The Skin and Neurologic Disease

Neurofibromatosis Type I

Neurofibromatosis type I (NF1; von Recklinghausen disease), an autosomal dominant disorder (OMIM 162200 ), is characterized by café-au-lait spots, fibromatous dermal tumors, and Lisch nodules of the iris as well as neoplasms of both the peripheral and the central nervous system (CNS). The earlier designation as peripheral neurofibromatosis (strictly speaking, a misnomer) served to distinguish this disorder from the genetically and clinically distinct central neurofibromatosis, now neurofibromatosis type II (NF2; OMIM 101000 ), as well as schwannomatosis 1 (SWNTS1, OMIM 162091 ) and 2 (SWNTS1, OMIM 615670 ).

NF1 is the most common single-gene disorder of the nervous system, affecting 1 in 3,500 individuals. It results from heterozygosity for a mutant form of a large gene on chromosome 17q11.2 that encodes a cytoplasmic protein with multiple regulatory functions. The NIH consensus criteria permit unequivocal diagnosis of NF1 even without demonstration of the genetic mutation, by clinical observation of at least two of the following: (1) the presence of six or more café-au-lait macules with a diameter of ≥5 mm in children younger than 6 years and ≥15 mm in older people ( Fig. 21-1 ); (2) two or more neurofibromas of any type or one plexiform neurofibroma; (3) axillary or inguinal region freckling; (4) optic pathway glioma; (5) two or more Lisch nodules (whitish tumors of the iris); (6) dysplasia of the sphenoid bone or thinning of the cortex of long bones with or without pseudarthrosis; and/or (7) a first-degree relative exhibiting these changes.

The familiar café-au-lait spots are present at birth, as are plexiform neurofibromas and focal bone dysplasias, but axillary freckling, optic gliomas, Lisch nodules, and neurofibromas appear later in childhood. Of these, axillary freckling is the most diagnostically reliable, being present in all individuals with NF1 by the end of puberty. Café-au-lait spots alone are not diagnostic of NF1 because fewer than five spots are found frequently in individuals who are well. Café-au-lait spots as an isolated trait can be transmitted as an autosomal dominant (OMIM 114030 ) or as occasional features in other heritable disorders including tuberous sclerosis, the microcephalic disorders Nijmegen breakage syndrome (ataxia telangiectasia variant VI, OMIM 251260 ), X-linked Russell–Silver syndrome (OMIM 312780 ), Turcot mismatch repair cancer syndrome (OMIM 276300 ; polyposis coli, rhabdomyosarcomas, medulloblastomas, ependymomas and other gliomas), the rare Westerhof growth retardation syndrome (OMIM 154000 ), and perhaps most famously in McCune–Albright polyostotic fibrous dysplasia (OMIM 174800 ). The old clinical pearl that the rough border of McCune–Albright café-au-lait spots distinguishes them from the smooth borders seen in NF1 is not reliable.

Malignant neoplasms or benign tumors of the nervous system occur in 45 percent of individuals with NF1. Optic nerve gliomas develop in 15 percent. However, neurologic involvement most often results from benign neurofibromas in the root entry zone of peripheral nerves, causing radiculopathy or compression of the spinal cord. Plexiform neurofibromas, which can be nodular or diffuse, arise from nerve trunks. Diffuse plexiform neurofibromas are usually congenital and undergo transformation in about 4 percent of cases into malignant peripheral nerve sheath tumors that are severely painful, tender, and hard. The more common dermal neurofibromas are usually innocent, permitting conservative management in asymptomatic people. The incidence of non-neural tumors is also increased modestly, especially rhabdomyosarcomas of the urogenital tract and myelogenous leukemia.

In addition, there are neurologic sequelae not related to tumors. The most significant of these are poorly characterized T2 hyperintensities in the centrum semiovale (unidentified bright objects), the density of which correlates with mild cognitive impairment. In addition to these neurologic, ocular, and cutaneous manifestations, there may also be cardiovascular, gastrointestinal, and orthopedic manifestations.

