Author
Norberto Alvarez, MD
Assistant Professor; Department of Neurology
Harvard Medical School
Consulting Staff; Department of Neurology
Boston Children's Hospital
Boston, Massachusetts
Disclosure: Norberto Alvarez, MD, has disclosed no relevant financial relationships.
Editor
Lars Grimm, MD, MHS
House Staff
Department of Internal Medicine
Duke University Medical Center
Durham, North Carolina
Disclosure: Lars Grimm, MD, MHS, has disclosed no relevant financial relationships.
Reviewer
Robert A. Schwartz, MD
Professor and Head, Dermatology
Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health
UMDNJ-New Jersey Medical School
Newark, New Jersey
Disclosure: Robert A. Schwartz, MD, has disclosed no relevant financial relationships.
Phakomatoses, or neurocutaneous syndromes, are a group of mostly hereditary conditions, in which there is an association between skin/mucosal lesions and systemic disorders, usually neurological. In most instances the systemic disorders are more serious than the skin/mucosal lesions. The noncutaneous manifestations can be protean and so prompt identification of the characteristic cutaneous manifestations can lead to early diagnosis and treatment. A photograph of a patient with Sturge-Weber syndrome (SWS), a classic well-described phakomatosis, is shown with characteristic port-wine stain and glaucoma is shown. Image courtesy of Lamia Salah Elewa, MD.
Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem genetic disorder caused by a mutation in, or a deletion of, the NF1 gene. Dermatological findings are very important to suspect the diagnosis. The most common recognized skin lesions are café au lait spot, axillary or inguinal freckles, subcutaneous or cutaneous neurofibromas, and plexiform neurofibromas. Multiple cutaneous neurofibromas in a 28-year-old patient are shown.
Café au lait spots are the earliest manifestations of neurofibromatosis. They can be seen at birth. The number may increase with age. The presence of at least 6 macules at least 5 mm wide in children younger than 10 years (15 mm in adults) is one of the clinical criteria for the diagnosis of NF1. The macules have a brownish color and smooth borders (blue arrow). In this picture 2 neurofibromas can be seen, one in the upper right corner and the other one in the lower left corner (red arrows). Two or more neurofibromas are one of the clinical criteria for the diagnosis of the disease.
Other manifestations of NF1 are iris hamartomas (Lisch nodules), tumors such as optic nerve gliomas, pilocytic astrocytomas, pheochromocytomas, low-grade astrocytomas, bone dysplasia including sphenoid dysplasia, bowing of the tibia, thoracic cage asymmetry, scoliosis, learning disabilities with or without attention deficit hyperactivity disorder, epileptic seizures, osteoporosis, and hypertension as a symptom of a pheochromocytoma. An x-ray is shown demonstrating radial bowing, ulnar bowing, and obliteration of the intramedullary spaces.
Lisch nodules are the most common ocular manifestations. More than 95% of individuals with NF1 older than 10 years exhibit this finding. They consist of melanocytic hamartomas, the color usually being brown or yellow. They are evident as round elevations on the surface of the iris (blue arrows). They might be seen by the naked eye, but the best way to evaluate them is with slit-lamp examination.
Tuberous sclerosis complex (TSC) is caused by a mutation in the tumor suppressor genes TSC1 or TSC2. It is the second most common neurocutaneous disease. TSC is a multisystem disorder, affecting many organs, most frequently the brain, skin, eyes, heart, kidneys, and lungs. Even though genes have been identified, clinical manifestations, of which the skin lesions are one of the most important, are the main criteria for the diagnosis. Confetti skin lesions (shown) are hypomelanotic lesions that cluster and appear reticulated.
The typical skin lesions observed in TSC are ash-leaf spots (Fitzpatrick patches), confetti lesions, facial angiofibromas, shagreen patches, fibrous plaques, and periungual fibromas. Ash-leaf spots (left image) are hypomelanotic lesions that are observed more easily with the use of a Wood lamp. Shagreen patches (right image) are connective tissue hamartomas with a leathery texture, commonly found in the lumbar region. Image courtesy of Dirk M. Elston, MD.
The presence of either a forehead plaque or a facial angiofibroma constitutes one of the major diagnostic criteria for TSC. Forehead plaques (left image) are due to fibrosis with an excessive accumulation of collagen and blood vessels. Angiofibromas (right image) are pink or skin-colored telangiectatic papules. Image on right courtesy of Dirk M. Elston, MD.
The noncutaneous findings in tuberous sclerosis are numerous and can be grouped by organized systems.
Neurological: seizures, hydrocephalus, mental retardation, autism cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytoma(SEGAs)
Cardiac: rhabdomyomas
Renal: angiomyolipomas and renal cysts
Lungs: lymphangioleiomyomatosis (LAM) and pulmonary cysts
Ocular: retinal hamartomas and astrocytomas
ENT: pitting of dental enamel
The CT scan shown demonstrates bilateral renal angiomyolipomas in a 16-year-old adolescent.
