Neurocutaneous disorders

Neurocutaneous Disorders Neurocutaneous disorders is a catch-all phrase that includes all disorders involving both the nervous system and the skin. These may range from disorders in which cutaneous findings are essential to diagnosis to those with less significant involvement of the skin. This monograph will review several diagnoses with recent advancements in diagnosis and management, emphasizing etiology and pathogenesis, clinical features and presentation, differential diagnosis, and screening and management. It is divided into sections, highlighting disorders transmitted by different inheritance patterns. (Curr Probl Dermatol 2003;15:1-34.)

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Curr Probl Dermatol, January/February 2003

Introduction Neurocutaneous disorders is a catch-all phrase that includes all disorders that involve both the nervous system and the skin. These may range from disorders in which cutaneous findings are essential to diagnosis to those with less significant involvement of the skin. Because of the variety of disorders that involve the skin and nervous system, a few of the more essential diagnoses, as well as those with recent advancements in diagnosis and management, will be reviewed in this monograph. Many of these diseases are single-gene disorders, for which the genes have been discovered in the past few years. The monograph is divided into sections, highlighting disorders transmitted by different inheritance patterns.

Autosomal Dominant Disorders Neurofibromatosis (NF) is one of the most common neurocutaneous conditions and consists of 8 distinct forms. The first two types are the most common and are autosomal dominant disorders, with somewhat overlapping features: NF type 1 (NF1), also referred to as von Recklinghausen’s disease, and the less common form, NF type 2 (NF2).

Neurofibromatosis Type 1 First recorded by Tilesius in 17931 and later fully described as a syndrome by von Recklinghausen in 1882,2 NF1 has fascinated physicians and scholars for many centuries. This condition is one of the most common autosomal dominant disorders in human beings, with an occurrence of approximately 1 in 3,000 persons. NF1 accounts for 96% to 97% of all cases of NF and results from defects in the NF1 gene on chromosome 17.3 Unfortunately, NF1 has erroneously been labeled as identical to “Elephant Man’s disease,” causing unnecessary duress for individuals diagnosed with NF1.4 Etiology and Pathogenesis. The large gene for NF1 is located on the long arm of chromosome 17 at 17q11.2 and spans at lease 300 kilobasepairs of DNA.5 Neurofibromin is the protein encoded by this gene, and

Curr Probl Dermatol 2003;15:1-34. Copyright © 2003 by Mosby, Inc. 1040-0486/2003/$30.00 ⫹ 0 doi:10.1067/mdm.2003.2

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it likely has several functions.6 This protein is essential for negative regulation of the ras proto-oncogene in the cell.7,8 It therefore serves as a tumor suppressor. Loss of function of one copy of the NF1 gene (loss of heterozygosity) has been demonstrated in bone marrow of some children with NF1, who later have malignant myeloid disorders develop.3 In adult tissues, portions of this large gene appear to be differentially spliced and expressed, and many different mutations have been described.9 Deletions, point mutations, and insertions have been identified, all of which should impair the function of the gene.10 Although NF1 is inherited as an autosomal dominant disorder, 30% to 50% of cases are thought to be due to spontaneous new mutations, most of which are paternal in origin.11 Recently, somatic mosaicism for NF1 has been identified.3 This refers to the presence of an abnormality in one copy of the NF1 gene in some cells but not in others. In the case identified, a large deletion in the NF1 gene was documented, which suggested the possibility of postzygotic mutation. The concept of mosaicism provides one explanation for the phenotypic variability of this condition. Some of the mosaic patients express disease in limited areas of the skin. This variant is referred to as segmental NF.12 Clinical Features and Presentation. In 1987 a panel convened at the National Institutes of Health developed a consensus statement enumerating the clinical diagnostic criteria for NF1 and NF2.13 For NF1, the diagnostic criteria are met if two or more of the following features are present: (1) 6 or more cafe au lait (CAL) macules greater than 5 mm in prepubertal patients and greater than 15 mm in postpubertal patients; (2) two or more neurofibromas of any type or one plexiform neurofibroma; (3) axillary or inguinal freckling; (4) optic nerve glioma; (5) two or more Lisch nodules (iris hamartomas); (6) a distinctive osseus lesion such as sphenoid wing dysplasia or cortical thinning of long bones, with or without pseudoarthrosis; and (7) a first-degree relative with NF1 based on the preceding criteria. The cardinal dermatologic features of NF1 are CAL spots, neurofibromas (Fig 1-5), axillary and inguinal freckling, and pigmented iris hamartomas. CAL macules typically appear either at birth or during the first few years of an affected person’s life. They increase in number and size over time, particularly during puberty. These macules have a homogenous brown coloration, which deepens with exposure to sunlight

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FIG 3. Large CAL macule covers most of chest wall in young woman.

FIG 1. NF1: Multiple neurofibromas in patient with extensive axillary freckling.

FIG 4. Multiple neurofibromas.

FIG 2. CAL macule and neurofibromas.

and a regular border. Giant melanosomes, revealed by electron microscopy, are not specific for NF1 and, therefore, are not helpful diagnostically.3 When CAL macules overlay the spine, the possibility of a plexiform neuroma, as well as the potential of spinal dysraphism, is suggested. Magnetic resonance imag-

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ing (MRI) of the lumbosacral spine should be performed in this situation. In patients with NF1, the most common benign tumor is a neurofibroma, a perineural collection of Schwann’s cells, fibroblasts, mast cells, and vascular elements, which may be either circumscribed (cutaneous or subcutaneous) or noncircumscribed (plexiform). In women, almost 90% of neurofibromas occur in the periareolar location. Thus a breast examination is one of the best ways to detect subtle disease in an adult woman. Plexiform neurofibromas (Fig 6) can wrap in and around vital structures and cause pronounced disfigurement including compromised hearing. These are specific for NF1.14 Surgical treatment is the primary treatment option. One review suggested that half of all plexiform neurofibromas surgically treated in children will not progress.15

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FIG 5. Multiple neurofibromas.

FIG 6. Plexiform neurofibroma.

Both axial freckling and inguinal freckling constitute another major diagnostic criterion. Freckling often develops during puberty, and sprays of freckles sometimes overlay plexiform neurofibromas. Pruritis in these areas is thought to be related to biologic activity within neurofibromas.3 Optic nerve glioma is estimated to occur in 15% of patients with NF1.3 Although these tumors usually

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develop by the time the patient is 10 years old, symptoms of proptosis, decreased visual acuity, or precocious puberty (resulting from pituitary compression) may not occur until years later. Treatment of optic nerve gliomas is often surgical and results in loss of vision; chemotherapeutic management is being investigated.16 Lisch nodules, another major diagnostic criterion for NF1, are iris hamartomas. Early development of Lisch nodules will be detectable with careful examination of patients under a slit lamp by age 6 years.17 Thus serial ocular examinations can be helpful in establishing the diagnosis of NF1 in a child or young adult with a single criterion, such as 6 CAL macules. Distinctive osseus lesions of NF1 include sphenoid wing dysplasia, which often results in pulsating exophthalmos or pseudoarthrosis of the tibia or fibula. This can predispose individuals to pathologic fractures and false joint formation. Usually, only one long bone per patient is affected and male patients are more commonly affected than female patients.17 In addition to the diagnostic criteria described above, NF1 can be compounded by a broad spectrum of complications such as stenosis of the renal arteries, aqueduct stenosis, optic glioma, and learning disabilities; overt mental retardation is uncommon.18 Most patients with NF1 do not have dysmorphic features, but a subset has a similar appearance.19 Characteristic features include triangular facies, prominent or low-set helices, ptosis, down-slanting palpebral fissures, and webbed neck. NF1 is an extremely variable disorder. The clinical presentation ranges from benign, predominant cutaneous expression to severe disfigurement and life-threatening complications. The disorder is variable both between families and within families. Because additional features develop as a patient ages, careful clinical follow-up is imperative.20 Malignant Risk. Patients with NF1 have an estimated 3% to 15% lifetime risk of malignant disease developing. NF patients have a “single hit” in a gene controlling tumor growth. Hence, with the occurrence of spontaneous mutations over one’s lifetime, a “second hit,” which may initiate tumor formation, is likely to occur. These tumors may be benign, such as the neurofibroma, or malignant. The two most common types of malignant tumors are neurofibrosarcoma and optic nerve gliomas (see “Clinical Features and Presentation” section).21 Neurofibrosarcoma, also known as malignant schwannoma, malignant peripheral nerve