Neurofibromatosis Type II

This genetically distinct autosomal dominant disorder (OMIM 101000 ; also known as NF2, bilateral acoustic neurofibromatosis, or BANF) is characterized by tumors of the eighth cranial nerve in the cerebellopontine angle, meningiomas, and schwannomas of the dorsal roots of the spinal cord. It is less common than NF1 by an order of magnitude, affecting 1 in 25,000 live births in association with heterozygosity for a mutant form of merlin, a critical regulator of cell–cell adhesion, transmembrane signaling, the actin cytoskeleton, and resultant inhibition of proliferation. It is encoded on chromosome 8. Other mutations of this gene result in a clinically related but distinct Mendelian disorder, congenital cutaneous schwannomatosis 1 (OMIM 162091 ) or in some familial predispositions to meningiomas (OMIM 607174 ). Typically, NF2 presents in young adults, but hearing loss has been reported as early as age 6. Proposed diagnostic criteria for definite NF2 are bilateral vestibular schwannomas; or a family history of NF2 in one or more first-degree relatives plus (1) unilateral vestibular schwannomas at age less than 30 years, or (2) any two of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. Bilateral acoustic neuromas occur in less than 5 percent of most series. The cutaneous manifestations are also distinct from that of NF1. Café-au-lait spots are present in about 40 percent of individuals, but only about 1 percent have six, the minimum seen in NF1. There are three types of cutaneous tumors: (1) discrete well-circumscribed, slightly raised, roughened areas of skin often pigmented and accompanied by excess hair, which are seen in about one-half of affected individuals; (2) subcutaneous well-circumscribed, nodular tumors located on peripheral nerves seen in about one-third; and (3) violaceous papillary skin neurofibromas, similar to those seen in NF1, in about one-fifth. One-third of NF2 patients have no cutaneous lesions.

Tuberous Sclerosis

This autosomal dominant neurocutaneous disorder was originally described as a phakomatosis, as had been NF1. It is characterized by hamartomas in multiple organ systems, including the brain, skin, heart, kidneys, and lung. The characteristic brain lesions, named tubers because of their fancied resemblance to potatoes, are benign, but some 5 to 15 percent of affected individuals also develop malignant brain neoplasms, most frequently subependymal giant cell astrocytomas. These often develop at the foramen of Monro or elsewhere on the wall of the lateral ventricle or the retina. More frequent neurologic presentations are learning difficulties, behavioral problems, autism, or epilepsy, often the severe West syndrome. The characteristic skin lesions are pale “ash leaf spots,” present in 90 percent of affected individuals. These are difficult to spot on light-skinned individuals unless examined with an ultraviolet Wood light ( Fig. 21-2 ). Such an examination will also facilitate the recognition of smaller confetti-like hypopigmented patches that are present in about one-third of patients, but only rarely in normal individuals. In addition to these flat hypopigmented lesions and occasional café-au-lait spots, there are three kinds of distinctive raised cutaneous lesions: shagreen patches ( Fig. 21-3 ), periungual fibromas ( Fig. 21-4 ), and facial angiofibromas. The latter can be mistaken for acne on casual inspection. There are also systemic manifestations: usually asymptomatic cardiac rhabdomyomas, present at birth and regressing in childhood, but sometimes associated with arrhythmias; renal cysts, angiolipomas, and carcinomas; and pulmonary lymphangioleiomyomas.

Tuberous sclerosis (TSc) can result from mutation of either of two genes. About 70 percent of cases (TSc 2, OMIM 613254 ) result from heterozygous mutation of tuberin encoded on chromosome 16p13.3, the remainder (TSc 1, OMIM 191100 ) from mutations of the gene encoding hamartin on chromosome 9q34.13. Unlike the case for the phenotypically distinct NF1 and NF2, each of which results from disruption of either of two independent, noninteracting proteins, TSc 1 and TSc 2 are practically indistinguishable clinically. This is as would be predicted by the known interaction of hamartin and tuberin to form a single complex, the activity of which is disrupted by mutation of either subunit. This complex regulates the activity of the downstream pathway of the mammalian target of rapamycin (mTOR), which is disrupted by mutation in another neurocutaneous disorder, the Cowden multiple hamartoma syndrome (OMIM 158350 ).

Melanoma

Melanoma is the most lethal of skin cancers, largely because of its propensity for early and highly neurotropic metastasis. In most instances, involvement of the nervous system by melanoma is by metastasis from a primary cutaneous lesion first to a local regional lymph node, then to the lung whence it metastasizes further to brain, bone, or liver. Unlike the usual solitary brain metastases from more common primaries such as lung, breast, and kidney, brain metastases of melanoma are characteristically multiple. The other two types of primary cutaneous neoplasms, the more common basal cell carcinoma and the more invasive squamous cell carcinoma, do not metastasize to the brain.

