Vries, 2010). Mood disorders also are increased.

Computed tomography (CT) best demonstrates the calcified subependymal nodules that characterize TSC (Fig. 65.3). CT sometimes shows superficial cerebral lesions, but they are far more obvious with T2-weighted MRI (Fig. 65.4). T2-weighted scans show evidence of abnormal neuronal migration in some patients as high-signal linear lesions running perpendicular to the cortex. SENs along the ventricular surface give the characteristic appearance of candle guttering. More than one-fourth of patients with TSC show cerebellar anomalies.

Fig. 65.3 Computed cranial tomography scan from a child with tuberous sclerosis complex demonstrates typical calcified subependymal nodules; a large calcified parenchymal lesion (arrowhead) and low-density cortical lesions (arrows) are seen as well.

(Reprinted with permission from Roach, E.S., Kerr, J., Mendelsohn, D., et al., 1991. Diagnosis of symptomatic and asymptomatic gene carriers of tuberous sclerosis by CT and MRI. Ann N Y Acad Sci 615, 112-122.)

Fig. 65.4 Noncontrast T2-weighted magnetic resonance imaging scan from a child with tuberous sclerosis demonstrates extensive high-signal cortical lesions typical of tuberous sclerosis.

Subependymal giant-cell astrocytomas (SEGAs) develop in 6% to 14% of patients with TSC. Unlike the more common cortical tubers and SENs, giant-cell astrocytomas can enlarge (Fig. 65.5) and cause symptoms of increased intracranial pressure, particularly if extension into the lateral ventricles creates an obstructive hydrocephalus. Clinical features include new focal neurological deficits, increased intracranial pressure, unexplained behavior change, or deterioration of seizure control. Acute or subacute onset of neurological dysfunction may result from sudden obstruction of the ventricular system by an intraventricular SEGA. Rarely, acute deterioration occurs because of hemorrhage into the tumor itself.

Fig. 65.5 A, Noncontrast T1-weighted magnetic resonance imaging scan from a child with tuberous sclerosis shows an irregular mass (arrow) with a central signal void caused by calcification protruding into the left frontal horn. B, Another scan with gadolinium a few months later shows contrast enhancement and minimal tumor growth.

Giant-cell tumors are usually benign but locally invasive, and early surgery can be curative. Identification of an enlarging SEGA before the onset of symptoms of increased intracranial pressure or appearance of new neurological deficits is ideal. Periodic screening to identify SEGA may improve surgical outcome. Recent work suggests that rapamycin inhibits the growth of SEGAs (Franz et al., 2006).

Retinal Features

The frequency of retinal hamartomas in TSC varies from almost negligible to 87% of patients, probably reflecting the expertise and technique of the examiner. Pupillary dilatation and indirect ophthalmoscopy are important, particularly in uncooperative children. Findings vary from classic mulberry lesions adjacent to the optic disc (Fig. 65.6) to plaque-like hamartoma or depigmented retinal lesions. Most retinal lesions are clinically insignificant, but some patients have visual impairment caused by large macular lesions, and very few patients have visual loss caused by retinal detachment, vitreous hemorrhage, or hamartoma enlargement. Occasionally, patients have a pigmentary defect of the iris. Funduscopic examination is valuable at the time of diagnosis, to monitor existing abnormalities or evaluate for new symptoms. The histological features of retinal hamartomas, subependymal nodules, and subependymal giant-cell astrocytomas are similar.

Fig. 65.6 A retinal astrocytoma (mulberry lesion) adjacent to the optic nerve is typical of those found in tuberous sclerosis.

(Reprinted with permission from Roach, E.S., 1992. Neurocutaneous syndromes. Pediatr Clin North Am 39, 591-620.)