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sheath tumor, or neurogenic sarcoma, consists of cells histologically similar to Schwann’s and perineural cells. An estimated 50% of patients with neurofibrosarcoma have NF1. Rapid growth of a plexiform neurofibroma, development of focal neurologic signs, and persistent pain are suggestive of neurofibrosarcoma.3 Other malignancies associated with NF1 include malignant myeloid disorders, carcinoid, rhabdomyosarcoma, osteosarcoma, Wilms’ tumor, ganglioneurofibroma, and medulloblastoma.17,22,23 Patients with NF1 who also have juvenile xanthogranulomas at presentation have recently been shown to have a greater statistical risk of having chronic myelogenous leukemias develop.24 Rarely does a patient have multiple malignant tumors develop.25 Differential Diagnosis. The specific guidelines outlined by the National Institutes of Health have allowed for an accurate clinical diagnosis. However, there are a few variants and overlapping syndromes that deserve attention. Segmental NF (NF-5)26 should be considered in individuals who have characteristic cutaneous findings of NF confined to a particular region of the body. As a result of mosaicism, the clinical findings in segmental NF are not as widespread and may be easily overlooked. Watson’s syndrome is a variant of NF1, in which molecular analysis has shown a large deletion in the same gene encoding the protein neurofibromin.27 The clinical findings of Watson’s syndrome are multiple CAL macules, a small number of neurofibromas, short stature, pulmonary valve stenosis, and decreased intelligence. Although genetically different, Noonan’s syndrome has been observed in a subset of patients with NF1, and there are overlapping features between the two conditions. Screening and Management. The American Academy of Pediatrics Committee on Genetics published recommendations for the management of children with NF1.28 Diagnosis should be confirmed on the basis of outlined requirements and should also include slitlamp examinations of all first-degree relatives of an index case, as well as a complete review of the condition, its inheritance pattern, and its natural history. Annual physical and ophthalmologic examinations during school years, as well as audiology, speech, and language examinations before elementary school, are recommended. Blood pressure should be checked once or twice a year. Growth abnormalities, scoliosis, and rapid enlargement or pain associated with neurofibromas should be monitored closely.3

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Treatment of NF1 is primarily symptomatic; cure is not yet possible. Multicenter trials of medications to limit growth of optic nerve gliomas and plexiform neurofibromas have been initiated.3 Continuity of care and management by a multidisciplinary team, including assistance from neurologists, neurosurgeons, otolaryngologists, ophthalmologists, and radiologists, are optimal for patients with this disorder.20

Neurofibromatosis Type 2 NF2, also known as central NF, accounts for about 3% of cases of NF and results from defects in the NF2 gene on chromosome 27. Much less common than NF1, the incidence of NF2 is estimated at 1 in 50,000 persons.29 Some evidence suggests that there are two subtypes of NF2, a milder Gardner variant and a more severe Whishart type.30 In this review the two variants will be discussed as one entity. Etiology and Pathogenesis. The gene for NF2 is located on chromosome 22 at 22ql1.3 In patients with NF2, loss of heterozygosity for this region of chromosome 22 has been demonstrated in acoustic neuromas, neurofibromas, and meningiomas.31 As discussed with regard to the pathogenesis of NF1, the protein encoded by the NF2 gene may also act as a tumor suppressor. Clinical Features and Presentation. The diagnostic criteria for NF2 are either (1) bilateral eighth nerve masses confirmed by computed tomography (CT) or MRI or (2) a first-degree relative with NF2 and either a unilateral eighth nerve mass or two of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity.13 Skin manifestations in NF2 are less prominent than in NF1. CAL macules tend to be fewer in number and show less distinct hyperpigmentation. Intertriginous freckling is not present. Neurofibromas, especially the plexiform variant, are the least common cutaneous finding in NF2.32 One characteristic skin finding includes cutaneous and subcutaneous schwannomas, the most common of the various tumors seen in NF2. Schwannomas typically present as superficial, discrete, slightly raised papules, in which the surface is rough, often pigmented, and covered by excess hair.29 Such tumors may involve cranial or peripheral nerves, and the latter spherical tumors can often be palpated at either end.33 Schwannomas of spinal nerve sheath tumors are also

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common, which may result in spinal cord ependymomas.34 Although formerly referred to as acoustic neuromas, eighth nerve tumors are actually vestibular schwannomas. In a study of 93 patients with unilateral vestibular schwannomas, none met the diagnostic criteria for NF1, but 5 had clinical findings of NF2.35 Therefore NF2 should always be included in the differential diagnosis of patients with a unilateral vestibular schwannoma. Of patients with NF2, 85% are estimated to have development of posterior subcapsular cataracts.36,37 MRI with gadolinium is the best diagnostic modality by which to image the heads of patients with NF2.3 Differential Diagnosis. Multiple schwannomatosis is characterized by multiple schwannomas of the skin and spinal cord, but this disorder lacks the cutaneous findings of NF1 and the diagnostic vestibular tumors of NF2.38 Molecular studies show that some forms of schwannomatosis are variants of NF2.39 Screening and Management. Molecular testing has been recommended for all persons at risk of an inherited gene mutation for NF2 from a parent.40 If test results are positive, baseline neurologic, audiologic, and radiographic (MRI) evaluations of the head and entire spine should be performed. If no tumors are detected, these evaluations are recommended every 3 years. For patients known to have NF2, annual or biannual neurologic, audiologic, and radiographic evaluations are recommended when they are between 15 and 45 years of age.20 DNA Testing for NF1 and NF2. Mutation analysis is available for NF1 by using protein truncation assays and for NF2 by using single-stranded conformation polymorphism and direct DNA sequencing.41 With current techniques, approximately 70% of mutations in the NF1 gene and 60% of mutations in known familial cases of NF2 can be detected.40 Mutation analysis can be useful to confirm a diagnosis when a patient does not fulfill clinical diagnostic criteria. If a mutation is detected, other family members can be screened by DNA testing rather than by clinical evaluation. DNA testing is not useful for the isolated patient with NF1 or NF2 who has no detectable mutation; family members must be screened clinically in these cases. Prenatal diagnosis is possible if other affected family members are identified. In this situation, linkage analysis can be performed.40

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Tuberous Sclerosis Complex Tuberous sclerosis complex (TSC), the second most common neurocutaneous disorder,42 was first reported by von Recklinghausen43 in 1862 and named by Bourneville44 in 1880. The transmission is autosomal dominant. However, approximately 65% to 85% of cases arise from spontaneous mutations and, therefore, are not inherited. The incidence of TSC is estimated between 1 in 6,000 and 1 in 10,000 individuals,45 and there is no predilection for gender or race.42 In 1908 Vogt46 described the classic triad of adenoma sebaceum, seizures, and mental retardation, but less than a third of patients display all of these features. Instead, it is important to recognize that tuberous sclerosis may present with an array of manifestations affecting multiple organ systems.47 Etiology and Pathogenesis. Tuberous sclerosis is a disorder of cellular differentiation and proliferation.48 Two TSC genes have been identified, one is on chromosome 9q34 (TSC1) and the other is on chromosome 16pl3.3 (TSC2).49,50 The TSC2 gene on chromosome 16 is adjacent to the gene for adult polycystic kidney disease.49 Linkage analysis has shown that half of tuberous sclerosis families have inherited the TSC1 gene, whereas the other half have inherited the TSC2 gene. Jones et al51 found TSC1 mutations to be less common among sporadic cases and mental retardation to be significantly less frequent in these carriers. Hamartomatous lesions of TSC are thought to occur as a consequence of inactivation of a tumor suppressor gene.52,53 The loss of heterozygosity for the two genes is consistent with the occurrence of “second hit” mutations, and this appears to be much more common in enlarging benign tumors or malignant tumors than in stable benign tumors.52 However, loss of heterozygosity at the TSC1 locus has been appreciated in less than 10% of hamartomas in TSC1, which indicates that there are other pathogenic mechanisms yet to be discovered.54 Clinical Features and Presentation. Cutaneous findings include hypomelanotic macules (thumb-print, confetti, or ash-leaf spots) (Fig 7), facial angiofibromas (adenoma sebaceum) (Fig 8), ungual fibromas (Fig 9), and the shagreen patch (Fig 10). Hypomelanotic macules are seen in at least 90% of affected patients, but these lesions are not specific for tuberous sclerosis, as one or two often occur in the general population.55 These lesions are not considered major features unless they are numerous.56 The earliest

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FIG 7. Large hypopigmented macule in patient with tuberous sclerosis.

detectible abnormalities in TSC are hypopigmented macules and rhabdomyomas, both of which are often present at birth. Hypopigmentation can appear as a confetti spot, a thumb print, or the classic ash-leaf spots. These can be detected in patients of all ages, although they may be subtle in light-skinned persons,57 in whom they may be identified more readily with the use of ultraviolet (UV) (Wood’s) light.42 Facial angiofibromas, which consist of vascular, fibrous, and dermal tissue elements, are found in 75% of all patients with tuberous sclerosis. These lesions typically appear initially as pink-red papillary lesions, occur in a malar distribution, and begin to appear at early school age.42,57 Ungual fibromas are fleshy lesions that occur beneath the nails. They occur in only 25% of affected persons, arise in early adulthood, and are fairly specific for tuberous sclerosis.42 A shagreen patch is a cluster of connective tissue hamartoma that appears as an irregularly shaped plaque with a green to red hue and is commonly found on the patient’s back or flank. These lesions are relatively common in patients without tuberous sclerosis and are not specific for the disease. When such a lesion occurs on the

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FIG 8. Multiple papular lesions of adenoma sebaceum in patient with tuberous sclerosis.

