Neurofibromatosis 1

Neurofibromatosis 1, or NF-1 (previously known as von Recklinghausen disease), is the most common of the neurocutaneous syndromes and affects about 1 in 3000 individuals. Although usually inherited as an autosomal dominant disorder, up to 50% of cases may be sporadic. Molecular genetic testing for mutations of the NF1 gene is clinically available. The NF1 gene has been localized to chromosome 17q. Neurofibromin, its gene product, acts as a tumor suppressor, and its function is altered in affected patients. Characteristic clinical manifestations include multiple hyperpigmented skin macules (café-au-lait spots), axillary or inguinal freckling, multiple skin neurofibromas, and iris hamartomas (Lisch nodules). Associated abnormalities may include optic gliomas; other CNS tumors of glial or meningeal origin; neurofibromas of spinal or peripheral nerves; pheochromocytoma, macrocephaly, and cognitive impairment; and bony abnormalities. Diagnostic criteria for NF-1 are summarized in Table 15-1.

Table 15-1 Diagnostic Criteria for Neurofibromatosis 1

Multiple café-au-lait spots, the most frequently encountered cutaneous abnormality, are brown hyperpigmented macules with smooth margins, usually most numerous over the trunk (Fig. 15-6, A; and see Chapter 8, Fig. 8-131, A-C). Other abnormalities of cutaneous pigmentation may include axillary or inguinal freckling or extensive areas of hyperpigmentation (Fig. 15-6, B and C). Hyperpigmented skin lesions almost always precede neurologic symptoms and often increase in size and number with advancing age. They are not necessarily present at birth and may be inconspicuous in early childhood, becoming more prominent at puberty. Ninety-seven percent of patients with NF-1 have at least five café-au-lait spots by 20 years of age.

Figure 15-6 Neurofibromatosis 1 (NF-1). Clinical manifestations of cutaneous pigmentary abnormalities. A, Most common are multiple café-au-lait spots over the trunk. B and C, Also seen are axillary freckling and extensive areas of hyperpigmentation.

(Courtesy Michael Sherlock, MD, Lutherville, Md.)

Although multiple café-au-lait spots are a clinical hallmark of NF-1, they may also occur as an autosomal dominant trait unassociated with the other features of neurofibromatosis. Genetic investigations in such families have excluded linkage to the NF1 locus on chromosome 17, indicating a distinctly different genetic association. Multiple café-au-lait spots can be found, as well, in a variety of other conditions (Table 15-2). They are a prominent feature of McCune-Albright syndrome, the additional manifestations of which include skeletal dysplasia and endocrine abnormalities. Those seen in McCune-Albright syndrome are often large and have irregular (“coast of Maine”) margins (see Chapter 8, Fig. 8-131, D), in contrast to the smooth (“coast of California”) borders characteristic of the hyperpigmented lesions of NF-1. Café-au-lait spots also may be encountered in tuberous sclerosis and neurofibromatosis 2 (NF-2) but are seldom prominent. They are present in about 10% of the general population (typically four or less in number) and are not by themselves a sign of disease.

Table 15-2 Conditions Associated with Café-au-lait Lesions

Additional cutaneous manifestations of NF-1 may include extensive plexiform neuromas at the terminal distribution of nerve fibers (Fig. 15-7; and see Chapter 8, Fig. 8-81) or small subcutaneous nodules—neurofibromas—scattered along the course of nerve trunks (Fig. 15-8).

Figure 15-7 Neurofibromatosis 1 (NF-1). Extensive plexiform neurofibroma of the palm.

(Courtesy Michael Sherlock, MD, Lutherville, Md.)

Figure 15-8 Neurofibromatosis 1 (NF-1). Subcutaneous neurofibroma along the course of a nerve trunk.

(Courtesy of Michael Sherlock, MD, Lutherville, Md.)

Pigmented hamartomas of the iris, termed Lisch nodules, are seen in more than 90% of patients with NF-1 who are older than age 6 years and can be found in nearly one third of younger individuals (Fig. 15-9). They do not occur in the normal population. Although these hamartomas are asymptomatic and do not correlate with the extent or severity of other manifestations, they are helpful in establishing the diagnosis.

Figure 15-9 Neurofibromatosis 1 (NF-1). Pigmented hamartomas of the iris (Lisch nodules).

