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

From Roach, E.S., Sparagana, S.P., 2010. Diagnostic criteria for tuberous sclerosis complex. In: Kwiatkowski, D.J., Whittemore, V.H., Thiele, E.A. (Eds.), Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics. Weinheim, Wiley-VCH Verlag GmbH & Co., pp. 21-25. Used with permission.

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.)

Ocular Features

Glaucoma is the main ophthalmological problem associated with SWS. The risk of developing glaucoma has two age peaks, the first in infancy and the second in late childhood. Amblyopia and buphthalmos (enlarged globe) are present in some newborns. In others, the glaucoma becomes symptomatic later and, if untreated, causes progressive blindness. Periodic measurement of the intraocular pressure is mandatory, particularly when the nevus is near the eye. Patients with SWS also may develop choroid angiomas or heterochromasia of the iris ipsilateral to the nevus.

Neurological Features

Epileptic seizures, mental retardation, and focal neurological deficits are the principal neurological abnormalities of SWS. Seizures usually start in conjunction with hemiparesis. Seizure onset before age 2 years increases the likelihood of future mental retardation and refractory epilepsy. Mental retardation is likely in children with refractory seizures, whereas children who never experience seizures usually have normal intelligence. Few children who remain normal after age 3 years will later develop severe intellectual impairment.

Seizures eventually develop in 72% to 80% of patients with SWS with unilateral lesions and in 93% of patients with bihemispheric involvement. Although some begin in adult life, 75% of seizures begin during the first year, 86% by age 2, and 95% before age 5. Focal motor seizures or generalized tonic-clonic seizures are the most typical seizure type initially associated with SWS. Other initial seizure types are infantile spasms, myoclonic seizures, and atonic seizures. The first few seizures are often focal, even in patients who later develop generalized tonic-clonic seizures or infantile spasms. Older children and adults are more likely to have complex partial seizures or focal motor seizures. Seizures can be refractory or may remain well controlled for long intervals.

The neurological impairment caused by SWS depends in part on the site of the intracranial vascular lesion. Because the occipital region frequently is involved, visual-field deficits are common. Hemiparesis often develops acutely in conjunction with the initial flurry of seizures. Although often attributed to postictal weakness, hemiparesis may be permanent or persist longer than typical of a postictal deficit. Some children develop sudden weakness without seizures, either as repeated episodes of weakness similar to transient ischemic attacks or as a single stroke-like episode with persistent neurological deficit. Not all patients have permanent focal neurological signs.

Early developmental milestones may be normal, but mild to profound mental deficiency eventually develops in approximately half of patients. Only 8% of the patients with bilateral brain involvement are intellectually normal. Behavioral concerns are frequent, even in patients who are not intellectually disabled. The clinical condition eventually stabilizes, resulting in residual hemiparesis, hemianopia, retardation, and epilepsy, but without further deterioration.

Diagnostic Studies

Most children with a facial port-wine nevus do not have an intracranial angioma. Neuroimaging studies help distinguish children with SWS from those with isolated cutaneous lesions. Although gyral calcification is a typical feature of SWS, the tram-track appearance first described on standard radiographs is uncommon and is almost never present in neonates. CT shows intracranial calcification much earlier (Fig. 65.15) than standard skull radiographs Extensive cerebral atrophy is apparent even with CT, but MRI more readily shows subtle atrophy.

Fig. 65.15 Computed tomographic scan from a typical patient with Sturge-Weber syndrome; the gyriform calcification pattern (arrow) is easily seen in the left occipital area.

(Reprinted with permission from Garcia, J.C., Roach, E.S., McClean, W.T., 1981. Recurrent thrombotic deterioration in the Sturge-Weber syndrome. Childs Brain 8, 427-433.)

MRI with gadolinium contrast (Fig. 65.16) effectively demonstrates the abnormal intracranial vessels in patients with SWS. Functional imaging with positron emission tomography (PET) demonstrates reduced metabolism of the brain adjacent to the leptomeningeal lesion. However, patients with recent-onset seizures may have increased cerebral metabolism near the lesion. Single-photon emission computed tomography (SPECT) shows reduced perfusion of the affected brain. Both PET and SPECT often reveal vascular changes extending well beyond the area of abnormality depicted by CT (Maria et al., 1998). Although functional imaging is not necessary for all patients, it may help initially to establish a diagnosis and may help localize the lesion before surgery.

Fig. 65.16 A, Magnetic resonance imaging study from a child with Sturge-Weber syndrome; this T1-weighted axial view without contrast infusion is normal. B, On the coronal view with gadolinium, the scan reveals a left frontal leptomeningeal and intraparenchymal angioma.

Cerebral arteriography is no longer routine in the evaluation of SWS but is sometimes useful in atypical patients or prior to surgery for epilepsy. The veins are more abnormal than the arteries, with enlarged, tortuous, subependymal and medullary veins and sparse superficial cortical veins. Failure of the sagittal sinus to opacify after ipsilateral carotid injection may be due to obliteration of the superficial cortical veins by thrombosis; the abnormal deep venous channels probably have a similar origin as they form collateral conduits for nonfunctioning cortical veins. Microscopic hemorrhages are noticeable on pathology specimens, although significant intracranial hemorrhage is rare.

Treatment

Generally, the more extensive the intracranial lesion, the more difficult it is to control seizures with medication. Resection of a localized brain vascular lesion or hemispherectomy can often improve seizure control and may promote better intellectual development (Bourgeois et al., 2007). Despite general agreement on the efficacy of surgical resection, debate remains concerning patient selection and the timing of surgery. Almost one patient in five has bilateral cerebral lesions, limiting the surgical options unless one hemisphere is clearly responsible for most of the seizures. Often the patient selected for surgery is one with refractory seizures, clinical dysfunction (e.g., hemiparesis, hemianopia) of the area selected for resection, and failure to respond to an adequate trial of anticonvulsants. Patients with less extensive lesions should have a limited resection rather than a complete hemispherectomy. The limited resection preserves as much normal brain as possible, even at the risk of having to do another operation later. Corpus callosotomy is useful for patients with refractory tonic or atonic seizures and extensive disease. In effect, the surgical considerations in children with SWS are similar to those used with other epileptic patients.

Neurological Features

The initial symptoms of VHL usually arise from effects of the vascular anomalies in the CNS. In the CNS, the most common site of hemangioblastomas is the cerebellum in approximately half of patients (Fig. 65.17), followed by spinal and medullary sites. Cerebral hemangioblastomas are present in less than 5% of patients with VHL. The cerebellar hemispheres are affected far more frequently than the cerebellar vermis. Cerebellar hemangioblastomas may begin in the second decade of life.