Furthermore, tumors of the nervous system (including gliomas, medulloblastomas, ependymomas, meningiomas, and acoustic neurilemmomas) have an increased likelihood as secondary tumors in patients with cutaneous melanoma as well as in their family members. The molecular bases underlying these associations are only partially understood.

An increased incidence of cutaneous melanomas is seen in a more complex heritable neurocutaneous syndrome, xeroderma pigmentosa (OMIM 610651 ). This autosomal recessive disorder is characterized by increased sensitivity to sunlight as well as widespread neurologic involvement. Signs include microcephaly, mental retardation, ataxia, ventriculomegaly, cerebellar atrophy, basal ganglia calcification, and disordered central and peripheral myelination.

In addition to those syndromes in which melanoma originates in the skin, there is also the rare neurocutaneous melanosis (OMIM 249400 ), in which there is a primary melanoma of the CNS in over 50 percent of cases, but no malignant melanoma in the periphery. In this disorder there are large multiple pigmented skin nevi (>20 cm) ( Fig. 21-5 ), as well as cranial nerve palsies from histologically benign melanocytic invasion of the meninges, Dandy–Walker malformation, and suprasellar calcifications. Death usually occurs in childhood.

Fabry Disease

Fabry disease is an X-linked neurocutaneous disorder (OMIM 301500 ) characterized by stroke, peripheral neuropathy, and progressive renal and cardiac failure. These sequelae occur both in hemizygous males as well as in heterozygous females, albeit later and usually, but not invariably, with less severity. A pathognomonic whorl-like corneal dystrophy is seen with equal severity in both sexes. Affected males are easily recognized by a purpuric skin rash: discrete angiokeratoma, most prevalent between the knees and nipples. Females, having two X chromosomes, are twice as likely to have the pathogenic mutation of α-galactosidase (also commonly known as ceramide trihexosidase). Nevertheless, affected female heterozygotes frequently remain undiagnosed because they rarely have the characteristic cutaneous lesions, even though they can have severe neurologic, cardiac, and renal manifestations.

Stroke is a late manifestation of the vascular deposition of lipid in Fabry disease. It was underappreciated until survival was prolonged by renal transplantation and, now, by enzyme-replacement therapy. A painful small-fiber neuropathy with autonomic dysfunction and episodic severely painful abdominal crises, reminiscent of those of the hepatic porphyrias, occurs early in the disease. Other early manifestations are small infarctions in the retina and kidneys. The latter lead to renal failure, which had previously caused death of affected hemizygotes by the third decade.

Although Fabry disease is also referred to as angiokeratoma diffusum, these skin lesions are not pathognomonic. They are also manifestations of other Mendelian neurocutaneous disorders associated with mental retardation: aspartylglucosaminuria (OMIM 208400 ; seizures), fucosidosis (OMIM 230000 ; seizures and peripheral neuropathy), lysosomal beta A mannosidosis (OMIM 248510 ), Ramon syndrome (OMIM 266270 ; a posterior cerebral leukoencephalopathy), Kanzaki disease (OMIM 609242 , adult-onset mild cognitive impairment), and Bannayan–Riley–Ruvalcaba syndrome (OMIM 153480 ; megaencephaly, meningioma, pseudopapilledema).

Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disorder also known eponymously as Osler–Weber–Rendu syndrome, is a vascular dysplasia that gives rise to hemorrhagic and ischemic strokes. These arise from a diverse set of peripheral as well as central vascular abnormalities, ranging from ischemic strokes and brain abscesses from paradoxical emboli passing through pulmonary venous malformations to intracerebral vessels, and subarachnoid hemorrhages from cerebral arteriovenous malformations. It is important to search for previously unsuspected pulmonary arteriovenous malformations before assuming local vascular pathology as a cause of stroke, because these pulmonary lesions can be effectively obliterated by embolization. The mucocutaneous telangiectasias for which the disorder is named are most often found on the tongue, lips, palate, fingers, face, conjunctiva, trunk, nail beds, and fingertips. Similar systemic vascular malformations are responsible for frequently problematic recurrent epistaxis, hepatic cirrhosis, and gastrointestinal hemorrhage later in life. Depending on the vascular anatomy, there may be either a polycythemia or an anemia.