Short stature and macrocephaly are common in patients with NF-1, and skeletal abnormalities are found in 51% (Fig. 15-10). Osseous lesions, if present, usually appear in the first year of life. The characteristic findings include the following:

Figure 15-10 Neurofibromatosis 1 (NF-1). Radiographic manifestations of skeletal abnormalities. A, Severe angular scoliosis and vertebral dysplasia. B, Congenital bowing and pseudarthrosis of the tibia and fibula. C, Scalloping of the posterior margins of the vertebral bodies resulting from dural ectasia.

(Courtesy Department of Radiology, Children’s Hospital of Pittsburgh, Pittsburgh, Pa.)

Patients with NF-1 can be affected with various tumors of the brain, spinal cord, and peripheral nerves, although at much less frequency than in patients with NF-2. Optic nerve glioma is the most common CNS tumor and affects 15% of patients with NF-1, usually occurring by age 3 to 6 years. It often presents as progressive visual loss with optic atrophy and tends to be less aggressive than in patients without NF-1. Ependymomas, meningiomas, brainstem gliomas, and astrocytomas also have been reported.

Magnetic resonance imaging (MRI) scans frequently show areas of increased signal intensity on T₂-weighted images of the globus pallidus, brainstem, or cerebellar white matter (Fig. 15-11). These are commonly termed unidentified bright objects (UBOs) and are believed to represent increased fluid within the myelin associated with dysplastic glial proliferation. UBOs do not appear to correlate with neurologic dysfunction. However, their presence helps confirm the diagnosis of NF-1. Computed tomography (CT) seldom demonstrates corresponding abnormalities.

Figure 15-11 Neurofibromatosis 1 (NF-1). T₂-weighted magnetic resonance imaging (MRI) demonstrates high signal–intensity areas in the region of the globus pallidus bilaterally.

(Courtesy Division of Neuroradiology, University Health Center of Pittsburgh, Pittsburgh, Pa.)

Learning disabilities and behavior problems are common and may affect up to 40% of patients with NF-1. Although their full-scale intelligence quotient is generally lower than that of the general population, severe mental retardation is rare. Approximately 10% of patients with NF-1 have seizures.

A small percentage of patients with NF-1 have dysplasia of the renal or carotid arteries. Renal artery stenosis can cause systemic hypertension, and adult patients with NF-1 may develop pheochromocytoma with concomitant hypertension. Cerebral artery dysplasia can include moyamoya syndrome with abnormal vessels of the circle of Willis, predisposing to cerebral infarction in children and cerebral hemorrhage in adults.

Neurofibromatosis 2

Neurofibromatosis 2, or NF-2 (also known as bilateral acoustic neurofibromatosis), is a distinct genetic disorder characterized by autosomal dominant inheritance of bilateral acoustic neuromas with a penetrance of more than 95%. NF-2 occurs in approximately 1 in 50,000 people. It results from a mutation of the NF2 gene on the long arm of chromosome 22. The NF2 gene product, merlin or schwannomin, serves to suppress tumor formation, and its dysfunction leads to the common occurrence of CNS tumors in patients with NF-2. Most patients eventually develop bilateral acoustic neuromas (vestibular schwannomas).

Symptoms usually first appear in the teens or early twenties, when pressure on the vestibulocochlear or facial nerve complex results in impaired auditory discrimination, hearing loss, tinnitus, unsteadiness, or facial weakness. Presenile lens opacities, found in half the patients examined, may precede the onset of symptoms referable to acoustic neuroma. Other Schwann cell tumors of cranial nerves, spinal roots, or the spinal cord, as well as multiple CNS tumors of meningeal or glial origin, may develop. Cutaneous manifestations such as café-au-lait spots, cutaneous neurofibromas, and axillary or inguinal freckling are less common in NF-2 than in NF-1, and Lisch nodules are not typical. Diagnostic criteria for NF-2 are summarized in Table 15-3.

Table 15-3 Diagnostic Criteria for Neurofibromatosis 2

Tuberous Sclerosis

Tuberous sclerosis (TS) is inherited as an autosomal dominant trait. Two genes appear to cause the disorder: TSC1 located on chromosome 9q and TSC2 on chromosome 16p. Their gene products (hamartin for TSC1 and tuberin for TSC2) have tumor suppressor activity, which is dysfunctional in affected patients. Both genes produce similar phenotypes when expressed. Genetic testing is available and currently detects 60% to 80% of cases. Although 1 in 6000 to 9000 people in the population carry a TS gene, expression is highly variable and full expression of disease is seen in only 1 in 150,000 members of the population. Most carriers have hypopigmented macules (ash-leaf spots) as their only manifestation. Spontaneous mutation appears to account for the majority of newly diagnosed cases, and in up to 2% of patients without a positive family history, the disorder may be the result of germline mosaicism.