SWS, or encephalotrigeminal angiomatosis, is a neurocutaneous disorder characterized by the presence of cutaneous angiomas (port-wine stain) mostly, but not limited, in the distribution of the ophthalmic (V1) and/or maxillary (V2) branches of the trigeminal nerve. A child with a bilateral facial port-wine stain from SWS is shown. Leptomeningeal angiomas are frequently present. The skin lesions are red or purple patches that may be isolated to the skin, but may also be seen in other areas of the body. They can be associated with malformations of the leptomeningeal vessels of the brain or the choroidal vessels of the eye. In most instances (85%) the lesions are unilateral with involvement of more than 1 dermatome (68%).
The neurological complications of SWS are numerous. Seizures, often intractable, are found in 75%-90% of patients. Focal deficits include hemiparesis, hemianopsia, and stroke-like episodes. Developmental delay is more common in patients with bilateral skin lesions. Buphthalmos and glaucoma may result in blindness. CT may demonstrate calcifications, brain atrophy, ipsilateral choroid plexus enlargement, and abnormal draining veins. MRI with contrast may show leptomeningeal angiomas, even as early as in newborns. These T1-weighted axial MRI images demonstrate left cerebral hemiatrophy associated with leptomeningeal angiomatosis. Image courtesy of Lamia Salah Elewa, MD.
Osler-Weber-Rendu syndrome, or hereditary hemorrhagic telangiectasia (HHT), is a rare autosomal dominant disorder of interest to neurologists because CNS arteriovenous aneurysms may appear later in life. Neurological involvement is seen in around 10% of individuals with this condition. Epistaxis is usually the first symptom followed by telangiectasias. Skin lesions consists of dark red lines or small pulsating vascular papules present on the skin, oral and/or nasal mucosa, and conjunctiva. In some cases 1-3 mm, star-shaped nonpulsating telangiectasias are seen. A photograph of sublingual telangiectasias is shown. Image courtesy of Dirk M. Elston, MD.
One third of patients with Osler-Weber-Rendu syndrome will develop pulmonary arteriovenous malformations. With progressive disease, these patients develop worsening right-to-left shunting and hemoptysis. Treatment with coil embolization is needed in advanced cases. A pulmonary angiogram in a patient with HHT reveals a large vessel feeding an arteriovenous malformation (arrow).
Incontinentia pigmenti is an X-linked dominant disorder lethal to male patients. Skin abnormalities occur in 4 stages. Stage 1, the vesicular stage, occurs from birth to 2 weeks. Infants present with inflammatory vesicles and bullae in a linear pattern on the extremities, trunk, and scalp. Recurrent crops of erythematous macules and papules may erupt for weeks. Skin biopsy specimens at this stage reveal increased eosinophils. Stage 2, the verrucous stage, occurs from 2-6 weeks, with hyperkeratotic streaks, pustules, and papules occurring exclusively on the extremities. Stage 3, the hyperpigmentation stage, occurs from 3-6 months and is characterized by marbled swirls of hyperpigmentation along Blaschko lines (shown). Stage 4, the hypopigmentation stage, occurs in adult women, when follicular atrophy and hypopigmentation replace hyperpigmented swirls. Image courtesy of military teaching file.
Epidermal nevi (EN) are congenital hamartomas of embryonal ectodermal origin. Several clinical syndromes have been described on the basis of the different dermatological lesions, but the common feature in all of them is the presence of skin lesions associated with other systemic involvement. In most instances the skin lesions are less visible in early infancy. With age they become darker with hyperkeratosis and a verrucous appearance. In some instances they become malignant (basal cell carcinoma, squamous cell carcinoma). Epileptic seizures are seen in most of the patients. Other neurological manifestations include paresis of cranial nerves VI and VII, hemiparesis, and cortical blindness. Brain malformations include hemimegalencephaly, cortical dysgenesis, cortical atrophy, and agenesis of the corpus callosum. A characteristic epidermal nevus in a child with Jadassohn nevus phakomatosis is shown.
Ataxia-telangiectasia (AT) is a genetic disease characterized by progressive cerebellar ataxia, associated with the presence of telangiectasias in the eyes and skin. Progressive cerebellar ataxia is the first symptom, usually observed around the first year of life. The typical telangiectasias appeared in the conjunctiva of the eyes around the age of 3-7 years (arrows). Telangiectatic lesions will appear later in the face, palate, antecubital fossa, and popliteal fossa.
Additional features of AT include mental retardation, speech delay, oculomotor abnormalities, coarse hair and skin, thymic hypoplasia, deficiency of immunoglobulin A, and malignancies including leukemia and Hodgkin lymphoma. An MRI demonstrates a high signal lesion in the right mediastinum (arrow), corresponding to lymphoma in a patient with AT.
Author
Norberto Alvarez, MD
Assistant Professor; Department of Neurology
Harvard Medical School
Consulting Staff; Department of Neurology
Boston Children's Hospital
Boston, Massachusetts
Disclosure: Norberto Alvarez, MD, has disclosed no relevant financial relationships.
Editor
Lars Grimm, MD, MHS
House Staff
Department of Internal Medicine
Duke University Medical Center
Durham, North Carolina
Disclosure: Lars Grimm, MD, MHS, has disclosed no relevant financial relationships.
Reviewer
Robert A. Schwartz, MD
Professor and Head, Dermatology
Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health
UMDNJ-New Jersey Medical School
Newark, New Jersey
Disclosure: Robert A. Schwartz, MD, has disclosed no relevant financial relationships.
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