FIG 9. Periungual fibromas and ash-leaf macule on thigh.

forehead, it is called a fibrous forehead plaque.42 Congenital lymphedema of an extremity has been reported in patients with tuberous sclerosis.58 Central nervous system lesions of tuberous sclerosis include cortical hamartomas (tubers), focal cortical dysplasia, subependymal nodule, subependymal giant cell astrocytoma, and retinal phakoma (astrocytomas);

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FIG 10. Shagreen patch (connective tissue nevus) in patient with tuberous sclerosis.

spinal cord involvement is rare.55,59,60 Symptoms from these lesions may manifest as seizures, mental retardation, and behavior disturbances. It is important to note that many patients with tuberous sclerosis do not have neurologic impairment.57 A strong correlation has been found between the presence of cognitive impairment, age of onset of seizures, and ultimate outcome of seizure control.61 Radiographic distinction of cerebral lesions is crucial from a diagnostic standpoint and when planning therapeutic strategies. Renal lesions are significant in tuberous sclerosis, although the condition has traditionally been recognized as a neurologic and dermatologic disorder.62 Renal involvement exists in up to 80% of patients and may lead to significant morbidity and mortality. One study cited renal disease as the leading cause of death in adults with tuberous sclerosis.54 Angiomyolipomas are by far the most frequent renal lesion, and the risk of hemorrhagic complications appears to be related to the size of the lesion.63 Serial follow-up with CT scan or ultrasound is indicated because these lesions increase in size and number over time in most patients.47 Renal cysts and polycystic kidney disease are also frequently noted in patients with tuberous sclerosis. This is because the TSC gene is adjacent to the polycystic kidney gene, and mutations in the region may affect the functioning of both genes (contiguous gene syndrome). The cysts are often asymptomatic but may lead to renal insufficiency or progress to endstage renal disease.63,64 Other organ system involvement includes the cardiac, ophthalmologic, and pulmonary systems. Cardiac rhabdomyomas are very common and often multiple in

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neonates with TSC; they have little clinical significance but may allow for in utero diagnosis via fetal sonography.65 Retinal involvement occurs in up to 75% of patients and ranges from mulberry lesions near the optic disc margin to plaque-like hamartomas and depigmented lesions called achromic patches.66 Optic lesions are usually clinical insignificant, but there are reports of visual compromise from these lesions.57,67 Pulmonary involvement is less common, occurring in 1% to 5% of cases.42,68 Lymphangiomyomatosis tends to develop in menstruating female patients, and the growth of these lung lesions is hormone-dependent. Spontaneous pneumothorax or chylous effusions may occur and can cause acute respiratory failure.42 Differential Diagnosis. The diagnosis of TSC is usually quite apparent when the physician appreciates the defining cutaneous and neurologic features. Because certain findings such as ash-leaf macules and hamartomas are common in the general population, it is important to make the diagnosis of TSC only after two major features or one major feature, along with two minor features, has been identified. CT or MRI demonstration of cortical tumors and subependymal nodules is highly specific for diagnosis.69 Screening and Management. Because genetic transmission can be from one of two chromosomes, and the majority of cases are actually new mutations, prenatal diagnosis is difficult. Careful examination of the parents of an affected child may differentiate between the inherited disorder and a new mutation.70 Family members should undergo a physical examination with Wood’s lamp to accentuate ash-leaf spots and dilated funduscopy to delineate retinal phakomas (astrocytomas).71 For inherited cases, genetic counseling of parents is important, as approximately 50% of offspring will be afflicted.

Basal Cell Nevus Syndrome (Gorlin’s Syndrome) The basal cell nevus syndrome (BCNS) is a rare autosomal dominant condition that consists of developmental anomalies and susceptibility to cancer, especially basal cell carcinoma (BCC). Although Jarisch72 and White73 described the first cases in 1894, their syndromic association was not appreciated until the late 1950s,74,75 and the genetic basis of this disorder has only recently been elucidated.76 Etiology and Pathogenesis. BCNS is caused by mutations in the patched gene (PTCH) gene that resides on chromosome 9q.77,78 All families in which

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FIG 11. Multiple BCCs in patient with BCNS.

FIG 12. Palmar pits in patient with BCNS.

BCNS has been reported have a causative gene that links to this site. The PTCH protein is involved in the hedgehog-signaling pathway; activation of this pathway causes increased expression of several genes. The observation of increased PTCH messenger RNA in BCCs suggests that this activation causes transformation of keratinocytes to BCCs.76 The Knudson “twohit” model has been applied to BCNS; two somatic hits are necessary for sporadic cases of BCCs, but only one somatic hit plus the inheritance of one defective allele of the PTCH gene is necessary for BCNS.76,79 Clinical Features and Presentation. The three abnormalities traditionally considered to be most characteristic of BCNS are BCCs (Fig 11), pits of the palms and soles (Fig 12), and cysts of the jaw.74 Although the pathogenesis of BCC in this syndrome is similar to sporadic cases of BCC, what distinguishes these lesions is the large number starting at an early

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age, predominantly between puberty and 35 years.80 Among persons with BCC, it has been estimated that approximately 2% of those younger than 45 years have the syndrome in contrast to 22% of those younger than 19 years.81 Nevoid BCCs most commonly arise on the face, neck, and upper trunk but may occur anywhere. The periorbital areas, eyelids, nose, malar region, and upper lip are the facial sites most often affected. The 1- to 10-mm lesions may be pearly to flesh-colored to reddish brown and isolated or grouped and may resemble moles, nevi, skin tags, or hemangiomas, as depicted by the name basal cell nevus syndrome.74 The skin tumors, originally thought to be independent of sun exposure, are more common in sun-exposed areas, are more common in white patients, and are linked to radiation exposure. Unilateral linear nevoid BCCs with comedones may represent postzygotic somatic mutation. Increase in size, ulceration, bleeding, and crusting of a lesion are indicative of aggressive behavior.82 In a few instances, death has resulted from invasion of the brain, lung, or peritoneum; few cases of metastasis have been reported.83,84 Palmar or, less commonly, plantar pits are small defects in the stratum corneum that occur in 65% of patients with BCNS. These 1- to 2-mm asymmetric lesions rarely occur on the sides or dorsa of the fingers or toes and appear to be age-related, as they are rarely seen in children.74 Pits usually appear pink but may be dark in color if dirt has accumulated, as in the case of patients who perform manual labor. Cases of BCC arising from the base of palmar or plantar pits has been reported.85 Jaw cysts, also called odontogenic keratocysts, occur in over 80% of patients and are often the first detectable abnormality of BCNS. Cysts develop throughout the first decade of life, usually after 7 years of age, and peak during the second and third decade.86 Most often, cysts are large, bilateral, and asymmetric and involve both jaws, and they occur in the mandible about 3 times as often as in the maxilla.87,88 Despite widespread extension throughout the jaws, cysts are usually asymptomatic and are often detected radiographically during routine dental checkups.74 Sometimes cysts may erode through bone and extend to soft tissues, where they cause swelling, pain, and occasional tooth loss. Both ameloblastoma and squamous cell carcinoma have rarely developed in jaw cysts.89 High recurrence rates of 30% to 60% are estimated in various series; thus excision is not recommended unless symptoms develop.90

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FIG 13. Calcification of falx cerebri in patient with basal nevus syndrome.

Milia, epidermoid cysts, chalazia, and comedones are other cutaneous manifestations. Milia, or small keratin-filled cysts, are frequently found intermixed with nevoid BCCs of the face in at least 30% of patients.91,92 Multiple epidermoid cysts of 1 to 2 cm occur on the limbs and trunk in over 50% of cases.93 Several authors have also described associated chalazia and comedones in BCNS.80,94 Tissue overgrowth is another common finding of BCNS, and it is linked to the disease-specific mutation that causes its activation.11,77 Patients may have an overall body size that is larger than that of other family members, and some may even exhibit a marfanoid build.74 Skeletal abnormalities frequently include a large head circumference with frontal and biparietal bossing, low occiput, and increased interorbital distance.95 Calcification of the falx cerebri (Fig 13) is seen at least 85% of adult patients,74 and abnormalities of the rib, spine, and phalanges are present in 33% to 50% of patients.96-98 Malignant Risk. In addition to skin tumors, a proclivity to other types of neoplasia exists. Patients with BCNS are more likely to have medulloblastoma,

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meningioma, ovarian fibroma, ovarian fibrosarcoma, fibrosarcoma of the jaws, cardiac fibroma, fetal rhabdomyoma, and lymphatic cysts of the mesentery.74 Differential Diagnosis. The Bazex-Dupre-Christol syndrome,99 the Rombo syndrome,100 and a syndrome with BCCs, milia, and coarse, sparse hair101 are very rare syndromes that include the development of multiple BCCs. In contrast to BCNS, hair abnormalities are present in all three of these syndromes. Patients with chronic arsenic ingestion may have multiple BCCs in the presence of arsenical keratoses but lack the other characteristic findings of BCNS.102 Patients with xeroderma pigmentosum have multiple BCCs develop but also have severe photosensitivity and a unique set of phenotypic findings different from those with BCNS.46 Screening and Management. Diagnosis is made only when multiple typical defects are present on examination of the patient. The types and severity of abnormalities may vary significantly, even among a family known to have members with BCNS.74 The first finding that a dermatologist will encounter is numerous BCCs arising at an early age. The patient should then be questioned about other family members who have findings consistent with BCNS. However, it is important to realize that 25% to 30% of cases are the result of spontaneous mutations, and therefore there are no affected family members.77 Skin examination may also reveal palmar/plantar pits or other cutaneous findings discussed earlier. Radiologic evaluation for jaw cysts, calcification of the falx, and associated skeletal abnormalities should be conducted.96-98 Careful surveillance of patients is crucial, as it is not possible to tell which BCC will become aggressive. Periodic follow-up visits are warranted every 3 to 6 months with total body skin examination.74 Cryotherapy is the treatment of choice, as it is the best tolerated and leaves minimal scarring. Surgery, including Moh’s technique103; electrodesiccation and curettage104; topical 5-fluorouracil105; and oral retinoids106 have all been successfully used. Treatment options should be addressed on a case-by-case basis, with patient satisfaction balanced by the need for early intervention. Although identification of the PTCH gene mutation may become the confirmative diagnostic test of the future, for now, it is only a research tool. Despite the unavailability of genetic testing, genetic counseling should be carried out, as BCNS will develop in 50% of the patients’ children.