Fig. 65.17 Magnetic resonance imaging showing multiple cerebellar hemangioblastomas.

Early symptoms of cerebellar and brainstem hemangioblastomas include headache, the most common symptom, followed by ataxia, nausea and vomiting, and nystagmus. Symptoms are often intermittent or slowly progressive, but up to 20% of patients have an acute onset of symptoms following mild head trauma. Spinal hemangioblastomas typically present with focal back or neck pain and sensory loss or weakness. Because of their typical intramedullary location, spinal hemangioblastomas frequently lead to syringomyelia. The conus medullaris and the cervicomedullary junction are the most common sites. Brainstem hemangioblastomas tend to arise in the area postrema in the medulla, where they may be associated with syringobulbia. Occasionally, hemangioblastomas occur in the cerebral hemispheres or sites near the third ventricle, such as the pituitary gland or its stalk, the hypothalamus, or optic nerve. The incidence of cerebellar hemangioblastomas increases with age, so that 84% of patients with VHL have at least one such tumor by age 60 years.

Hemangioblastomas are best visualized using contrast-enhanced MRI. Routine screening of the brain and spinal cord should include precontrast and postcontrast T1-weighted images with thin sections through the posterior fossa and spinal cord and surface coil imaging of the entire spinal cord. Arteriography is not necessary for diagnosis but is valuable in demonstrating the feeding vessels if surgical resection is planned.

Endolymphatic sac tumors occur in 10% to 15% of these individuals. Sometimes they are bilateral. Presenting symptoms can be abrupt change in hearing accompanying hemorrhage or vertigo and tinnitus (Butman, 2008).

Ocular Features

Childhood onset of symptoms is unusual, but retinal hemangioblastomas may occur in children as young as 1 year. Retinal hemangioblastomas may be asymptomatic, especially if they occur in the periphery of the retina. Vision loss occurs when the lesions are large and centrally located, even in the absence of hemorrhage. Arteriovenous shunting leads to fluid extravasation. Hemorrhage may lead to retinal injury and detachment, glaucoma, uveitis, macular edema, and sympathetic ophthalmitis.

Systemic Features

Renal cysts are present in more than half of individuals with VHL, although, as with CNS and retinal hemangioblastomas, the patients may be asymptomatic. Extensive renal cysts rarely lead to renal failure. Of greater concern is renal cell carcinoma, which develops in more than 70% of patients and is the leading cause of death. These tumors are usually multiple and tend to occur at a younger age than sporadic renal cell carcinoma. Simple renal cysts arise from distal tubular epithelium, whereas renal cell carcinoma tumors arise from proximal tubular epithelium.

Pheochromocytomas occur in 7% to 19% of patients and may be the only clinical manifestation of VHL, even in carefully screened individuals. Tumors may be bilateral and occur outside the adrenal glands. Symptoms of pheochromocytoma include episodic or sustained hypertension, severe headache, and flushing with profuse sweating—or even hypertensive crises, stroke, myocardial infarction, and heart failure. Diagnostic laboratory investigation demonstrates excessive catecholamine concentrations in serum and urine.

Cysts and tumors of the pancreas and epididymis are also features of VHL. Pancreatic tumors include nonsecretory islet cell tumors, simple cysts, serous microcystic adenomas, and adenocarcinomas. Pancreatic cysts are the most common of these lesions and are asymptomatic unless they obstruct the bile duct or become numerous enough to cause pancreatic insufficiency. Islet cell tumors coincide frequently with pheochromocytomas, possibly because both tumors derive from neural crest cells. Epididymal cystadenomas also may be asymptomatic but palpable and cause discomfort.

Molecular Genetics

Confirming initial suspicions, the VHL gene is a tumor-suppressor gene located on chromosome 3p25-26. A mutation in the VHL gene also appears in many sporadic clear-cell renal carcinomas that present later in life as compared to those with VHL disease. It demonstrates a role in the function of hypoxia-induced factor, HIF2α. This regulation contributes to increased vascularization and up-regulation of proangiogenic genes and other oxygen-sensitive genes via hypoxia response elements (HRE). These genes include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGF-α), glucose transporter-1 (GLUT1), carbonic anhydrase IX, and erythropoietin (EPO), among others. In particular, VEGF is important in angiogenesis; its levels in ocular fluid of patients is significantly higher than in unaffected subjects. Recognition of these affected genes has focused trials of certain therapies (Clarkson and Cookson, 2008).

Hundreds of known mutations exist. Despite complex genotype-phenotype relationships, some clinical correlations are possible. Missense mutations in this gene are associated with pheochromocytoma, whereas nonsense, frameshift, and splice-site mutations as well as deletions predominate in families without pheochromocytomas. Microdeletions and microinsertions, nonsense mutations, or deletions appear in 56% of families with VHL type 1, whereas missense mutations account for 96% of those responsible for VHL type 2 (Chen et al., 1995). Specific mutations in codon 238 account for 43% of the mutations responsible for VHL type 2, and one group of patients (type 2C) appears to be at low risk for any feature of VHL except pheochromocytoma.

Treatment

Careful screening (Box 65.3) is the most important aspect of management of VHL. Screening is mandatory for all first-degree relatives in a family with VHL or pheochromocytoma. Other indications for clinical screening include pancreatic cysts, multiple or bilateral renal cell tumors, retinal hemangiomas, and cerebellar hemangioblastomas. Availability of molecular analysis for the VHL gene reduces the number of asymptomatic relatives requiring surveillance; only relatives who have inherited the VHL mutation need annual screening.

Neurological Features

Neurological complications are common. Frequent complaints include headache, dizziness, and seizures. Less common complications include paradoxical embolism with stroke, intraparenchymal or subarachnoid hemorrhage, and meningitis or brain abscess.

Paradoxical embolism via a pulmonary arteriovenous fistula (AVF) leads to cerebral infarction. Rarely, a clot may form within the fistula itself before migrating into the arterial circulation. Intermittent symptoms with subsequent improvement result from repeated small emboli. The cause of transient ischemic attacks during hemoptysis is air embolism from a bleeding pulmonary AVF. Approximately 1% develop cerebral abscess or meningitis, probably because septic microemboli bypass the normal filtration of the pulmonary circulation via a pulmonary AVF.

Vascular anomalies may be found anywhere in the brain, spinal cord, or meninges, and more than one type of lesion may be present in the same patient—making this a diagnosis for consideration in patients with multiple cerebrovascular malformations. Approximately one-fourth of HHT patients are likely to have a cerebral vascular malformation. AVMs, high-flow pial fistulae, and telangiectasias are most common; cavernous malformations, venous angiomas and vein of Galen malformations also occur, but less commonly.