The more prominent features of this neurocutaneous disorder include seizures (96%), mental retardation (60%), intracranial calcification (49%), tumors of various organs (including the brain, heart, liver, and kidneys), and cutaneous lesions. Seizures are the most frequent presenting complaint. Clinical expression can be quite variable even among affected members of the same family. Diagnostic criteria are summarized in Table 15-4.

Table 15-4 Diagnostic Criteria for Tuberous Sclerosis

The characteristic skin lesion of tuberous sclerosis is the angiofibroma (adenoma sebaceum). These are seen as erythematous papules distributed over the nose and malar region of the face (Fig. 15-12). Approximately 40% of children with tuberous sclerosis demonstrate these lesions by 3 years of age.

Figure 15-12 Tuberous sclerosis. A, This adolescent boy had adenoma sebaceum in a characteristic malar distribution and chin lesions as well. B, A close-up view of nasal lesions is shown.

Hypomelanotic macules with irregular borders, termed ash-leaf spots, are another common cutaneous manifestation (Fig. 15-13, A and B). These generally appear earlier than adenoma sebaceum and may be present at birth. They are detectable by 2 years of age in more than half of affected children. They resemble vitiligo but differ in that they are not completely devoid of melanin. In fair-skinned infants, these nevi may be demonstrable only under Wood lamp light.

Figure 15-13 Tuberous sclerosis (TS). A, An ash-leaf spot is an oval depigmented nevus with irregular borders. B, This child with TS has numerous hypopigmented macules over his scalp, and the hair growing from these is hypopigmented as well (a phenomenon termed poliosis).

(Courtesy Robin Gehris, MD, Children’s Hospital of Pittsburgh, Pittsburgh, Pa.)

Another valuable cutaneous marker is the shagreen patch, a plaque of thickened skin with a cobblestone or orange-peel texture often seen on the dorsal aspect of the trunk (Fig. 15-14). Histologically, the shagreen patch is a connective tissue nevus.

Figure 15-14 Tuberous sclerosis. Shagreen patch. This plaque of thickened skin with a cobblestone texture is distinctive but is one of the less common cutaneous manifestations.

(Courtesy Michael Sherlock, MD, Lutherville, Md.)

Additional dermatologic manifestations of tuberous sclerosis include periungual fibromas (Fig. 15-15) and macular areas of hyperpigmentation. Recognition of the cutaneous features can suggest an etiologic diagnosis in some patients with mental retardation or seizures. Oral examination may reveal pitting of dental enamel.

Figure 15-15 Tuberous sclerosis. Periungual fibromas. These nodular lesions can occur singly or multiply in the ungual or periungual areas.

(Courtesy Michael Painter, MD, Children’s Hospital of Pittsburgh, Pittsburgh, Pa.)

In patients with tuberous sclerosis, CT scans often demonstrate subependymal nodules seen as intracranial calcifications that appear as multiple scattered areas of increased density adjacent to the walls of the lateral and third ventricles (Fig. 15-16). CT is superior to MRI for demonstration of small calcifications. No relationship has been established between the extent of periventricular calcification and clinical severity as judged by developmental function or seizure frequency. CT may also demonstrate asymptomatic but typical intracranial calcifications in individuals who lack external manifestations of the disorder. This can help identify subclinical cases and improve the accuracy of genetic counseling in affected families.

Figure 15-16 Tuberous sclerosis. This computed tomography (CT) cut through the foramina of Monro shows the multiple periventricular calcific deposits characteristic of this disorder.

(Courtesy Division of Neuroradiology, University Health Center of Pittsburgh, Pittsburgh, Pa.)