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Epidermal Nevus Syndrome Epidermal nevus syndrome is a rare condition that refers to the association of epidermal nevi with abnormalities in other organ systems including the nervous, skeletal, cardiovascular, and urogenital systems.107 Although most cases occur sporadically, autosomal dominant transmission has been reported as well.108,109 Both sexes are affected equally, and the age of diagnosis ranges from birth to 40 years.109 One of the authors has made the diagnosis in a 58-year-old woman (N.B.S.). The exact incidence of epidermal nevus syndrome is unknown. The first cases were described by Pack and Sunderland108 in 1941, but Solomon and Esterly109 provided a detailed account of the spectrum of epidermal nevi seen in epidermal nevus syndrome. More recently, Happle110 has defined some subvariants of the epidermal nevus syndrome, including the Schimmelpenning syndrome (see “Differential Diagnosis” section). Etiology and Pathogenesis. Epidermal nevi are organoid nevi that arise from the pluripotential germinative cells in the basal layer of the embryonic epidermis. These basal layer cells give rise to keratinocytes and also to skin appendages. Although nevi have been classified according to their predominant cell component, different areas of the same lesion may show different components, and predominant tissue may vary as the lesion develops.107 For example, a single lesion extending from the head to the neck may show a nevus sebaceous histology in the upper portion and a nevus verrucous histology in the lower portion. Therefore Solomon and Esterly109 suggest that the generic term epidermal nevus should be used to encompass all of these variants. The concept of autosomal lethal genes surviving only in a mosaic state was proposed by Happle110 to explain the genetic basis of several syndromes that are thought to fall under the umbrella term epidermal nevus syndrome. These syndromes (see “Differential Diagnosis” section) are characterized by sporadic occurrence, distribution of lesions in a scattered or asymmetrical pattern, variable extent of involvement, lack of diffuse involvement of entire organs, and equal sex ratio.111 The mosaic may arise either from a gametic half chromatid mutation or from an early postzygotic mutation.111 Clinical Features and Presentation. Epidermal nevi are the cornerstone cutaneous finding that should prompt the clinician to search for abnormalities in

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FIG 14. Systematized linear epidermal nevus.

other organ systems and, when both are present, diagnose epidermal nevus syndrome. Although the head and neck area (especially for the nevus sebaceus of Jadassohn) are the most common sites of occurrence, epidermal nevi may involve any part of the body, with many different patterns of distribution (Fig 14). In over 80% of patients, the onset of epidermal nevi is in the first year of life. These lesions may extend beyond their original distribution, but most lesions reach stability in late adolescence without any further progression.109 Nevi that are present at birth or located on the head are less prone to extension.107 Solomon and Esterly109 described 7 different clinical varieties of epidermal nevi. Nevus unius lateris is the most common type of epidermal nevus. The others, in order of decreasing frequency, are as follows: ichthyosis hystrix, acanthotic epidermal nevus, linear nevus sebaceous, localized linear verrucous nevus, velvety epidermal nevus of the axilla, and mixtures of several types of lesions. Other epidermal nevus types that have been described include inflammatory linear verrucous nevus112 and nevus comedonicus.113 Inflammatory linear verrucous epidermal nevus is a distinct variety of epidermal nevus that occurs in approximately 6% of patients.107 Clinically, the lesion appears inflammatory, and histologically, it appears psoriasiform. This type of nevus is believed to be a limited version of the CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderms and limb defects).110 Various cutaneous associations of epidermal nevi have been described.107 Vascular nevi, hypopigmentation, CAL macules, multiple acquired nevocellular nevi, small congenital nevocellular nevi, and der-

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FIG 15. Patient with epidermal nevus syndrome (also shown in Figs 16 and 17).

FIG 16. Patient with epidermal nevus syndrome (also shown in Figs 15 and 17).

matomegaly have all been described.109 Dermatomegaly specifically refers to an increase in skin thickness, warmth, and hairiness. Of these cutaneous abnormalities, hemangiomas and pigmentary changes (Figs 1517) are common associated cutaneous findings, occurring in 10% to 20% of patients.107,109,114 Other less common cutaneous abnormalities that have been reported in persons with epidermal nevi include giant congenital nevocellular nevi,115 aplasia cutis congenital,115,116 chondroma,115 woolly hair nevi,117,118 and straight hair nevi.119 Psoriasis localizing in the area of an epidermal nevus as a Koebner’s phenomenon has been described.120,121 Abnormalities of the nervous, skeletal, cardiac, and renal systems are the most commonly associated with epidermal nevus syndrome.109 Until the study of

Curr Probl Dermatol, January/February 2003

FIG 17. Patient with epidermal nevus syndrome (also shown in Figs 15 and 16).

Rogers et al,107 no study in a large number of unselected patients with epidermal nevi had been done to determine the frequency of other organ system abnormalities. Of 119 patients with epidermal nevi, 33% were noted to have one or more abnormalities in other organ systems, 16% were noted to have two or more abnormalities, and 5% were noted to have five or more abnormalities. Skeletal abnormalities, including various bone deformities, bone cysts, atrophies, and hypertrophies, have been reported in 15% to 70% of persons with epidermal nevus syndrome.114,122 Neurologic abnormalities, including ocular defects, mental retardation, and seizures, are seen in approximately 15% of patients.109,114 Mental retardation and seizures may be associated with cerebrovascular malformations, cortical atrophy, hydrocephalus, and intracranial calcifications. The association of central nervous abnormalities in patients with epidermal nevi on the head has been debated.107 Malignant Risk. Epidermal nevi in patients with this syndrome may undergo malignant transformation in much the same way as isolated epidermal nevi; however, this is generally limited to the nevus sebaceus of Jadassohn and its associated systematized nevus syndrome.109,123 Visceral malignancies associated with the epidermal nevus syndrome include Wilms’ tumor109; nephroblastoma124; adenocarcinoma of the salivary gland,125 esophagus, and stomach108; breast cancer108; astrocytoma126; and mandibular ameloblastoma.126,127 Differential Diagnosis. At least 6 different syndromes have been described as subsets of the epidermal nevus syndrome. Five of these syndromes were

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described by Happle.110 The Schimmelpenning syndrome consists of sebaceous nevi associated with cerebral anomalies, coloboma, and conjunctiva lipodermoid. The nevus comedonicus syndrome consists of comedone nevi, cataracts, skeletal defects, and electroencephalographic abnormalities. These first two syndromes have not been linked to a specific inheritance pattern. The pigmented hairy epidermal syndrome consists of Becker’s nevus, ipsilateral breast hypoplasia, and skeletal defects. The proteus syndrome consists of soft, flat epidermal nevi, limb gigantism, skeletal hyperplasia, and subcutaneous hamartomas. Proteus syndrome and pigmented hairy epidermal syndrome have paradominant inheritance. Recently, some of the cases of Proteus syndrome have been found to relate to a mutation in the P-TEN protein, the genetic cause of familial polyposis coli.128 CHILD syndrome is X-linked dominant and consists of congenital hemidysplasia (CH), ichthyosiform dermatitis (I), and limb defects (LD). Phakomatosis pigmentokeratotica129 is another type of epidermal nevus syndrome, distinguished by the presence of a sebaceous nevus and contralateral speckled lentiginous nevus of the papular type, which is associated with skeletal or neurologic abnormalities. Screening and Management. Any patient with epidermal nevi, especially those with extensive or numerous lesions, should be examined for associated systemic manifestations of the epidermal nevus syndrome. Specifically, these patients require a focused history and physical examination that address developmental history, attainment of milestones, history of seizures, and abnormalities of the bones, eyes, and urinary tract.107 A careful family history should also be obtained to check for autosomal dominant cases; genetic counseling may then be useful. Because patients with epidermal nevi are at significant risk for having other systemic abnormalities that may reveal the epidermal nevus syndrome, a detailed history and physical examination at the time of presentation, as well as close followup, are imperative.110 A biopsy is in order for establishing the histologic type of lesion. Epidermal nevi with an epidermolytic hyperkeratosis pattern can be associated with gonadal mosaicism and, consequently, transmission of the genes responsible for epidermolytic hyperkeratosis (ie, keratins 1 and 10) to offspring.130