Systemic Features

Cardiac

Approximately two-thirds of patients with TSC have a cardiac rhabdomyoma, but few demonstrate clinical symptoms. Cardiac rhabdomyomas are hamartomas, tend to be multiple, and involute with time. These lesions sometimes are evident on prenatal ultrasound testing (Fig. 65.7)—usually after 24 weeks gestational age—and most who develop cardiac dysfunction present soon after birth with heart failure. A few children later develop cardiac arrhythmias or cerebral thromboembolism from the rhabdomyomas. The cause of congestive heart failure is either by obstruction of blood flow by intraluminal tumor or by lack of sufficient normal myocardium to maintain perfusion. Some patients stabilize after medical treatment with digoxin and diuretics and eventually improve; others require surgery. Echocardiography and electrocardiogram establish the diagnosis. Arterial aneurysms can occur. For existing rhabdomyomas, perform surveillance studies every 6 to 12 months until stabilization or involution occurs. The size of these lesions may increase with hormone exposure—a consideration in the neonate, pubertal individual, and child treated with ACTH for infantile spasms.

Fig. 65.7 Prenatal ultrasound study reveals a large cardiac rhabdomyoma (arrow) and two smaller rhabdomyomas (arrowheads) in a child who subsequently proved to have tuberous sclerosis.

(Reprinted with permission from Weiner, D.M., Ewalt, D.E., Roach, E. S., et al., 1998. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 187, 548-561.)

Renal

Renal angiomyolipomas occur in up to three-fourths of patients with TSC, usually presenting by 10 years of age. Most of these lesions are histologically benign tumors with varying amounts of vascular tissue, fat, and smooth muscle (Fig. 65.8). Bilateral tumors or multiple tumors in a kidney are common. The prevalence and size of renal tumors increase with age, and tumors larger than 4 cm are much more likely to become symptomatic than smaller tumors. Renal cell carcinoma or other malignancies are less common but affect TSC patient at younger ages than the general population. Coalescing angiomyolipomata can contribute to end-stage renal disease. Endovascular embolization of the larger renal angiomyolipomata prevents hemorrhage and other complications (Ewalt et al., 2005). Rapamycin limits the growth of these tumors, at least transiently.

Fig. 65.8 A large angiomyolipoma of the lower pole of a kidney removed at surgery; several smaller angiomyolipomas (arrows) can be seen in the same specimen.

(Reprinted with permission from Weiner, D.M., Ewalt, D.E., Roach, E.S., et al., 1998. The tuberous sclerosis complex: a comprehensive review. J Am Coll Surg 187, 548-561.)

Single or multiple renal cysts are also a feature of TSC; these tend to appear earlier than the renal tumors. Ultrasound or cranial CT easily identifies larger cysts, and the combination of renal cysts and angiomyolipomas is characteristic of TSC. Individual renal cysts may disappear. Surveillance imaging is recommended, at least every 2 to 3 years—more frequently in those with existing or symptomatic renal involvement.

Cutaneous Features of Neurofibromatosis Type 1

Cutaneous lesions of NF1 (Fig. 65.9) include café-au-lait spots, subcutaneous neurofibromas, plexiform neurofibromas, and axillary freckling. Café-au-lait spots are flat, light to medium brown areas that vary in shape and size. They typically are present at birth but increase in size and number during the first few years of life. Later in childhood, skin freckling, 1 to 3 mm in diameter, often occurs symmetrically in the axillae (Crowe sign) and other intertriginous regions. Most children with 6 or more café au lait spots as their only diagnostic criterion will go on to meet diagnostic criteria, usually by age 6.

Fig. 65.9 A, Typical café-au-lait spots (arrow) in a child with neurofibromatosis type 1. B, Subcutaneous neurofibromata in a patient with neurofibromatosis type 1. C, Plexiform neurofibroma in a boy with neurofibromatosis type 1.

(Reprinted with permission from Roach, E.S., 1988. Diagnosis and management of neurocutaneous syndromes. Semin Neurol 8, 83-96.)

Neurofibromas are benign tumors arising from peripheral nerves (see Fig. 65.9, B). These tumors are composed predominantly of Schwann cells and fibroblasts but contain endothelial, pericytes, and mast cell components. Neurofibromas can develop at any time; their size and number often increase after puberty.