Screening should begin with MRI and MR angiography (MRA) of the brain, although cerebral angiography is most sensitive. Angiography every 5 years with interim surveillance is recommended. MRI is the best procedure for patients with known AVMs.

Treatment

As with most of the neurocutaneous syndromes, treatment of HHT is limited to the management of complications. Because many of the neurological complications of the disease arise secondary to a pulmonary AVF, resection or embolization of the fistula is essential. Treatment of cerebral AVMs is embolization, excision, or radiosurgery. Periodic transfusion and chronic iron administration may be necessary. To reduce risk of brain abscess in cases of undiagnosed pulmonary AVM, antibiotic prophylaxis is a recommendation prior to dental procedures (Faughnan et al., 2011).

Cutaneous Features

The skin findings are distinctive and in fact are the only constant feature of HI. Hypopigmented whorls, streaks, and patches are present at birth and tend to follow Blaschko lines (Fig. 65.18), pathways demarcating embryonic skin development. In HI, the hypopigmented skin lesions are usually multiple, involve several body segments, and may be unilateral or bilateral. They may be observable at birth but commonly develop in infancy, depending on the degree of skin pigmentation. Woods lamp examination may enable detection of hypopigmented lesions. The degree or distribution of skin depigmentation does not appear to correlate with either the severity of neurological symptoms or associated organ pathology. The hypopigmented lesions follow Blaschko lines in two-thirds of patients and are patchy in others. Other skin findings in patients with HI include café-au-lait spots, cutis marmorata, aplasia cutis, nevus of Ota, trichorrhexis, focal hypertrichosis, and nail dystrophy. Electron microscopy of the hypopigmented lesions consistently shows a marked reduction of melanocytes (Cavallari et al., 1996). In the proximity of preserved melanocytes, the basal keratinocytes contain a nearly normal content of melanosomes. Depigmented areas contain an increased number of Langerhans cells.

Fig. 65.18 Characteristic swirling pigmentation of the trunk of a 4-month-old infant with hypomelanosis of Ito. This patient also had seizures and cataracts.

Many different cytogenetic anomalies occur in HI. Most patients are mosaic for aneuploidy or unbalanced translocations, with two or more chromosomally distinct cell lines either within the same tissue or between tissues. Genetic alterations in HI include ring chromosome 22, mosaic trisomy 18, 18/X translocation, and others. Mosaicism for sex chromosome aneuploidy also occurs. Many individuals have normal lymphocyte karyotypes, but it is important to recognize that mosaicism may be tissue specific, so karyotype abnormalities may be demonstrable in fibroblasts but not in lymphocytes.

Neurological Features

The frequency of neurological abnormalities in patients with typical skin lesions ranges from 50% to 80% (Nehal et al., 1996). Seizures and mental retardation are the most common neurological abnormalities. Approximately half of patients with HI have seizures, usually with onset in the first year of life. Focal seizures are most common.

Macrocephaly is more common than microcephaly. Generalized cerebral or cerebellar hypoplasia is the most common abnormality on imaging. Severe cortical neuronal migration anomalies, hemimegalencephaly, and lissencephaly occur as well. Hemimegalencephaly may be ipsilateral or contralateral to the cutaneous hypopigmentation. Extensive periventricular white-matter lesions are another common finding. Small periventricular cysts and gray-matter heterotopias occur as well. About a third of patients with HI have normal cranial MRI studies.

Systemic Features

Some 50% to 70% of patients with HI have noncutaneous defects. Ocular findings include microphthalmia, heterochromia iridis, dacryostenosis, pannus, corneal opacities, cataract, optic atrophy, retinal detachment, and pigmentation anomalies of the retina. The most common musculoskeletal anomaly is hemihypertrophy, but other anomalies include short stature, pectus carinatum and excavatum, cleft palate, butterfly vertebrae, scoliosis, and clinodactyly and polysyndactyly. Dental anomalies are frequent, including conical or hypoplastic teeth, hypoplastic dental enamel, and cleft lip and palate. Cardiac defects include tetralogy of Fallot, pulmonary stenosis, and septal defects. Disorders of endocrine and renal development occur infrequently.

Cutaneous Features

The skin manifestations are characteristic. Skin abnormalities progress in stages any time from the newborn period to adulthood. The duration of each stage is variable and may overlap with other stages. The lesions typically evolve from blister (stage 1) to verrucous (stage 2) to linear and pigmented (stage 3) and finally to atrophic and hypopigmented (stage 4). Skin lesions develop along Blaschko lines. The blister or bullous stage often presents in the neonatal period and is often evaluated as an infectious process. Verrucous transformation is most typical during infancy, and abnormalities of the nails and teeth as they erupt become notable. The hyperpigmented stage is prominent in childhood and adulthood but begins to fade in the second or third decade. The hypopigmented or atretic stage may demonstrate loss of normal hair and subcutaneous structures in addition to or aside from changes in coloration. Not all stages occur in all individuals, especially the hypopigmented stage.

Abnormalities of hair include alopecia in areas that may have been previously affected or unaffected by skin pigmentation changes. Scalp hair may be thin or coarse. Abnormalities of eyebrows may be present as well. Nails may be brittle or demonstrate pits; these findings may wax and wane and raise concern for fungal infection. Tooth abnormalities may include abnormal shape or malpositioning.

IP carries an increased risk of retinal detachment. This is most likely to occur in early childhood and is rare after 6 years of age. Dilated funduscopic examination demonstrates retinal neovascularization as a precursor to detachment. Frequent surveillance ophthalmological examination is important, especially early in life, and may be helpful in making the diagnosis in at-risk family members not otherwise symptomatic.

Neurological Features

Neurological abnormalities have been overestimated in the past, and the incidence appears less with laboratory confirmation available. Seizures occur more frequently in this population. Most affected females have normal intelligence. Affected males are more likely to have developmental delay. Neurological abnormalities are more likely to occur in individuals with ocular abnormalities. Some demonstrate cerebral or cerebellar atrophy.

Genetics

Transmission is X-linked dominant, and nuclear factor kappa B (NF-κB) essential modulator (NEMO) is the causative gene. Deletion in exons 4 to 10 is the responsible mutation in 80% to 90% of patients (Nelson, 2006). This protein is involved in prevention of apoptosis. The mutation is expected to be lethal in males; however, males with somatic mosaicism or an additional X chromosome, as in Klinefelter syndrome, have survived. These individuals demonstrate immunodeficiency and ectodermal dysplasia rather than the characteristic skin findings described.