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Autosomal Recessive Disorders Xeroderma Pigmentosum Xeroderma pigmentosum (XP) is an autosomal recessive disease characterized by sun sensitivity, photophobia, early onset of freckling, and subsequent photodamage and neoplastic changes on sun-exposed surfaces. Its frequency in the population is estimated to be approximately 1 in 1 million persons in the United States.131 Neurologic abnormalities are seen in up to 30% of patients with XP.131-134 XP with neurologic involvement is seen in all ethnic groups but is most common in Japan.133 These neurologic abnormalities may be mild, such as hyporeflexia, or severe, such as mental retardation, sensorineural deafness, spasticity, or ataxia.131-134 De Sanctis–Cacchione syndrome is a form of XP that involves the cutaneous and ocular manifestations of classic XP plus additional neurologic and somatic abnormalities, including the following: microcephaly, progressive mental deterioration, low intelligence, hyporeflexia or areflexia, choreoathetosis, ataxia, spasticity, Achilles tendon shortening, dwarfism, and immature sexual development.135 It was first reported in 1932 when De Sanctis and Cacchione described 3 brothers with the syndrome.135 Etiology and Pathogenesis. XP is a disorder in which there are inherited defects in the excision repair of thymine dimers in DNA damaged by UV radiation.136 The rates of DNA repair differ between individual patients, ranging from less than 2% to 55% of normal.131 XP has been divided into several different complementation groups that have different DNA repair defects. The first 5 groups discovered were titled A through E in order of increasing residual DNA repair synthesis.131,137 Complementation groups F, G, H, and I have residual rates of repair that overlap with those of the other groups. An additional group, the variant, replicates its DNA after UV irradiation in abnormally short fragments.138 Patients with XP and neurologic abnormalities are most commonly found in group A or group D.131 It has been shown that fibroblasts from patients with a history of acute sun sensitivity or with neurologic abnormalities were more sensitive to killing by UV radiation in culture than those of patients with XP without such a history. It has been suggested that XP neurologic disease is due to the patient’s DNA repair defect.131,139 It is hypothesized that there is a lethal accumulation of

Curr Probl Dermatol, January/February 2003

FIG 18. Facial freckling in 9-year-old with XP.

unrepaired neuronal DNA damaged not by UV, which cannot reach the nervous system, but by intraneuronal metabolites and/or physicochemical events. This hypothesis is based on the relationship between the severity of a patient’s DNA repair defect and the age of onset and rapidity of progression of the neurodegeneration.134 Patients with XP have been shown to have sensitivity to DNA-damaging agents other than UV irradiation as well.140 These agents include psoralens, chlorpromazine, cisplatin, carmustine, and benzo[a]pyrene derivatives found in tobacco smoke. Clinical Features and Presentation. In patients with XP and neurologic involvement, there may be somatic abnormalities present at birth or no manifestations of the disease. The earliest manifestation of XP occurs at 1 to 2 years of age and is commonly an acute sun sensitivity reaction.133 This is seen as prolonged erythema, edema, and blistering after sun exposure.131 Freckling occurs during early childhood (Fig 18), followed by cutaneous telangiectasias, atrophy, or actinic keratoses.132 Later in childhood, neoplasms may occur. The median age of first skin neoplasm is 8 years, as compared with a median age of 60 years in the US population in general.132,133 BCCs are the most commonly reported skin cancer, followed by squamous cell carcinomas (Fig 19) and then melanoma. The sites of distribution for BCCs and squamous cell carcinomas in patients with XP are concentrated more on the face, head, and neck compared with the US population in general. The median age for first melanoma in patients with XP is 19 years.133 Ocular abnormalities in XP are manifest on the tissues exposed to UV radiation, namely the lids, conjunctiva, and cornea. Atrophy of the skin of the eyelids leads to loss of lashes and ectropion. Entropion and loss of the lid have also been reported.132,133 Photophobia may be present at a young age and may be associated with conjunctival injection. Corneal

Curr Probl Dermatol, January/February 2003

FIG 19. Multiple squamous cell carcinomas in patient with XP.

abnormalities include exposure keratitis, leading to corneal clouding and/or vascularization.133 This may cause impairment of vision. Neoplasms of the eye occur most frequently at the limbus, followed by the cornea and conjunctiva. The most frequent reported histologic type reported was squamous cell carcinoma, followed by epithelioma/BCC and then ocular melanoma. In patients with ocular neoplasms, half of ocular neoplasms occurred by age 11 years. The frequency of ocular abnormalities in patients with XP and neurologic symptoms was similar to that in patients without neurologic symptoms.132 Neurologic abnormalities may develop in infancy or may be delayed until the second decade.132,134 The most common neurologic abnormality is low intelligence, seen in 80% of patients with neurologic involvement. Abnormal motor activity is seen in 30% of patients, consisting primarily of spasticity and ataxia. Reflexes are abnormal in 20% of patients with areflexia, hyporeflexia, or Babinski’s sign noted. Biopsy studies of the peripheral nerve indicate that XP neurologic disease is a primary neuronal degeneration.134 Impaired hearing is seen in 18% of patients with XP. Deep tendon reflex testing and audiometry

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can serve as a clinical screening tool for neurologic involvement in patients with XP. Microcephaly is present in 24% of patients.133 CT scan of patients with XP may show cortical atrophy, dilated lateral ventricles, a thickened calvarium, and pneumatization of frontal sinuses.141 Electroencephalography may show abnormalities such as intermittent spindles of grouped theta waves with abnormal slow background activity and a poorly developed alpha rhythm, suggesting immature brain development or a regression from normal brain function in many areas including the diencephalon.141 Somatic abnormalities are confined almost exclusively to patients with XP and neurologic deficits. A slow rate of growth was noted in 23% of patients. Secondary sexual development was delayed in 12% of patients. Internal neoplasms may also be increased in patients with XP. There are reports of neoplasms of the brain, spinal cord, lung, uterus, breast, pancreas, stomach, kidneys, and testes, as well as leukemia, in patients with XP.132,133 The most common cause of death for patients with XP is cancer, followed by infection. The survival probability of patients with XP who have neurologic abnormalities is not significantly different from that of those without neurologic abnormalities.133 Differential Diagnosis. The differential diagnosis of XP should include other disorders with sun sensitivity such as Cockayne’s syndrome, trichothiodystrophy, and Bloom syndrome. These disorders can mimic XP, because they relate to helicase gene defects. Cockayne’s syndrome is an autosomal recessive degenerative disease characterized by cachectic dwarfism, deafness, and pigmentary retinal degeneration.140 Patients have photosensitivity but lack the pigmentary abnormalities seen in XP.142 Trichothiodystrophy, also called Tay syndrome or IBIDS syndrome, is an autosomal recessive disease in which patients have ichthyosis, sulfur-deficient brittle hair, intellectual impairment, decreased fertility, and short stature. Some patients are also sun-sensitive. Bloom syndrome is an autosomal recessive disease characterized by sun sensitivity, facial telangiectasia, short stature, and immunodeficiency.143 Patients have increased frequency of neoplasms of the skin and internal viscera.143 Screening and Management. Treatment is based on early diagnosis of skin neoplasms and protection of the skin from UV radiation.144 Patients should be taught to protect all body surfaces from UV radiation by wearing protective clothing, UV-absorbing glasses,

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and sunscreens with a sun protective factor (SPF) of at least 15. Patients and their families need to be educated to recognize suspicious-looking lesions and to perform regular self-examinations. They should also be seen by a dermatologist every 3 to 6 months. Premalignant lesions may be treated with liquid nitrogen or topical 5-fluorouracil. Large areas of involvement have been treated with dermatome shaving or dermabrasion.145,146 Patients should also avoid environmental mutagens such as cigarette smoke and unshielded fluorescent light bulbs.140 Oral isotretinoin has been shown to prevent skin cancers in patients with XP but should only be used in patients with multiple skin cancers because of its toxicity.147 This disorder is the first in which cutaneous gene therapies have successfully delivered the targeted gene product via a cutaneous delivery system. Recent studies have proved the efficacy of the bacterial DNA repair enzyme T4 endonuclease V, delivered topically, in lowering the rate of development of actinic keratoses and BCCs.148 Prenatal diagnosis of XP is possible by measuring UV-induced unscheduled DNA synthesis in cultured amniotic fluid cells149 or by DNA diagnosis of trophoblast cells.150