Plexiform neurofibromas often occur on the face and can cause substantial deformity (see Fig. 65.9, C). Patients with plexiform tumors of the head, face, or neck and those who presented before 10 years of age are more likely to do poorly (Needle et al., 1997). Plexiform neurofibromas have a 5% to13% lifetime risk of malignant degeneration into malignant peripheral nerve sheath tumors. Malignant peripheral nerve sheath tumors (MPNST) carry poor 5-year survival rates despite treatment with surgery, chemotherapy, and radiation. PNFs and MPNST are difficult to distinguish radiographically and sometimes even pathologically.

Systemic Features of Neurofibromatosis Type 1

Lisch nodules are pigmented iris hamartomas (Fig. 65.10). They are pathognomonic for NF1. Lisch nodules do not cause symptoms; their significance lies in their implications for the diagnosis of NF1. Lisch nodules are often not apparent during early childhood, so their absence does not exclude the diagnosis of NF1. Rarely, children with NF1 have retinal hamartomas, but these usually remain asymptomatic.

Fig. 65.10 Lisch nodules (arrow) of the iris in a patient with neurofibromatosis type 1.

(Reprinted with permission from Roach, E.S., 1992. Neurocutaneous syndromes. Pediatr Clin North Am 39, 591-620.)

Dysplasia of the renal or carotid arteries occurs in a small percentage of patients with NF1. Renal artery stenosis causes systemic hypertension. Another potential cause of hypertension is pheochromocytoma. Several forms of cerebral artery dysplasia occur, most commonly moyamoya syndrome, which promotes cerebral infarction in children and brain hemorrhage in adults. Arterial aneurysms occur as well.

The most common skeletal manifestations in NF1 consist of short stature and macrocephaly. Macrocephaly is independent of hydrocephalus accompanying aqueductal stenosis, which also occurs in this disorder. Other skeletal abnormalities include long-bone dysplasia (resulting in pathological fractures and subsequent pseudoarthrosis), scoliosis, and bony erosion secondary to adjacent tumor. Dysplasia of the sphenoid wing is common.

LEOPARD syndrome (lentigenes, ECG conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal (male) genitalia, retardation of growth, deafness) is an autosomal dominant disorder whose features also include café au lait spots and obstructive cardiomyopathy. The café-au-lait spots and cardiac abnormalities may suggest NF1. Legius syndrome is another autosomal dominant NF-like syndrome; it is characterized by similar cutaneous features but little tumorigenesis.

Neurological Features in Neurofibromatosis Type 1

NF1 affects the nervous system in several ways, but the clinical features vary even within the same family. Tumors occur in the brain, spinal cord, and peripheral nerves.

Optic nerve glioma (Fig. 65.11) is the most common CNS tumor caused by NF1. Approximately 15% of patients with NF1 have unilateral or bilateral optic glioma. The growth rate of these tumors varies, but they tend to behave less aggressively in patients with NF1 than those without NF1. When symptomatic, the presenting features are optic atrophy, progressive vision loss, pain, or proptosis. Precocious puberty is a common presenting feature of chiasmatic optic nerve tumors in children with NF1. Management options include observation with serial brain MRI or treatment with radiation, chemotherapy, or excision. Radiation is less favored, especially given possible exacerbation of vasculopathy in this population.

Fig. 65.11 Computed cranial tomography scan from a child with neurofibromatosis type 1 shows bilateral optic nerve gliomas, larger in the right optic nerve (arrow) than the left.

(Reprinted with permission from Roach, E.S., 1992. Neurocutaneous syndromes. Pediatr Clin North Am 39, 591-620.)

Ependymomas, meningiomas, and astrocytomas of the CNS occur in patients with NF1 less often than in patients with NF2. Neurofibromas and schwannomas are common but not always symptomatic; they develop on either cranial nerves or spinal nerve roots. The symptoms from these tumors (discomfort, pain, numbness, weakness, and bowel/bladder dysfunction) reflect their size, location, and rate of growth.