Cutaneous Features

Telangiectasias typically do not develop until age 3 to 6 years, well after the onset of ataxia. Two other dermatological features of AT that may be overlooked are hypertrichosis and occasional gray hairs. Hypertrichosis is noticeable particularly over the forearms. These often-overlooked features in the context of a child with slowly progressive ataxia provide clues to the correct diagnosis. Progeric changes such as poikiloderma, loss of subcutaneous fat, and sclerosis also have been associated. Abnormal radiosensitivity may underlie reports of basal cell carcinomas in young adults. Cutaneous granulomas, commonly associated with immunodeficiency states such as severe combined immunodeficiency and X-linked hypogammaglobulinemia, may appear as the initial cutaneous manifestation of AT.

Neurological Features

Ataxia, the first manifestation of AT, appears when the child learns to walk in the second year of life. Truncal ataxia predominates early in the course of the disorder, affecting sitting, balance, and gait. Muscle strength is normal, and attainment of early gross motor milestones is usually on time. The ataxia is slowly progressive, and children typically require a wheelchair by the age of 12 years. As the child matures, limb ataxia, intention tremor, and segmental myoclonus become apparent. Choreoathetosis may be difficult to distinguish from dysmetria and intention tremor, but it may dominate the clinical picture in older children. At times, the choreoathetosis may resemble segmental myoclonus of the limbs or trunk. Progressive dystonia of the fingers may appear in the second and third decades of life. Axial muscles are affected, and a stooped posture gradually develops. Progressive dysarthria is present. (See also Chapter 72.)

Abnormal eye movements are nearly universal in children with AT. Voluntary ocular motility is impaired; nystagmus and apraxias of voluntary gaze such as disorders of smooth pursuit and limitation of upgaze are the most common abnormalities. Oculomotor apraxia may precede appearance of the telangiectasias but is often misidentified as an attention-seeking behavior. Strabismus is seen in many young children with AT, but it is often transitory and does not warrant corrective surgery.

In adult patients with AT, the neurological features include progressive distal muscular atrophy and fasciculations, with relative preservation of proximal strength. The gradual loss of vibration and position sense indicates involvement of the spinal cord dorsal columns, and neuropathological and electrophysiological studies reveal a primarily axonal peripheral polyneuropathy.

Serial brain imaging in older children and adults shows nonprogressive cerebellar atrophy. Autopsy studies confirm the radiographical impression of cerebellar degeneration, with reduced numbers of Purkinje cells, granular and basket cells of the cortex, and neurons in the nuclei of the vermis. Degenerative changes are more extensive in adults, involving the substantia nigra, brainstem nuclei, and spinal cord. Relative sparing of the cerebral cortex decreases significant neuropsychological deficits.

Immunodeficiency and Cancer Risk

Roughly 10% to 15% of patients with AT develop a lymphoid malignancy by early adulthood. T-cell malignancies are more common than B-cell tumors, although both are more frequent than in the general population. This increased risk of T-cell tumors may be due to the increase in chromosomal rearrangement observed in T lymphocytes from patients with AT. T-cell tumors may occur at any age, whereas B-cell lymphomas tend to arise in older children. AT is in a family of disorders (including Nijmegen breakage syndrome, Bloom syndrome, and Fanconi anemia) characterized by specific cellular defects in response to deoxyribonucleic acid (DNA)-damaging agents.

Other tumor types reported in association with AT include dysgerminoma, gastric carcinoma, liver carcinoma, retinoblastoma, and pancreatic carcinoma. In fact, nonlymphoid tumors, primarily carcinomas, represent approximately 20% of all malignancies in patients with AT. Cerebellar astrocytoma, medulloblastoma, and glioma also have been linked to AT in case reports.

Frequent sinopulmonary infections are another characteristic of AT. A third of patients have a potentially severe immune deficiency. Recurrent or chronic sinusitis, bronchitis, pneumonia, and chronic progressive bronchiectasis were frequent causes of death in previous years but now usually respond to antibiotic treatment. The thymus gland is often small or absent on chest roentgenography, and at autopsy may be only rudimentary.

Laboratory Diagnosis

Useful laboratory tests in the diagnosis of AT include serum α-fetoprotein, immunoglobulins, and cellular radiosensitivity tests. Nearly all patients with AT have an elevated α-fetoprotein level, which is utilized as a screening diagnostic test. Approximately 80% have decreased serum immunoglobulin (Ig)A, IgE, or IgG, especially the IgG2 subclass. Characteristic cellular features are reduced lifespan in culture, cytoskeletal abnormalities, chromosomal instability, hypersensitivity to ionizing radiation and radiomimetic agents, defective radiation-induced checkpoints at the G1, S, and G2 phases of the cell cycle, and defects in signal transduction pathways (Rotman and Shiloh, 1997).

The gene associated with AT (ATM) is a large gene located at chromosome 11q22-23, and more than 100 ATM mutations occur widespread throughout the ATM gene. Although the function of the ATM gene product is not clear, it belongs to a family of large proteins involved in cell cycle progression and checkpoint response to DNA damage. One postulation is that oxidative stress specifically activates ATM by initiating signal transduction pathways responsible for protecting cells from such insults. Thus, the production of reactive oxygen species by ionizing radiation may play an important role in mutagenesis in cells with absent or abnormal ATM.

The high risk of malignancy in AT underscores the importance of early diagnosis in affected individuals and subsequent routine surveillance for leukemia and lymphoma. Treatment of the neurological deficits is symptomatic at present. Whether neuroprotective medications or medications that modulate neuronal growth factors can slow neurodegeneration in AT is unknown. Treatment options include vitamin E, α-lipoic acid, and folic acid for their theoretical reduction in chromosomal breaks and subsequent translocations or inversions. Genetic counseling and prenatal diagnosis are available.

Cutaneous Features

Epidermal nevi are linear or patchy slightly raised lesions that typically present at birth but may appear first in early childhood. The most common location is on the head or neck. Only 16% of congenital nevi subsequently enlarge, compared with 65% of nevi arising after birth. Nevi on the head and neck rarely enlarge, whereas more than half of lesions elsewhere extend beyond their original boundaries.

Most nevi contain more than one tissue type, complicating dermatological classification; the nevus name typically reflects the predominant tissue. Verrucous nevi are the most common type.

Neurological Features

Neurological involvement is variable but more likely when other extracutaneous disease is present. The location of the nevus appears to correlate with the likelihood of neurological symptoms, with neurological complications of ENS most often occurring in the setting of an epidermal nevus on the face or scalp. Cognitive deficits are common, and seizures occur in more than half of those affected. Usually ipsilateral to the nevus, focal epileptiform discharges and focal slowing are the most common EEG abnormalities. Infantile spasms with hypsarrhythmia may occur. Other neurological symptoms include cranial nerve palsies, hemiparesis (especially in patients with hemimegalencephaly), microcephaly, and behavior problems. Spina bifida and encephaloceles rarely occur.