This disorder is genetically heterogeneous. HHT type 1 (OMIM 187300 ) results from heterozygosity for a mutation of the gene on chromosome 9q34.11 encoding endoglin, a homodimeric membrane glycoprotein expressed mostly on the vascular endothelium, a component of the transforming growth factor-β receptor complex; HHT type 2 (OMIM 600376 ), from heterozygosity for mutation of the gene on chromosome 12q13.13 encoding activin receptor-like kinase 1; and HHT type 5 (OMIM 615506 ) from heterozygous mutation in the GDF2 gene (OMIM 605120 ) on chromosome 10q11 encoding growth/differentiation factor 2. HHT type 3 (OMIM 601101 ) has been mapped to chromosome 5q31.3-q32 and HHT type 4 (OMIM 610655 ) to chromosome 7p14. The genes mutated in the latter two entities have not yet been identified.

Homocystinuria

Homocystinuria is a feature of several different neurologic disorders, only one of which, homocystinuria due to cystathionine β-synthase deficiency (OMIM 236200 ), is associated either with cutaneous lesions or with stroke. In this disorder cutaneous hypopigmentation, malar flush, and livedo reticularis are not as striking as the Marfan-like disproportionate tall stature and ectopia lentis, which provide the most evident clues to diagnosis. Neurologic features include ischemic thromboembolic strokes in about 25 percent of homozygotes, as well as mild mental retardation, seizures, and a variety of psychiatric disturbances that include personality disorders and depression. Diagnosis is critical, because over half of affected individuals respond to simple treatment with pyridoxine, vitamin B ₆ . Furthermore, even pyridoxine nonresponders benefit from dietary modification to reduce methionine and increase cysteine as well as supplementation with betaine.

The classic syndrome associated with homozygosity for mutations in the gene cystathionine β-synthetase is rare, but heterozygotes—encountered more commonly—are also at greater risk of ischemic stroke than the general population. Lacking the characteristic cutaneous or systemic signs, these individuals can only be detected by biochemical or genetic screening. As is always the case with rare autosomal recessive disorders, the vast majority of heterozygotes will not have an affected homozygous relative to prompt suspicion of the diagnosis.

Endocarditis

Septic emboli leading to ischemic or hemorrhagic stroke or intracranial hemorrhage from rupture of mycotic aneurysms occur in 40 percent of individuals with bacterial endocarditis. In developed countries, acute endocarditis commonly occurs because of unhygienic self-administration of intravenous drugs; infections of surgically implanted artificial cardiac valves are another important cause. In the developing world, secondary infection of unrepaired congenital valvular abnormalities or those damaged by rheumatic fever are also an important contributor to infective endocarditis.

The classic cutaneous findings associated with infective endocarditis are subungual splinter hemorrhages, Janeway lesions, and Osler nodes. Splinter hemorrhages (1- to 3-mm, red to reddish-brown, longitudinal hemorrhages appearing under the nail plate) are commonly seen also as a response to repetitive trauma in otherwise healthy individuals, such as manual laborers or elderly individuals using walkers. In addition they have been reported as occasional findings in antiphospholipid syndrome, another neurocutaneous syndrome associated with stroke.

The more diagnostic Janeway lesions are nontender, large, irregular, flat macules that appear on the palms or the soles, frequently on the planar surface of a toe. These are culture-positive sites of septic emboli. In contrast, Osler nodes are tender, purple, slightly raised nodules ranging in size from 1 to 10 mm. These are typically seen on the tips or sides of toes or fingers. Unlike the Janeway lesions, they are sites of vasculitis, not embolization. Both of these lesions can appear on the thenar or hypothenar eminences.

The presence or absence of neurologic complications dictates the optimal timing of surgery for both native and prosthetic valve endocarditis, as do cardiac function and the control of the infection. In the absence of embolic events or rapidly deteriorating cardiac function, cardiac surgery is best delayed for 1 or 2 weeks of antibiotic treatment before subjecting the patient to the risks of surgery, not the least of which is cardiac bypass and attendant anticoagulation. However, if there is a stroke or transient ischemic attack, and intracranial hemorrhage has been excluded by scanning, surgery is recommended without delay.