Macrocephaly is seen in half of NF1 patients, typically attributable to megalencephaly related to increases in white-matter volume. Approximately 60% to 78% of patients with NF1 have increased signal lesions within the basal ganglia, thalamus, brainstem, and cerebellum on T2-weighted MRIs (Fig. 65.12). These areas are not routinely visible with CT. The origin and significance of these radiographic lesions are unclear, and they are referred to at times as unidentified bright objects (UBOs). Whether these MRI lesions correlate with the likelihood of cognitive impairment still is debatable; radiographic findings do not correlate with neurological deficits. Patients with NF1 tend to have full-scale intelligence quotient (IQ) scores within the low-normal range and to exhibit behavioral problems. These symptoms may be related to vascular changes in myelin sheath. Deep gray-matter radiological findings tend to decrease with time, while cortical and subcortical findings do not decrease or increase.

Fig. 65.12 Coronal T2-weighted magnetic resonance imaging scan shows bilateral high-signal lesions in the basal ganglia, abnormalities typical of neurofibromatosis type 1.

Clinical Features of Neurofibromatosis Type 2

Patients with NF2 have few cutaneous lesions, and these tend to be subtle. Instead, patients often have multiple types of CNS tumors (thus the designation of central NF). Café-au-lait spots and subcutaneous neurofibromas are less common. Lisch nodules are uncommon, although some patients show presenile posterior subcapsular cataracts.

Most patients who meet established diagnostic criteria for NF2 (see Table 65.3) eventually develop bilateral vestibular schwannomas, previously termed acoustic neuromas (Fig. 65.13). Symptoms of NF2 typically develop in adolescence or early adulthood but can begin in childhood. Common complaints with large acoustic tumors include hearing loss, tinnitus, vertigo, facial weakness, poor balance, and headache. Unilateral hearing loss is relatively common in the early stages. Consider screening with annual auditory brainstem responses or brain MRI.

Fig. 65.13 Cranial magnetic resonance imaging scan from a child with neurofibromatosis type 2 shows bilateral vestibular tumors (arrows).

(Reprinted with permission from Roach, E.S., 1992 Neurocutaneous syndromes. Pediatr Clin North Am 39, 591-620.)

Other CNS tumors occur, but much less often than vestibular schwannomas. The term MISME syndrome (multiple inherited schwannomas, meningiomas, and ependymomas) applies to this disorder. The clinical features of these tumors depend primarily on the lesion’s location within the brain and spinal cord. Schwannomas of other cranial nerves occur in some patients. Meningiomas, ependymomas, and astrocytomas also occur with increased frequency. Patients with NF2 may develop multiple simultaneous tumor types, and baseline imaging at the time of diagnosis should include the brain and spinal cord.

Merlin is a novel regulator of TSC/mTORC1 signaling, such that rapamycin is being evaluated in the management of NF2 tumors (James et al., 2009).

Cutaneous Features

The nevus typically involves the forehead and upper eyelid but also may involve both sides of the face and extend onto the trunk and limbs (Fig. 65.14). Nevi that involve only the trunk, or facial nevi that spare the upper face, rarely are associated with intracranial angioma. The facial angioma is usually obvious at birth; it may thicken over time and develop a nodular texture. Reactive hypertrophy of adjacent bone and connective tissue may occur. Some children have the characteristic neurological and radiographic features of SWS yet have no skin lesions. More frequently, the typical cutaneous and ophthalmic findings are present without clinical or radiographic evidence of an intracranial lesion. Only 10% to 20% of children with a port-wine nevus of the forehead have a leptomeningeal angioma. Although the leptomeningeal angioma is typically ipsilateral to a unilateral facial nevus, bilateral brain lesions occur in at least 15% of patients, including some with a unilateral cutaneous nevus.

Fig. 65.14 A, A patient with the classic distribution of the port-wine nevus of Sturge-Weber syndrome on the upper face and eyelid. B, Another patient whose port-wine nevus involves both sides of the face and extends onto the left trunk and arm.

(A reprinted with permission from Roach, E.S., 1989. Congenital cutaneovascular syndromes, In: Vinken, P.V., Bruyn, G.W., Klawans, H.L. (Eds.), Handbook of Clinical Neurology, vol. 11, Vascular Diseases. Elsevier, Amsterdam, pp. 443-462. B reprinted with permission from Roach E.S., Riela, A.R., 1995. Pediatric Cerebrovascular Disorders, second ed. Futura, New York.)