Cerebrovascular anomalies occur in approximately 10% of patients with ENS. Intracranial blood vessels may be dysplastic, dilated, or occluded. A few patients have had AVMs and aneurysms. Ischemia or hemorrhage from intracranial blood vessel anomalies may result in porencephaly, infarctions, and dystrophic calcification.

Other Features

Tumors occur with moderate frequency in association with ENS. The nevus itself may undergo malignant transformation, often into a basal cell carcinoma. Extracutaneous tumors have included astrocytomas, Wilms tumors, rhabdomyosarcomas, and gastrointestinal carcinomas, among others.

Skeletal abnormalities are quite frequent but often secondary to neurological dysfunction that alters skeletal development. Certain skeletal anomalies may be a primary part of ENS, such as abnormal vertebrae. Limb anomalies include clinodactyly, limb reduction defects, syndactyly, polydactyly, bifid thumbs, and talipes equinovarus.

Half of patients with ENS have ocular abnormalities such as colobomas. Disorders of globe growth include either microphthalmia or macrophthalmia. Retinal lesions such as scarring, degeneration, and detachment may occur. Strabismus and lipodermoid lesions of the conjunctivae are more frequent but less serious findings.

Approximately 10% of patients with ENS have cardiovascular and genitourinary malformations. Single reports describe hypoplastic left-sided heart, ventricular septal defect, coarctation of the aorta, pulmonic stenosis, patent ductus arteriosus, and dilated pulmonary artery. Horseshoe kidney, cystic kidneys, duplicated collecting system, and ureteropelvic junction obstruction also occur.

Neuroimaging

Megalencephaly ipsilateral to the epidermal nevus is the most frequent finding on neuroimaging, but bilateral involvement is common also. In some patients, megalencephaly results from asymmetrical growth of the skull, with the brain being of normal size. MRI of the skull may show a widened diploic space. Often, enlargement of the calvarium and the ipsilateral cerebral hemisphere are present together. In addition, several types of cerebral dysplasia are associated with ENS, also primarily ipsilateral to the epidermal nevus. Focal pachygyria is the most common type of cortical dysplasia in ENS. The surface of the affected hemisphere may be smooth, the cortical mantle thickened, and the adjacent white matter abnormal.

Cutaneous Features

The characteristic lesions are dark to light brown hairy nevi present at birth (Fig. 65.19). Multiple small nevi (satellite nevi) usually are present around one giant nevus that most commonly appears on the lower trunk and perineal area (swimming trunk nevus). A giant nevus is absent in 34% of patients with NCM. Approximately one-third of patients have a large nevus over the upper back (cape nevus). The giant nevi may fade over time, but satellite nevi continue to appear during the first few years of life.

Fig. 65.19 Large, dark, hairy nevus covering most of the back of an infant with neurocutaneous melanosis.

Diagnostic criteria for NCM have been suggested: (1) large or multiple (three or more) congenital nevi (large is ≥ 20 cm in an adult, 9 cm on the scalp of an infant, or 6 cm on the body of an infant); (2) no evidence of cutaneous melanoma except in patients in whom the examined portions of the meningeal lesions are benign; and (3) no evidence of meningeal melanoma except in patients in whom the examined areas of the cutaneous lesions are benign. Some authors argue that a definitive diagnosis of NCM requires histological confirmation of the CNS lesions. However, in the context of the typical melanocytic cutaneous nevi and characteristic neuroimaging findings, leptomeningeal or brain biopsy is unnecessary.

Biopsy of a congenital nevus reveals extension of the nevus cells into the deep dermis or even the subcutis between collagen bundles and around nerves, hair follicles, and blood vessels. Nevus cells tend to form cords or nests. Sheets of nevomelanocytes in the dermis may display a few mitoses and large atypical cells positive for S100 and HMB45 antibodies and formaldehyde-induced green-specific fluorescence. The occurrence of atypical mitoses in the dermis may constitute an early stage of malignant melanoma (Sasaki et al., 1996). The greatest risks in NCM are the high incidence of malignant transformation of melanotic cells and spinal and intracranial pathology.

Neurological Features

Neurological symptoms may result from leptomeningeal melanosis, intracranial melanoma, or intracerebral or subarachnoid hemorrhage. Malformations of the vertebral column, spine, and brain also may impair neurological function. The median age of neurological complications is 2 years, but infants may be affected (DeDavid et al., 1996). Leptomeningeal melanosis is probably the most common cause of neurological symptoms, especially in children. This tends to occur at the base of the brain along the interpeduncular fossa, ventral brainstem, upper cervical cord, and ventral surface of the lumbosacral cord. Marked leptomeningeal melanosis (Fig. 65.20) is present in the vast majority of patients with NCM and associated with interruption of cerebrospinal fluid (CSF) flow. This leads to hydrocephalus and increased intracranial pressure with typical symptoms of irritability, vomiting, seizures, and papilledema. In infants, symptoms may include rapidly increasing head circumference or tense anterior fontanel. Cranial nerve deficits such as limitation of upgaze and lateral gaze are common. Myelopathy occurs when leptomeningeal proliferation affects the spinal cord or spinal nerves.

Fig. 65.20 Leptomeningeal melanosis at autopsy in a patient with neurocutaneous melanosis.

The likelihood of symptomatic neurological involvement correlates with location of large nevi. Large congenital melanocytic nevi occur on the back in nearly 80% of patients. In one series, all 33 patients with neurological symptoms had a nevus over the back, whereas none of 26 patients with nevi restricted to the limbs had neurological abnormalities. Patients occur with leptomeningeal melanosis confirmed by biopsy and CNS involvement but without skin lesions.

Laboratory Findings

CSF from patients with neurological symptoms may show a mild pleocytosis and elevated pressure and protein. CSF cytopathology shows numerous round cells with abundant cytoplasm and ovoid nuclei, and light brown cytoplasmic granules (presumably melanin) may be seen. The most characteristic histological feature is the presence of numerous irregular fingers projecting from the cell body, which may aid in diagnosis of NCM.

Neuroimaging

Approximately half of neurologically asymptomatic children with NCM have abnormal cranial neuroimaging study results. Cranial MRI demonstrates lesions with T1 shortening in the cerebellum, in the anterior temporal lobe (especially the amygdala), and along the basilar meninges (Fig. 65.21). Some of these lesions also show T2 shortening. The pons, medulla, thalami, and base of the frontal lobe often are affected. Gadolinium-enhanced MRIs rarely may show enhancement of the pia-arachnoid. In one study, all five children with neurological symptoms of increased intracranial pressure showed leptomeningeal thickening and enhancement. Conversely, asymptomatic children never showed leptomeningeal thickening. Inferior vermian hypoplasia and Dandy-Walker malformation have been reported. Spinal MRI study results are usually normal.