The characteristic gross abnormality of the brain in TS is the presence of multiple gliotic nodules (hamartomas) of varying size, which constitute the tubers for which this disorder is named. These are located over the convolutions of the cerebral hemispheres and beneath the ependymal lining of the lateral and third ventricles. Heterotopic nodules of identical structure may be found in the cerebral white matter as well. Although cortical tubers are rarely apparent on CT scans, they are readily identified by MRI studies (Fig. 15-17). Severely affected patients have a greater number of cerebral cortical lesions detected by MRI scans, suggesting that MRI may be useful in predicting eventual clinical severity in young children with newly diagnosed tuberous sclerosis. Tumors may arise from cortical or subependymal tubers, complicating the course of the disease by producing increased intracranial pressure and other symptoms associated with intracranial mass lesions. Up to 80% of patients with tuberous sclerosis develop seizures of variable types that are often difficult to control. Infantile spasms are common and may be the presenting symptom leading to diagnosis. Patients with a history of infantile spasms and those who develop other types of seizures when very young tend to have more severe seizure disorders and poorer cognitive function.

Figure 15-17 Tuberous sclerosis. MRI demonstrates multiple cortical tubers that appear as areas of increased signal intensity in this T₂-weighted image. The signal abnormalities arise predominantly within the white matter subjacent to the tuber.

(Courtesy Division of Neuroradiology, University Health Center of Pittsburgh, Pittsburgh, Pa.)

Subependymal giant cell astrocytomas (SEGAs) (Fig. 15-18) can affect 10% of patients with tuberous sclerosis and are clinically manifested by symptoms of obstructive hydrocephalus. The site of obstruction is often at the level of the foramen of Monro in the lateral ventricles. Such patients may present with signs of increased intracranial pressure (headache, vision changes, and/or papilledema), behavior change, or worsening seizure control.

Figure 15-18 Tuberous sclerosis. CT scan demonstrates a large subependymal astrocytoma, which intermittently obstructed the ventricular system, producing episodic symptoms of increased intracranial pressure.

(Courtesy Division of Neuroradiology, University Health Center of Pittsburgh, Pittsburgh, Pa.)

Visceral lesions associated with tuberous sclerosis include cardiac rhabdomyoma, renal angiomyolipomas, pulmonary lymphangiomyomatosis, and hepatic hamartoma. Cardiac rhabdomyomas occur in up to two thirds of patients and may be multiple. They tend to regress over the first few years of life and are usually asymptomatic, although occasionally an affected newborn may have obstructive congestive heart failure. About three fourths of patients with tuberous sclerosis have renal angiomyolipomas, which are often bilateral and multiple. Most remain clinically silent, but tumors greater than 4 cm in size are more likely to be symptomatic and may cause hematuria or proteinuria. Renal disease is the most common cause of death in adults with the disease and may be manifest as flank pain, hematuria, or retroperitoneal hemorrhage. Renal cysts occur earlier and less often than do angiomyolipomas. Rarely, children with tuberous sclerosis can present in infancy with polycystic kidney disease. Chronic renal failure and malignant transformation of renal tumors are rare. Pulmonary lymphangiomyomatosis affects less than 2% of patients, mostly females, and is rare before the adult years. Symptoms include dyspnea, spontaneous pneumothorax, and hemoptysis. Hepatic hamartoma is clinically insignificant.

Sturge-Weber Syndrome

The cardinal manifestations of Sturge-Weber syndrome are as follows:

The port-wine stain (Fig. 15-19) is usually present at birth and consists of a pink-to-purple macular cutaneous vascular malformation. Only patients with lesions involving the cutaneous distribution of the ophthalmic division of the trigeminal nerve (i.e., forehead and upper eyelid) are at risk for associated neuro-ocular complications (Fig. 15-20). Repeated ophthalmologic and CT or MRI examinations are indicated only in this high-risk group, which has a 10% to 20% incidence of associated intracranial angiomas.

Figure 15-19 Sturge-Weber syndrome. A nonelevated purple cutaneous vascular malformation, often termed a port-wine stain, is seen in a trigeminal distribution, including the ophthalmic division.

Figure 15-20 Sturge-Weber syndrome. Cutaneous distribution of the division of the trigeminal nerve. Only patients with facial port-wine stains that involve the ophthalmic division are at risk for associated neuro-ocular symptoms.