Ataxia-Telangiectasia Ataxia-telangiectasia (AT) is an autosomal recessive multisystem disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, x-ray hypersensitivity, predisposition to lymphoid malignancies, and profound dysfunction of both humoral and cell-mediated immune systems. Estimates of its incidence range from 1 in 40,000 persons151 to 1 in 300,000 persons,152 with approximately 1% of the white population in the United States being heterozygous carriers of the AT gene. Pneumonia is the most common cause of death, followed by malignancy.153 It is reported that AT primarily affects persons of European descent.154 The disease was first reported in 1926 by Syllaba and Henner155 but was not mentioned again until Louis-Bar156 described a case in 1941. It was Boder and Sedgwick157 who coined the term “ataxiatelangiectasia” when they defined the disease as a distinct syndrome in 1957. Etiology and Pathogenesis. Exposure of normal mammalian cells to ionizing radiation results in a delay of progression from G1 to S phase and G2 phase to mitosis, as well as inhibition of DNA synthesis.158 Cultured AT cells have abnormal radioresistant DNA

Curr Probl Dermatol, January/February 2003

synthesis and fail to activate the G1/S or G2/M checkpoints in response to ionizing radiation.159,160 AT cells also show chromosomal instability and hypersensitivity to DNA-damaging agents such as x-rays and radiomimetic agents such as bleomycin.161 Responses to UV irradiation are normal.162 The gene mutated in AT (ATM) has been isolated, spans 184 kilobases of genomic DNA, and has 66 exons on chromosome 11q23.1.163 The protein product of ATM is a constitutively expressed 350-kd nuclear phosphoprotein.164 This protein shows homology with the phosphatidylinositol-3-kinase family.163 In response to DNA damage, ATM may phosphorylate p53, c-Abl, and replication protein A and activate signal transduction pathways.165,166 ATM is activated in response to double-strand DNA breaks and plays an important role in controlling a passage through the cell checkpoints.165 Over 100 mutations of the gene have been described in patients with AT.166 Clinical Features and Presentation. AT typically presents between 12 and 18 months of age, when a child is beginning to walk. The child may have difficulty with control of body posture and body movement. He or she may start to walk later than usual and may fall to one side or may exhibit swaying movements while walking or standing. The ataxia worsens with progressive hypotonia, decreased deep tendon reflexes, and intention tremor. The diagnosis of AT is typically made at 7 years of age.157 By 8 to 10 years of age, the child is usually confined to a wheelchair. Dysarthric speech, drooling, choreoathetosis, and myoclonic jerks become prominent. Muscle atrophy, particularly involving muscles of the extremities, develops.157,167 Mental function is normal early on but may decline slightly in later years. Neuropathologically, there is severe degeneration of the cerebellum, particularly the vermis. Purkinje’s cells, granular cells, and basket cells are reduced in number. Degenerative changes are also seen in the dentate and olivary nuclei and in the posterior and lateral columns. Nerve biopsy shows peripheral neuropathy and denervation atrophy of muscle fibers.168 Ocular telangiectasias appear between the ages of 3 and 5 years and remain unchanged throughout life. They are most prominent in the canthal regions and do not extend beyond the limbic regions. Most patients have vertical and horizontal saccadic apraxia, gaze nystagmus, or strabismus develop.167 Visual acuity is unaffected, and funduscopic examination results are normal.

Curr Probl Dermatol, January/February 2003

Subsequent to the ocular telangiectasias, cutaneous telangiectasias may develop on the malar prominences, ears, eyelids, anterior chest, popliteal and antecubital fossae, and dorsa of the hands and feet. Cutaneous telangiectasias usually appear before 10 years of age. Mottled hyperpigmentation and hypopigmentation are common in telangiectatic areas, giving the skin a poikilodermatous appearance.167 Histologically, the cutaneous telangiectasias arise from the subpapillary venous plexus. Scalp hair often becomes coarse and brittle with diffuse graying.42 During adolescence, facial skin may become progressively more atrophic and sclerotic, causing a mask-like appearance. The ears, arms, and hands may also become sclerodermoid.168 Histologically, a flattened epidermis is seen, with an increase in thick hyalinized collagen bundles in the superficial and deep dermis. Other pigmentary changes include CAL spots, multiple ephelides, and vitiligo. Hirsutism of the arms and legs, alopecia areata, multiple verrucae, atopic dermatitis, keratosis pilaris, and acanthosis nigricans have also been described in patients with AT. Noninfectious cutaneous granulomas are extremely common in patients with AT and are occasionally the presenting sign.169 These lesions respond poorly to treatment with topical steroids and immunoglobulins.169 Patients with AT have abnormalities of both the humoral and cellular immune systems. Serum IgA and IgE are deficient or absent.170,171 Subtypes of IgG are reduced, and low-molecular-weight IgM has also been observed.169,170,172 Circulating anti-IgA antibodies are common.173 Lymphopenia is observed in as many as one third of patients.171 There is a reduction in lymphocytes bearing T-cell markers and T helper cells, as well as those bearing receptors for IgM.171 Patients with AT generally exhibit poor responses to common skin test antigens.171 The thymus is absent or hypoplastic, and the spleen may be reduced in size.167 Lymph nodes show a reduction in number or complete absence of lymphoid follicles, reticular cell hyperplasia, loss of follicular pattern, and the presence of many histiocytes.168 The immunodeficiency in AT predisposes up to 80% of patients to recurrent bacterial and viral sinopulmonary infections. Patients with AT are predisposed to malignancy, with some having multiple neoplasms develop. The cancers are most frequently neoplasms of the lymphoid system.152 The risk for lymphoma has been found to be 250-fold and 750-fold greater for white and African American patients with AT, respectively,

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compared with the normal population.153 The lymphoid malignancies include both T- and B-cell cancers. T-cell tumors occur more frequently than B-cell tumors and are either T-cell acute lymphocytic leukemia or T-cell prolymphocytic leukemia.152 B-cell non-Hodgkin’s lymphoma is the most common B-cell malignancy.152 Defective endocrine function is also often present. Secondary sexual characteristics are poorly developed. Breast development in female patients is minimal, and genitalia are prepubertal in both sexes. Patients may have ovarian agenesis or testicular hypoplasia. Growth is typically retarded.157 An unusual type of diabetes with hyperinsulinism, hyperglycemia with no glycosuria or ketosis, and peripheral insulin resistance has been described.174 Mild hepatic dysfunction is found with elevations of alkaline phosphatase, aspartate transaminase, alanine transaminase, or lactic dehydrogenase levels. Bilirubin levels are normal. Virtually all patients have elevated levels of alpha-fetoprotein, and they may have detectable levels of carcinoembryonic antigen that may be compatible with some form of liver abnormality.175,176 Heterozygotes for the AT gene are at a higher risk for neoplasia, especially female breast cancer. Exposure to x-rays in heterozygous women may predispose them to the development of breast cancer, so women with a family history of AT should avoid routine mammography. Some studies estimate that AT heterozygotes account for 5% of all deaths caused by neoplasms before the age of 45 years.177 Differential Diagnosis. AT is a neurocutaneous disease characterized by defects in DNA repair. Others include XP (De Sanctis–Cacchione syndrome), Bloom’s syndrome, and Cockayne’s syndrome. Screening and Management. Treatment for AT is supportive and includes physical and occupational therapy to prevent contractures in patients with neurologic dysfunction, antibiotics for infection, and chest physiotherapy for pulmonary bronchiectasis. All available data support the use of all standard chemotherapeutic agents when cancers are being treated in patients with AT, with the exception of bleomycin and radiation therapy. These agents may lead to extensive tissue necrosis.161 Prenatal diagnosis has been achieved by measurement of amniotic alpha-fetoprotein levels, by increased spontaneous breakage of chromosomes of fetal amniocytes, and by the presence of a clastogenic factor in the amniotic fluid.178

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X-Linked Dominant Disorders Incontinentia Pigmenti Incontinentia pigmenti (IP), or Bloch-Sulzberger syndrome, is a rare X-linked dominant disorder that affects the skin, teeth, eyes, central nervous system, and skeletal system.179 As an X-linked trait, it is usually lethal to male patients, hence the preponderance of female patients with this condition. In fact, female patients represent about 98% of babies born with IP.180 IP is a multisystem disorder with prominent features of mosaicism or cutaneous patterns that connote an individual composed of two or more different cell lines.180 Researchers have recently described the genetic etiology of IP.181 Etiology and Pathogenesis. The X-linked dominant and male-lethal disorder IP is caused by mutations in a gene called NEMO.181 The NEMO gene codes for a protein, NF-kappa-B essential modulator. This gene is involved in various pathways including inflammation and apoptosis. The primary defect in IP is the failure of cells to resist apoptosis, resulting in early cell death.180 Cytogenetic studies of sporadic cases of IP exhibit an X/autosomal translocation involving a breakpoint at Xpl1, which suggests a gene locus on Xp11. Linkage analysis of familial IP, however, has identified a second locus in the Xq28 region.182 The structure of the gene NEMO has been reported,181 and it has been demonstrated that most patients with IP carry an identical deletion that arises from misalignment between repeats. This unusual and complex genomic region is susceptible to various types of pathogenic rearrangements, including the recurrent lethal deletion that is associated with this disorder. Although IP mostly affects female patients, there have been several cases of IP in male patients who have survived to birth. Three mechanisms have been proposed to explain male survival with regard to IP: the half-chromatid hypothesis, unstable permutation, and a higher rate of de novo germline mutations.182 X-chromosome inactivation in female patients during early embryogenesis results in a mosaic population of cells; this explains the linear and patchy cutaneous manifestations of IP.183 Many of the male patients have an unusual phenotype of a hypohidrotic ectodermal dysplasia–like syndrome.184 Clinical Features and Presentation. IP is characterized by skin lesions that are arranged in a linear