Fig. 65.21 T1-weighted cranial magnetic resonance imaging scan showing leptomeningeal melanosis over the cerebellum (arrow) and focal melanosis or melanoma in the temporal lobe (arrowhead).

It may be difficult to distinguish radiological evidence of CNS melanoma from benign melanin deposits. Serial imaging studies are the best way to follow clinically suspect MRI lesions. Certain neuroimaging findings help distinguish benign intracranial melanosis from melanoma; necrosis, perilesional edema, contrast enhancement, and hemorrhage are features of melanoma. Unfortunately, melanoma may not exhibit any of these findings until late in its course when metastasis is likely to have already occurred.

Neurovascular Features

There is a risk of aneurysms, and the most commonly affected intracranial vessel is the internal carotid artery, typically in or just beyond the cavernous sinus. Rupture of the aneurysm can occur spontaneously or during vigorous activity. Rupture within the cavernous sinus may create a carotid-cavernous fistula. Less often, the aneurysm occurs in other intracranial arteries and presents with subarachnoid hemorrhage. Most individuals become symptomatic in early adulthood, but some begin in childhood and adolescence.

Some patients develop a fistula after minor head trauma, but most occur spontaneously and even without an aneurysm. Clinical features of carotid-cavernous fistula include proptosis, chemosis, diplopia, and pulsatile tinnitus. The vascular fragility of type IV EDS makes both standard angiography and intravascular occlusion of the fistula difficult.

Arterial dissection occurs in both intracranial and extracranial arteries, and the initial features depend primarily on which artery is affected. One patient with a vertebral dissection developed a painful pulsatile mass of the neck. Dissection of an intrathoracic artery secondarily can occlude cervical vessels, and distal embolism from a dissection can cause cerebral infarction. Surgery is difficult because the arteries are friable and difficult to suture, and handling the tissue leads to tears of the artery or separation of the arterial layers. EDS IV should be considered in children and young adults with arterial dissection.

Neurological Features

Personality changes and decline in school performance may be the earliest neurological manifestations of this syndrome. Progressive loss of cognitive function typically begins in childhood, but some patients remain intellectually normal for many years. EEG shows nonspecific characteristics of metabolic encephalopathy such as slowing. Seizures may occur. Ataxia with gait disturbance, dysmetria, nystagmus, and dysarthria are common. Psychosis with auditory hallucinations, paranoid ideation, and catatonia occur rarely, but examination for cataracts and tendon xanthomas should be included in the evaluation of patients with new-onset psychosis. Parkinsonism may be the only neurological symptom. Cranial MRI typically shows involvement of the dentate nuclei (Gallus et al., 2006). Other findings include cerebral and cerebellar atrophy and diffusely abnormal white matter, presumably reflecting sterol infiltration with demyelination. Focal lesions of the cerebral white matter and globus pallidus are sometimes demonstrable on MRI.

Peripheral neuropathy is a prominent feature of CTX, with signs of pes cavus, areflexia, and loss of vibration perception. Sural nerve biopsy may show reduced densities of both myelinated and unmyelinated axons, and teased fibers show axonal regeneration and remyelination. Large-diameter myelinated nerve fibers particularly are affected. Schwann cells contain foamy macrophages and lipid droplets. Short-latency somatosensory evoked potentials may show prolonged central conduction times with tibial nerve stimulation, but normal conduction velocities with median nerve stimulation. Brainstem auditory evoked potentials and visual evoked potentials are abnormal in approximately half of patients studied. These electrophysiological parameters correlate with the ratio of serum cholestanol to cholesterol concentration and may improve with treatment with CDCA.

Xanthomas

The Achilles tendon is the most common site of tendon xanthomas, but the quadriceps, triceps, and finger extensor tendons also show xanthomatous involvement. Tendon xanthomas usually appear after the age of 20 years but may occur earlier. A substantial number of patients never develop xanthomas. Compared with xanthomas found in patients with familial hypercholesterolemia or hyperlipoproteinemia, these xanthomas appear similar grossly but contain high amounts of cholestanol and little cholesterol. The presence of early-onset cataracts, progressive dementia, and tendon xanthomas is pathognomonic of CTX syndrome. The differential diagnosis includes Marinesco-Sjögren syndrome multiple sclerosis, hereditary spastic paraparesis, olivopontocerebellar atrophy, and spinocerebellar degeneration.

Other Clinical Features

Onset of cataracts by age 10 years and diarrhea are characteristic of CTX. Cataracts can be bilateral and asymptomatic. Osteoporosis may lead to an increased risk of skeletal and vertebral fractures. Large paranasal sinuses occur in association with CTX. Renal disorders reported in patients with CTX include nephrolithiasis, nephrocalcinosis, and renal tubular acidosis.

Treatment

Treatment of CTX focuses on lowering cholestanol levels, primarily with CDCA. Other lipid-lowering agents such as cholestyramine or β-hydroxymethylglutarate-CoA inhibitors are not as effective alone, but the latter in combination with CDCA constitutes the most effective treatment. Long-term therapy can lead to striking improvement in neurological function, resolution of peripheral and intracranial xanthomas, and improvement of EEG and peripheral nerve conduction abnormalities as well as visual and somatosensory evoked potentials. It may be that early treatment is required, which ideally would begin before onset of clinical symptoms in individuals with a family history of CTX. The possibility that early treatment may improve the neurological symptoms of CTX underscores the importance of careful screening and genetic counseling of asymptomatic relatives of patients with this disorder. Treatment with cholic acid is also an option and may produce fewer side effects.

Clinical Features

Progressive facial hemiatrophy is characterized by unilateral atrophy of the skin, subcutaneous tissue, and adjacent bone (Fig. 65.24). The atrophic area is characteristically oblong or linear and sometimes begins as a raised erythematous lesion. The lesion sometimes begins after trauma to the area. The atrophy eventually stabilizes, leaving facial disfigurement.

Fig. 65.24 Unilateral atrophy of the skin and subcutaneous tissue (arrows) in a young boy with progressive hemifacial atrophy.

Epilepsy is probably the most common neurological problem associated with progressive facial hemiatrophy. Some patients develop a usually mild hemiparesis. Less common neurological features include cognitive impairment, cranial neuropathy, or even brainstem signs. Cerebral calcifications and white-matter lesions are common neuroimaging findings (Fig. 65.25).

Fig. 65.25 Computed tomographic scan revealing right frontal encephalopathy and calcification in a patient with progressive facial hemiatrophy.

Understanding of the cause of progressive facial hemiatrophy and related disorders is poor. Proposed mechanisms (e.g., cortical dysgenesis, dysfunction of the sympathetic nervous system, chronic localized meningoencephalitis) are inadequate to explain all of the clinical features.