Antiphospholipid Syndrome

The twin hallmarks of antiphospholipid antibody syndrome are either a thrombotic event, such as a stroke, or a complication of pregnancy seen in association with high titers of certain antibodies. Sometimes misleadingly referred to as lupus anticoagulants, these are thought to induce hypercoagulability by neutralizing anionic phospholipids on endothelial cells and platelets, predisposing to both arterial and venous thromboses. This syndrome can be seen either as a primary abnormality or in the setting of a number of different neurocutaneous disorders: primary inflammatory diseases such as systemic lupus erythematosus, systemic sclerosis, Behçet disease, Sjögren syndrome, and rheumatoid arthritis, or infections such as syphilis, Lyme borreliosis, and human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). In some instances, antiphospholipid syndrome has been shown to be a familial trait (OMIM 107320 ).

Cutaneous manifestations may be the initial clinical manifestation of the antiphospholipid syndrome. These include livedo reticularis, most commonly on the lower extremities; acrocyanosis, a Raynaud-like phenomenon; necrotizing vasculitis, with cutaneous ulceration and necrosis; erythematous macules; purpura, ecchymoses, and subungual splinter hemorrhages; and rarely, Degos malignant atrophic papulosis. The combination of livedo reticularis with multiple strokes has been designated as Sneddon syndrome. Antiphospholipid antibodies are associated with several neurologic syndromes, including stroke, transverse myelitis, and chorea. Many of these might be plausibly attributed to focal ischemia.

Takayasu Arteritis

Stroke in a young woman of Asian descent should prompt consideration of Takayasu arteritis (aortic arch syndrome or pulseless disease). The differential diagnosis of aortitis includes mycotic aneurysms, syphilis, mycobacterial infections, endocarditis, as well as various autoimmune disorders, including Behçet disease, ankylosing spondylitis, sarcoidosis, and Sjögren syndrome. The cutaneous manifestation of Takayasu arteritis is erythema nodosa, which occurs at an early phase in the disease. Fever and synovitis also develop prior to the large-vessel vasculopathy that defines the disorder. Neurologic involvement results from ischemic stroke from inflammation or stenosis of a proximal carotid or vertebral artery. Such strokes occur in about 20 percent of affected individuals. More commonly, involvement of the subclavian arteries leads to claudication and pulse asymmetries or frank loss of palpable pulses in the upper extremities.

The etiology of Takayasu arteritis appears to be autoimmune, with modest associations both to HLA-B52 and to elevations of serum levels of certain matrix metalloproteinases (OMIM 207600 ). The latter normalize after clinical improvement resulting from treatment with immunosuppressants.

Meningococcal Meningitis

Meningococcal meningitis is a fulminant disorder with a high mortality rate and serious sequelae (sensorineural hearing loss, seizures, motor deficits, hydrocephalus, cognitive abnormalities, and behavioral problems) in treated survivors. Fever, headache, and meningeal irritation develop over the course of 24 hours. The distinguishing feature of meningococcal disease is the concomitant evolution of a rapidly evolving petechial rash, usually over the trunk and lower extremities, but which can also develop on the face, mucous membranes, and arms ( Fig. 21-6 ). These cutaneous lesions can coalesce or develop into vesicles or bullae. In contrast, the cutaneous lesion associated with meningitis from infection with Haemophilus influenzae , previously the most common type of bacterial meningitis in children, is typically a solitary indurated area on the face, neck, upper chest, or arm. The meningococcal rash must also be distinguished from that of other disorders in Table 21-2 , notably Rocky Mountain spotted fever.

In the 10 to 30 percent of cases of meningococcemia that develop too rapidly to seed the choroid plexus and meninges, the prognosis is even worse than in those cases with meningitis. Early treatment at the first recognition of the short febrile prodome and rash is critical. Although most cases of meningococcemia, either with or without meningitis, occur in children, young adults in cramped quarters, including college students and military recruits, are also at risk.

The incidence of some meningococcal infections has been reduced significantly by the introduction of a vaccine, as has the incidence of the other two most common types of acute bacterial meningitis, resulting from infection with H. influenzae or Streptococcus pneumoniae . There are now three quadrivalent vaccines against the causative organism Neisseria meningitidis , targeting serogroups A, C, W-135, and Y. There are also serogroup-independent vaccines that are effective against serogroup B but, currently, none is effective against serogroup X. Worldwide, meningococcal infections remain one of the leading causes of meningitis in children.