The coincidence of seizures and a facial vascular nevus should suggest the diagnosis of Sturge-Weber syndrome, which can be confirmed by CT scan (Fig. 15-21) or MRI. These scans may be normal at birth but subsequently show areas of gyriform contrast enhancement corresponding to the leptomeningeal angiomatosis. Serial examinations often demonstrate progressive ipsilateral cerebral atrophy. Additional findings may include serpiginous calcifications of brain parenchyma underlying vascular malformations of the pia. These intracranial calcifications are first seen on CT scan but become evident on plain skull films by the end of the second decade.

Figure 15-21 Sturge-Weber syndrome. Although the CT scan is usually normal at birth, findings such as gyriform contrast enhancement, seen here in the left occipital, temporal, and parietal lobes (A), and associated hemispheric atrophy (B) may be observed as early as 4 months of age. Serpiginous parenchymal calcifications may be found in the older child (C).

(Courtesy Division of Neuroradiology, University Health Center of Pittsburgh, Pittsburgh, Pa.)

Associated ocular abnormalities are often encountered. Buphthalmos (corneal enlargement) or a coloboma may be present at birth, and glaucoma frequently develops in infancy or later childhood (Fig. 15-22). Dilated vessels in the sclera, conjunctiva, and retina are common, and angiomatous malformations of the choroid occasionally occur.

Figure 15-22 Buphthalmos. Enlargement of the cornea of the right eye is evident. This is one of the associated ocular findings in Sturge-Weber syndrome and should prompt urgent evaluation for associated glaucoma.

(From Booth IW, Wozniak ER: Pediatrics, Baltimore, 1984, Williams & Wilkins.)

The estimated incidence of facial cutaneous angioma is 1 in 5000, and the estimated frequency of the complete syndrome is 1 in 30,000. Among patients with the complete syndrome, seizures occur in 90%, and contralateral hemiparesis eventually develops in one third. Early developmental milestones are often normal, but about 50% develop cognitive difficulties ranging from mild to severe. Behavioral problems are common. Patients with refractory epilepsy are more likely to be more severely delayed. Although most cases are sporadic, genetic determination has not been ruled out. No cases of direct transmission from parent to child have been reported, however.

Klippel-Trénaunay Syndrome

Patients with Klippel-Trénaunay syndrome (KTS) are born with a port-wine stain that is usually located over the lateral aspect of one leg. Less often an arm and a leg may be affected. In rare instances more extensive, even bilateral, involvement is seen. The surface lesion is associated with an underlying vascular malformation, which provides an unusually rich blood supply to soft tissue and bony structures that results in hypertrophy (usually hemihypertrophy) and lymphedema (Fig. 15-23, A and B). These features are often evident in the newborn, and progressive enlargement occurs during the first few years. Most cases are sporadic. However, a few cases have been reported to be autosomal dominant.

Figure 15-23 Klippel-Trénaunay syndrome. A, This infant with KTS is unusual in that he has vascular malformations involving both lower extremities, which extend upward over the lateral aspects of the abdominal wall. B, In this view of his feet, one can appreciate a greater degree of hypertrophy on the right.

Ataxia-Telangiectasia

Ataxia-telangiectasia is a multisystem, autosomal recessive degenerative disorder characterized by ataxia, oculocutaneous telangiectasia, immunodeficiency, and a high incidence of neoplasia. The nature of the basic underlying defect is unknown. Affected individuals are extremely sensitive to ionizing radiation and have defective DNA repair mechanisms. Molecular genetic testing for ATM (ataxia telangiectasia mutated), the only gene associated with ataxia-telangiectasia, is clinically available. Ataxia is the usual presenting feature, and the course of the neurologic disturbance is rather stereotypic. Tremors of the head may be seen before 1 year of age, and unsteadiness of gait is evident when the child first walks. Progressive global ataxia and slurred, scanning, dysarthric speech are typical during the early school-age years. Loss of deep tendon reflexes and impairment of position and vibratory sensation are evident by the end of the first decade. Adolescence is marked by choreoathetosis, dystonic posturing, gaze apraxia, and progressive dementia. Nonclassic forms of ataxia-telangiectasia have included adult-onset cases and presentations with early dystonia.

The characteristic cutaneous manifestations of this disorder appear by 6 years of age. Telangiectases first appear on the bulbar conjunctivae (Fig. 15-24) and develop later over the malar regions, ears, antecubital fossae, neck, and upper chest.

Figure 15-24 Ataxia-telangiectasia. Characteristic telangiectases in the bulbar conjunctiva usually develop between 3 months and 6 years of age.