Cutaneous Features

Connective tissue abnormalities are a major feature of kinky hair syndrome and include loose skin, hyperextensible joints, bladder diverticula, and skeletal anomalies. The enzyme, lysyl oxidase, has copper-dependent steps that are impaired in the establishment of elastin and collagen cross-linking. Keratin cross-linking and melanin production also depend on copper, and copper deficiency leads to characteristic cutaneous features. The hair is light colored and brittle and on microscopic examination (Fig. 65.26) appears as pili torti (twisted hair) and trichorrhexis nodosa (complete or incomplete fractures of the hair shafts at regular intervals). Trichorrhexis nodosa is not pathognomonic of kinky hair syndrome; it also occurs in biotinidase deficiency and argininosuccinic aciduria. Skin may be diffusely hypopigmented or normal.

Fig. 65.26 A, Hair shaft from a patient with kinky hair disease. B, Normal hair.

Other Clinical Features

Kinky hair syndrome covers a clinical continuum from nearly normal to the severe classic infantile-onset form (Box 65.5). Newborns may be more prone to cephalohematomas or spontaneous bone fractures and develop temperature instability, diarrhea, and failure to thrive in early infancy. Sympathetic adrenergic dysfunction, including hypotension, hypothermia, anorexia, and somnolence, is attributable to the impairment of dopamine β-hydroxylase that requires copper for the synthesis of norepinephrine and other neurotransmitters.

One mild allelic variant of kinky hair syndrome is the occipital horn syndrome (also known as type IX Ehlers-Danlos or X-linked cutis laxa) in which connective tissue symptoms predominate, and cognitive and motor involvement is variable. This disorder is named for the characteristic exostoses (“orbital horns”) resulting from calcification of the trapezius and sternocleidomastoid muscles at their attachment to the occipital skull.

Neurological Features

In early-onset cases, hypotonia develops in the first few weeks to months and gradually develops into spastic quadriparesis with clenched fists, opisthotonus, and scissoring. Seizures are a prominent feature of this disorder, appearing by age 2 to 3 months, and may be partial or generalized. Myoclonic seizures are especially common. Developmental delay and regression appear between ages 4 to 6 months in the classic form.

Intracranial and extracranial blood vessels may be tortuous, kinked, and dilated (Kim and Suh, 1997); the cause may be defective or deficient elastin fibers in the walls of these blood vessels. Neuropathological studies show diffuse neuronal loss and gliosis that is particularly prominent in the cerebrum and cerebellum. Microscopic findings include abnormal dendritic arborization in the cerebellar cortex.

Neuroimaging

Cranial MRI and CT studies show diffuse cerebral atrophy with secondary subdural fluid collections, which may be large enough to cause mild compression of the ventricular system. The presence of large subdural fluid collections and metaphyseal fractures in an infant can lead to the erroneous diagnosis of child abuse. In older children, MRI studies typically reveal diffuse white-matter signal abnormalities suggestive of demyelination and gliosis, whereas in infants the white matter may be only focally affected. Diffuse brain atrophy, subdural effusions or hemorrhages, infarction, or edema also may be present. Routine MRI shows tortuous intracranial blood vessels, better seen by MRA or conventional angiography. Skull radiographs show wormian bones.

Genetic Studies

A gene involved in transmembrane copper transport, ATP7A (also referred to as MNK), has been implicated in both kinky hair disease and occipital horn syndrome. ATP7A maps to Xq13.3 and is highly homologous to the gene implicated in Wilson disease. ATP7A mRNA is present in several cell types and organs except liver, which explains the clinical observations that liver does not accumulate excess copper and is largely unaffected in kinky hair syndrome.

Infantile-onset kinky hair syndrome results from extensive mutations of ATP7A (e.g., large deletions, frame-shift mutations), whereas occipital horn syndrome is associated with promoter and splicing efficiency mutations, possibly leading to reduced levels of an otherwise normal protein product. Mutations of the ATP7A gene in the patients with the occipital horn syndrome have been base pair substitutions affecting normal messenger ribonucleic acid (mRNA) splicing (Tumer and Horn, 1997). Copper deficiency impairs the function of multiple enzymes that require copper as a cofactor: tyrosinase, cytochrome C oxidase, dopamine β-hydroxylase, and Cu/Zn superoxide dismutase, among others.

Diagnosis and Treatment

When suspected clinically, low serum copper and ceruloplasmin support the diagnosis. Plasma catecholamine analysis to evaluate for dopamine β-hydroxylase deficiency also may be helpful. Specialized centers can determine intracellular accumulation of copper. The large size of the ATP7A gene and the variety of mutations make detection of a specific genetic defect difficult, unless previously established for a given family. Carrier status is difficult to assess, although prenatal testing for copper content in chorionic villi or cultured amniotic-fluid cells is available.

The focus of treatment approaches is to restore copper to normal levels in brain and other tissues. Careful medical care is particularly important in extending the lifespan. Copper-histidine administered parenterally (subcutaneously) is the most promising treatment, and substantial clinical improvement in a small number of patients has been reported. Undoubtedly, response to copper-histidine treatment partly depends on the specific mutation of ATP7A involved. Such correlations are only now beginning.

Aggressive copper replacement beginning in early infancy may be necessary to significantly improve neurological outcome. Replacement therapy does not appear to help the connective tissue abnormalities in kinky hair syndrome. Preservation of some residual activity of adenosine triphosphatase (ATPase) may be required for significant clinical efficacy from copper replacement treatment, since it did not normalize neurological outcome in two children with the Q724H splicing mutation, which yields a nonfunctioning ATPase.

Complementation Groups

Complementation analysis has been important in understanding the genetic basis of XP. If two particular cell types with different metabolic abnormalities are fused, the cell produced may function normally. These two cell types have different complementation groups and presumably have a different genetic basis. In XP, eight complementation groups have been identified (XP-A through XP-G and a variant group). Although some general genotype-phenotype correlations among these complementation groups exist, considerable clinical overlap exists between them (Copeland et al., 1997). Complementation groups XP-A, XP-C, and XP-D are the most common. Despite the few individuals with XP-B available, cloning of the responsible gene (XPBC) was successful. The XPBC gene is located on chromosome 2q21 and encodes a protein that is a component of the basal transcription factor, TFIIH/BTF2. This protein helps regulate both DNA transcription initiation and nucleotide excision repair.