Curr Probl Dermatol, January/February 2003

FIG 20. Bullous lesions in linear array in patient with IP.

pattern185 and evolve through four classic stages that may occur concurrently or nonsequentially.179 Linear inflammatory vesicles or bullae appear at birth or during the first 2 months of life and may last from weeks to months (Fig 20).179 Lesions are filled with eosinophils, and the inflammatory response is thought to represent a selection against the functionally defective cell clone.186 Generally, inflammatory lesions are uncommon after age 6 months.187 The second stage consists of linear hyperkeratotic warty or verrucous plaques (Fig 21) , which replace the inflammatory lesions.179 These lesions usually spontaneously disappear within several months but may last until 1 year of age.188 As the warty lesions resolve, the child is left with persistent pigmentation (Fig 22).187 This most characteristic phase consists of slate-brown to bluegray pigmentation in rows where lesions once existed and in patchy whorls on areas where no lesions existed.179 The pigmentation may persist for many years, slowly fading until it is barely perceptible by the second or third decade of life.189,190 Hypopigmented or depigmented linear macules on the lower extremities and trunk, but sparing the skin appendages, comprise the final phase that appears during adulthood.179 These lesions are usually localized to the lower legs and seem to occur more frequently than what is reported in the literature.187 Hypopigmented macules and atrophic streaks have been found as the sole manifestation of IP in women who were diagnosed in infancy and in some mothers of patients.191 Late manifestations of IP, aside from hypopigmented macules, include subungual tumors, which have been reported in very few cases.192 These painful tumors appear between ages 15 and 30 years and can

Curr Probl Dermatol, January/February 2003

FIG 21. Verrucous (second-stage) lesions in linear array often follow vesicular stage.

provoke destruction of the underlying bone.187 Subungual tumors have been successfully heated with etretinate.193 Linear warty lesions of the palms and soles have also been described as rare late manifestations of IP.187,194 These lesions are not erythematous, do not have bony involvement, and are very limited in their distribution. Common systemic manifestations include dental anomalies, ophthalmic anomalies, and central nervous system findings. Dental anomalies affect both primary and secondary dentition and include hypodontia (small teeth), partial anodontia (lack of teeth), delayed eruption of teeth, impacted dentition, and malformed crowns (conical teeth).179 Ophthalmic abnormalities include strabismus, cataracts, coloboma, optic atrophy, anophthalmia, microphthalmia, and retinal vasculopathy.195 Hyperplastic retinopathy is the one treatable feature IP. Central nervous system findings include seizures, mental retardation, ataxia, spastic abnormalities, microcephaly, cerebral atrophy, hypoplasia of the corpus callosum, periventricular white matter damage, ischemic strokes, hydrocephalus, and cerebral

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hyperplastic retinopathy, there are no treatable features of IP.180

Menkes’ Syndrome

FIG 22. As time passes, only pigmentary lesions remain.

edema.196-200 Skeletal abnormalities201 and cardiovascular anomalies202 have also been reported. Malignancies such as kidney tumors, leukemias, retinoblastoma, and paratesticular rhabdomyosarcoma have been reported in children with IP.203 Differential Diagnosis. Each stage of the disease comes with its own differential diagnosis. In the initial blistering stage, one must rule out infectious conditions such as herpes simplex or bullous impetigo.179,183 The hyperkeratotic phase may resemble warts or linear epidermal nevi. The pigmentary stage must be differentiated from other genodermatoses that display mosaicism such as linear and whorled nevoid hypermelanosis and epidermal nevus syndrome.204 Macular amyloidosis with an IP-like pattern has been described.205 Screening and Management. IP follows an Xlinked dominant pattern of inheritance. Therefore obtaining a careful family history in a suspect patient is crucial for confirmation of the diagnosis and future genetic counseling. Because the Xq28 region has been identified as the locus in familial cases, gene testing may soon become available.183 With the exception of

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Menkes’ syndrome, also known Menkes’ kinky-hair syndrome, is an X-linked recessive disorder of copper metabolism, characterized by progressive neurologic degeneration, abnormalities of the skin and hair, and death in childhood. The estimated incidence of Menkes’ syndrome ranges from 1 in 100,000206 to 1 in 250,000207 live births. The association between copper deficiency and neurologic disease was made in 1937 by Australian veterinarians who noted ataxia in lambs who were pastured in copper-deficient fields.208 In 1962 Menkes et al209 described an X-linked recessive disorder with retardation of growth and peculiar hair and focal cerebellar degeneration in 5 male infants. Danks et al210 recognized the similarities between the wool of the affected sheep and the hair of the infants with Menkes’ syndrome in 1972 and concluded that Menkes’ syndrome was a human example of hair, skin, and neurologic abnormalities due to copper deficiency. Etiology and Pathogenesis. The defective gene in Menkes’ syndrome (ATP7A or MNK) has been localized to chromosome Xp13.3 by linkage analysis211 and encodes a copper-transporting (ATPase).212 MNK belongs to a large family of cation-transporting P-type ATPases.212 The P-type ATPases regulate intracellular ion concentration.213 MNK has been shown to localize to the trans Golgi network in fibroblasts.214 It is thought that MNK may function to donate copper to cuproenzymes. When copper levels are elevated, MNK redistributes to the plasma membrane, where it may function to extrude potentially toxic copper.214 The gene is expressed in the skeletal muscle, kidney, lung, and brain, but only in trace amounts in the liver.212 Loss of MNK function in Menkes’ syndrome results in failure of copper transfer across the gastrointestinal tract, blood-brain barrier, and placenta.213 There is a retention of copper in the duodenum, kidney, spleen, pancreas, skeletal muscle, and placenta.215 The activity of copper-dependent enzymes is reduced.213 Copper-dependent enzymes include dopamine-␤-hydroxylase, peptidylglycine-amidating monooxygenase, cytochrome c oxidase, superoxide dismutase, tyrosinase, and lysyl oxidase.213 Dopamine-␤-hydroxylase is critical in catecholamine synthesis, and its deficiency may be responsible for temperature instability,

Curr Probl Dermatol, January/February 2003

hypoglycemia, and eyelid ptosis.213 Peptidylglycineamidating monooxygenase deficiency leads to a deficiency in neuroendocrine peptides. Tyrosinase deficiency leads to decreased melanin synthesis and the reduced skin and hair pigmentation seen in Menkes’ syndrome.213 Lysyl oxidase catalyzes the oxidative deamination of lysyl residues, linking adjacent tropoelastin molecules into an elastin network. A deficiency of lysyl oxidase is thought to be responsible for the skin abnormalities in patients with Menkes’ syndrome,216 vascular tortuosity,216 bladder diverticula,217 and gastric polyps. Deficiency of superoxide dismutase could lower protection against oxygen-free radicals.213 Clinical Features and Presentation. Menkes’ syndrome most often occurs in male infants, who usually appear normal at birth.213 Neonates may have hypothermia, hypoglycemia, persistent jaundice, pectus excavatum, or umbilical or inguinal hernia.213 Typically, affected infants present at 2 to 3 months of age with seizures, hypotonia, failure to thrive, and loss of previously attained developmental milestones.213 Scalp hair and eyebrows are short, sparse, and twisted, giving the characteristic kinky appearance. Hair is least abundant in the parietal and occipital regions.216 It is hypopigmented and may be gray or white in color. Light microscopy of the hair shows pili torti, 180° twisting of the hair shaft.216 Other hair structure irregularities are the result of acquired degenerative changes to the hair shaft including trichorrhexis nodosa, trichoclasis, and inconsistent variation in bore.218 Transmission electron microscopy shows that the epidermis and papillary dermis are normal in histologic appearance, whereas the reticular dermis shows changes in the elastic fibers with degradation of the amorphous central core and retention of the microfibrillary and collagen structure.216 Blood vessels show fragmented elastin fibers within the internal elastic lamina, tunica media, and intima.216 Patients have a jowly facial appearance, with eyelid ptosis and loose, stretchy skin, especially at the nape of the neck and on the trunk.213 Osseous deformities such as pectus excavatum are common, as are wormian bones of the skull, metaphyseal spurs on long bones, and flaring of the ribs.219 Umbilical or inguinal hernias may be present.213 Neurologically, patients continue to have loss of developmental milestones and may be mentally retarded. Deep tendon reflexes are hyperactive. Visual fixation and tracking are often impaired, and MRI and electroencephalographic re-