Mutations in the XPCC gene, located on chromosome 3p25.1, cause XP-C. Patients with XP-C generally do not have prominent neurological dysfunction. The XPCC gene codes for a protein involved in global genome repair, but full understanding of its exact role is lacking. Complementation group D is the third most common complementation group. Characteristic of the abnormalities are mild to severe neurological dysfunction. The gene associated with XP-D is at chromosome 9q13. The gene product in XP-D is a component of TFFIIH/BTF2, as is XP-B, and accordingly, XP-B and XP-D have similar clinical features. Complementation group E (XP-E) is uncommon and associated with mild neurological and cutaneous symptoms. The precise localization and function of the XP-E gene of its associated protein, XPEC, has not been determined. No neurological symptoms occur in patients from complementation groups F or G or the variant group.

Related Syndromes

De Sanctis-Cacchione syndrome is a variant of XP in which patients have severe and progressive cognitive deficiency, dwarfism, and gonadal hypoplasia. Trichothiodystrophy and similar syndromes link to XP complementation groups B and D. Patients with trichothiodystrophy have brittle hair and nails because of sulfur-deficient matrix proteins, ichthyosis, and mental retardation. Patients with photosensitivity (P), ichthyosis (I), brittle hair (B), impaired intelligence (I), possibly decreased fertility (D), and short stature (S) fit into the PIBI(D)S syndrome. DNA repair studies of patients with trichothiodystrophy demonstrate reduced ultraviolet-induced DNA repair synthesis, and one patient assigned to XP-D. A variant of trichothiodystrophy is Tay syndrome, in which dysplastic nails and lack of subcutaneous fatty tissue are characteristic. Low birth weight, short stature, and mental retardation are also features of this disorder.

Cockayne syndrome combines cutaneous sunlight sensitivity, dwarfism, mental retardation, microcephaly, dental caries, peripheral neuropathy, and sensorineural deafness. The combined features of XP and Cockayne syndrome within complementation groups XP-B, XP-D, and XP-G indicate that there is considerable clinical heterogeneity and phenotypical overlap within the subsets of these complementation groups. Trichothiodystrophy may present with congenital ichthyosis (collodion baby) but persistent ichthyosis of the scalp, trunk, palms, and soles are the main features.

Cutaneous and Ocular Features

Cutaneous and ocular features of XP result primarily from ultraviolet light exposure (Box 65.6). The onset of cutaneous symptoms in XP is usually early; the median age of onset is 1 to 2 years, typically freckling or erythema and bullae formation after sun exposure. Nearly half of patients develop malignant skin lesions, with the median age of first skin neoplasm being only 8 years. The estimated incidence of basal cell carcinoma or squamous cell carcinoma is 4800 times greater than that observed for the general U.S. population. Light-skinned infants develop erythema and bullae after even brief sun exposure. Sun exposure also induces prominent macule formation (freckling or solar lentigenes), which over time enlarge and coalesce. Telangiectasias and epidermal and dermal atrophy develop in later years, and the skin becomes dry. Actinic keratosis, angiomas, keratoacanthomas, and fibromas also occur. Ocular tissues are particularly susceptible to ultraviolet damage. Keratitis and conjunctivitis with photophobia are common in patients with XP. Atrophy of the eyelids leads to loss of lashes and ectropion or entropion. Neoplasms of the eyelid, conjunctiva, and cornea include squamous cell carcinoma, epithelioma and basal cell carcinoma, and melanoma. The tip of the tongue, gingiva, and palate also are susceptible to sun exposure.

Most of what is known about the neurological features in XP comes from studies of Japanese patients with XP-A. Research indicates that the severity of neurological symptoms correlates with particular mutations within the XPAC gene, and presumably this is true in other types of XP (Maeda et al., 1995). The principal neurological symptoms in XP-A are progressive dementia, sensorineural hearing loss, tremor, choreoathetosis, and ataxia. Progressive dementia begins in patients with XP-A during the preschool years, and IQ scores after 10 years of age are invariably less than 50. Sensorineural hearing loss has a later onset, but most patients older than 10 years have hearing impairment. Cerebellar signs develop at approximately the same time as the hearing loss. Microcephaly is present in about half of patients.

EEG studies most often show nonspecific generalized slowing, but focal slow waves and focal spike discharges occasionally occur. Peripheral neuropathy is a prominent feature that may begin in the first decade of life. Deep tendon reflexes are absent in nearly all patients older than 6 years. Motor nerve conduction velocities are normal during the first 3 years of life but slow by 6 years. Similarly, all patients older than 6 years had either absent or prolonged sensory nerve conduction velocities. Electromyography shows a neuropathic pattern with large, prolonged, polyphasic motor unit potentials and incomplete recruitment of motor units. Nerve biopsy may show an age-dependent decrease of myelinated fibers, which was associated with rare acute axonal degeneration, sparse axonal regeneration, rare axonal atrophy, and few onion bulb formations, consistent with a neuropathic process.

Neural tissue lacks exposure to sun-induced DNA damage. Therefore, the cause of neurodegeneration in patients with XP remains unexplained. The high frequency of neurological symptoms in XP-B and XP-D but not in XP-C, XP-D, XP-G, and the variant group supports the notion that one cause of the neurological dysfunction in XP is dysfunction of DNA transcription rather than nucleotide excision repair. Deficits in excision repair may closely link to skin cancer susceptibility. In addition, recent work suggests that in XP, the cause of neurological injury is partly defective repair of lesions produced in nerve cells by reactive oxygen species generated as byproducts of an active oxidative metabolism. Specifically, two major oxidative DNA lesions, 8-oxoguanine and thymine glycol, are excised from DNA in vitro by the same enzyme system responsible for removing pyrimidine dimers and other bulky DNA adducts.

Treatment

Cancer surveillance and avoidance of precipitating factors is the most important aspect of health screening of individuals with XP. Optimism exists for genetic therapy to reduce cancer risk and perhaps improve neurological outcomes. In vitro studies offer hope that eventually, recombinant retroviruses can transfer and stably express the human DNA repair genes in XP cells to correct defective DNA repair (Zeng et al., 1997). Using the recombinant retroviral vector, LXSN, successful transfer of human XP-A, XP-B, and XP-C complementary DNAs (cDNAs) into primary and immortalized fibroblasts obtained from patients with XP-A, XP-B, and XP-C occurred. After transduction, monitoring of the complete correction of DNA repair deficiency and functional expression of the transgenes included ultraviolet survival, unscheduled DNA synthesis, and recovery of RNA synthesis. In a similar study, cloning of XP-F cDNA into a mammalian expression vector plasmid and introduced into group F XP (XP-F) cells. The XP-FR2 cells expressed a high level of XP-F protein and ERCC1 protein. They showed ultraviolet resistance comparable to that in normal human cells and had normal levels of ultraviolet-induced unscheduled DNA synthesis and normal capability to remove DNA adducts. This demonstrates that the nucleotide excision repair defect in XP-F cells is fully corrected by overexpression of XP-F cDNA alone.