Curr Probl Dermatol, January/February 2003

sults are usually abnormal.220 Neuropathologic findings in Menkes’ syndrome include loss of neuronal cells in the cerebral cortex and cerebellum, demyelination, dystrophic Purkinje’s cells, and vascular anomalies.221,222 Most patients with Menkes’ syndrome die by the age of 3 years as a result of infection or neurologic disease.223 Several female patients with Menkes’ syndrome resulting from chromosome rearrangement or XO/XX mosaicism have been described.224 Female carriers of the mutant Menkes’ gene show few abnormalities and may be difficult to identify. Pilus tortus is detectable in about half of carriers, and its presence is suggestive of the disease. Hypopigmentation in Blaschko’s lines has been reported in these carriers as well.225 Occipital horn syndrome (OHS) (also known as X-linked cutis laxa or type IX Ehlers-Danlos syndrome) is characterized by pathognomonic wedgeshaped calcifications at the base of the occipital bone and is thought to represent a milder form of Menkes’ syndrome.226 Patients with OHS primarily exhibit lax skin and joints and show only mild neurologic impairment. It has recently been found that the presence of barely detectable amounts of correctly spliced MNK transcript, 2% to 5% of normal, is sufficient to permit the development of the milder OHS phenotype, as opposed to Menkes’ syndrome.227 Typical laboratory values in patients with Menkes’ syndrome include serum copper levels lower than 70 ␮g/dL, serum ceruloplasmin levels lower than 200 mg/L, abnormal copper egress in cultured fibroblasts, and elevated placental copper levels.213 Norepinephrine levels may be low or normal.228 MRI of the brain may show atrophy, ventriculomegaly, vessel tortuosity, and decreased myelination.220 Differential Diagnosis. Pilus tortus, the kinky hair that is often considered to be pathognomic for Menkes’ syndrome, can be seen in a number of conditions including Bjo¨ rnstad’s syndrome, pseudomonilethrix, Bazex’s syndrome, Crandall syndrome, hypohidrotic ectodermal dysplasia, and trichothiodystrophy.218 Screening and Management. Copper-histidine therapy normalizes serum copper, ceruloplasmin, dopamine, and norepinephrine levels after 3 months of treatment.229 Early treatment is associated with improved neurologic functioning, including decreased seizures. In a minority of patients, however, connective tissue disorders persist.229 Lysyl oxidase may not incorporate copper-histidine well enough. In addition, it is reported that patients who had improvement in

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neurologic function had more severe somatic abnormalities, including OHS and orthostatic hypotension, develop.230 Studies suggest that early initiation of copper-histidine therapy may be beneficial in a subset of patients. Prenatal diagnosis of Menkes’ syndrome is possible for known or suspected female carriers by testing cultured chorionic villus cells for elevated copper content and abnormal egress of radiolabeled copper.231

Sporadic Disorders POEMS Syndrome POEMS syndrome is an uncommon multisystem disorder characterized by polyneuropathy, organomegaly (hepatomegaly, splenomegaly, or lymphadenopathy), endocrinopathy, monoclonal gammopathy, and skin changes that is a form of plasma cell dyscrasia. The syndrome usually presents in the fifth or sixth decade of life and is more common in men (male-tofemale ratio, 2.5:1). The mean survival after diagnosis is 8 years.232 The syndrome has been reported primarily in Japan, with case reports of the syndrome in the United States and Europe.233 The first description of POEMS syndrome is credited to Shimpo233a in a Japanese patient in 1968, although earlier reports of an osteosclerotic form of myeloma associated with peripheral neuropathy exist.234 Bardwick et al235 coined the acronym POEMS in 1980, based on the 5 main features of the syndrome. POEMS syndrome has also been called Crow-Fukase syndrome, Takatsuki syndrome, and PEP syndrome (polyneuropathy, endocrinopathy, and plasma cell dyscrasia). Etiology and Pathogenesis. The etiology and pathogenesis of POEMS syndrome are unknown, but it is thought that increased activity of proinflammatory cytokines236 and overproduction of vascular endothelial growth factor may contribute.237 It has recently been shown that patients with POEMS syndrome have elevated serum levels of interleukin 6 (IL-6), tumor necrosis factor ␣, and IL-1.236 In addition, serial evaluations of a patient with POEMS syndrome showed that serum levels of proinflammatory cytokines paralleled disease activity assessed by platelet count and neurologic involvement.236 Clinical Features and Presentation. Cutaneous findings are present in virtually all patients. The most

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common skin finding is hyperpigmentation, which occurs in more than 90% of patients.235 The distribution is generally diffuse, although there may be localization to the extensor surfaces of the extremities, back, neck, or axillae.235,238 Histologic studies have generally shown increased pigmentation of the basal epidermis,239 although there are reports of melanophages in the papillary dermis.235 Hypertrichosis in also common, particularly on the extensor surfaces, malar areas, and forehead.235,236,239 Leukonychia, clubbing of the fingers, and hyperhidrosis have frequently been described.233 Cutaneous angiomas are common and may resemble renal glomeruli on histologic examination. These glomeruloid hemangiomas are specific to POEMS syndrome.240 Most patients with POEMS syndrome also have peripheral edema and sclerodermatous changes. Unlike scleroderma, the skin is freely movable over the periosteum and deep fascia. Histologic studies of these changes show increased dermal collagen.241 Alopecia,242 idiopathic flushing,243 ichthyosis,244 Raynaud’s phenomenon,245 eruptive seborrheic keratoses,244 angioendotheliomatosis,246 Sweet’s syndrome,247 generalized histiocytomas,248 and cutaneous vasculitis244 have also been reported in POEMS syndrome. Peripheral polyneuropathy is the most frequent presenting sign of POEMS syndrome.249 The neuropathy is distal and bilateral, with a progressive proximal spread. Deep tendon reflexes are decreased in the lower extremities and possibly the upper extremities as well.233 Cerebrospinal fluid shows elevated protein levels with normal cell counts.233 Nerve biopsy results typically show demyelination and axonal degeneration.241 Hepatomegaly is common in POEMS syndrome, but liver function test results are usually normal.250 Histology of the liver is also usually normal but may show a portal infiltrate or portal fibrosis.233 There are also reports of idiopathic cirrhosis235 or regenerative nodular hyperplasia.250 Lymph node biopsy results show findings consistent with Castleman’s disease. Splenomegaly, when present, is often due to splenic localization of Castleman’s disease.233 This latter variant has been shown to be associated with human herpes virus (HHV-8) infection.251 A variety of endocrinopathies are associated with POEMS syndrome, including diabetes mellitus or glucose intolerance249; hypogonadism with impotence, gynecomastia, or secondary amenorrhea; and hypothyroidism.235,252 In men, serum testosterone lev-

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els are usually low and impotence is the most common endocrinologic complaint.252 The plasma cell dyscrasia of POEMS syndrome is characterized by a monoclonal component. The monoclonal component is almost always IgA or IgG.253 Painless sclerotic bone lesions are present in most patients and may represent a variant of osteosclerotic myeloma.232 POEMS syndrome is progressive. Late involvement of the respiratory musculature leads to bronchopneumonia, the most common cause of death from POEMS syndrome.254 Differential Diagnosis. POEMS syndrome is a plasma cell dyscrasia; however, it differs from multiple myeloma in several respects. The mean age of onset for patients with POEMS syndrome is 47 years, whereas that for onset of multiple myeloma is 62 years.255 The paraprotein level in POEMS syndrome is lower than that in multiple myeloma and remains stable throughout the disease course.256 The majority of patients with POEMS syndrome have few bone lesions, and the lesions they do have are radiographically sclerotic or mixed lytic-sclerotic in appearance,234,235 in contrast to the lytic lesions of multiple myeloma. In addition, the hypercalcemia, Bence Jones proteinuria, renal failure, and amyloidosis that are common in multiple myeloma are not seen in POEMS syndrome.256 Screening and Management. Patients with solitary plasma cell tumors have responded well to radiotherapy233 or surgical ablation.257 High-dose corticosteroids have been used with some success, but relapses are common. Systemic chemotherapy has also been tried, often in combination with high-dose corticosteroids.249 Neurotoxic chemotherapy agents such as vincristine should be avoided in patients with POEMS syndrome.258 Recently, all-trans retinoic acid has been used in combination with radiotherapy to treat POEMS syndrome and has resulted in lowered levels of proinflammatory cytokines, along with a platelet count and gammopathy that paralleled the levels of the cytokines.259

Conclusions We have reviewed the basic findings of a sampling of neurocutaneous disorders. Our understanding of neurocutaneous disorders has increased rapidly in recent years. In the case of NF, excellent genetic

Curr Probl Dermatol, January/February 2003

testing and prenatal counseling have become commercially available for this dominant condition. For tuberous sclerosis, the understanding of the genetic basis of the illness has revealed a new contiguous gene syndrome involving the polycystic kidney gene. For XP, genetic diagnosis and understanding of the pathogenesis have helped contribute to the creation of a legitimate gene therapy. For AT, identification of the carrier state can suggest enhanced risk of breast cancer. Recent advances in the characterization and understanding of epidermal nevi have taught dermatologists important lessons pertaining to mosaicism, both in disease expression and in risk of genetic transmission. These nevi have also highlighted the importance of Blaschko’s lines as a marker of localized cutaneous gene expression and mosaicism. Finally, the POEMS syndrome demonstrates that neurocutaneous syndromes may arise de novo at any age. There is much that has been learned and much to be explored.

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