NEUROCUTANEOUS SYNDROMES 13.1 Neurofibromatosis Type 1 A 5-year-old boy presented with headaches and “trouble seeing.” Dermatological examination revealed multiple café-au-lait spots and axillary speckling. His visual acuity was 20/70 OD and 20/200 OS. Images 13.1A–13.1D: Postcontrast axial, coronal, and sagittal T1-weighted and axial fluid-attenuated inversion recovery (FLAIR) images demonstrate a large, heterogeneously enhancing lesion arising from the optic nerves, chiasm, and tract, more so on the left, with mass effect on the temporal lobe and ventricular system. 1. Six or more café-au-lait spots or hyperpigmented macules greater than or equal to 5 mm in diameter in prepubertal children and 15 mm postpubertal 2. Axillary or inguinal freckles (>2) 3. Two or more typical neurofibromas or one plexiform neurofibroma 4. Optic nerve glioma 5. Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination 6. Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis 7. First-degree relative (eg, mother, father, sister, brother) with NF1 Image 13.1E: A café-au-lait spot (image credit Klaus D. Peter). Image 13.1F: Multiple Lisch nodules in a patient with NF1 (image: National Eye Institute). Image 13.1G: Multiple subcutaneous neurofibromas (image credit Klaus D. Peter). Images 13.1H and 13.1I: Coronal postcontrast T1-weighted and STIR images demonstrate an enormous plexiform neurofibroma extending from the retroperitoneum through the pelvis and right leg. Image 13.1J: Gross pathology of a neurofibroma (image credit Jensflorian). Images 13.1K and 13.1L: Lateral radiographs of the leg of a patient with NF1 demonstrate thinning of the long bones. Images 13.1M and 13.1N: Axial FLAIR images demonstrate hyperintensities in the basal ganglia and cerebellum in a patient with NF1. Image 13.1O: Top left: Low power view showing a well-circumscribed tumor in association with the peripheral nerve (red arrowhead). Top right: collagen bundles in a “shredded carrot” pattern in a myxoid (bluish) background. Bottom left: Patchy immunoreactivity for S-100. Bottom right: Neurofilament positive axons within the tumor. (Image courtesy of Dr. Seema Shroff, Fellow, Neuropathology, NYULMC.) 1. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. August 2014;13(8):834–843. 2. Rosenbaum T, Wimmer K. Neurofibromatosis type 1 (NF1) and associated tumors. Klin Padiatr. November 2014;226(6–7):309–315. 3. Ferner RE, Gutmann DH. Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol. 2013;115:939–955. 13.2 Neurofibromatosis Type 2 A 23-year-old female developed hearing loss and tinnitus. On examination, she was found to have bilateral sensorineural hearing loss as well as mild weakness and hyperreflexia in her legs. Images 13.2A–13.2C: Postcontrast axial and coronal T1-weighted and axial FLAIR images demonstrate bilateral vestibular schwannomas in a patient with neurofibromatosis type 2. Image 13.2D: Gross pathology of bilateral vestibular schwannomas (image credit The Armed Forces Institute of Pathology). Image 13.2E: Postcontrast axial T1-weighted image demonstrates bilateral schwannomas originating from the trigeminal nerve (red arrows) in addition to bilateral vestibular schwannomas in a patient with NF2. Images 13.2F–13.2I: Postcontrast axial and sagittal T1-weighted images demonstrate multiple meningiomas in a patient with NF2. Images 13.2J–13.2N: Postcontrast sagittal and axial T1-weighted images of the cervical spine demonstrate an extradural meningioma (green arrow in Image 13.2K), the dumbbell shape of peripheral nerve schwannoma (red arrows in Image 13.2L), and an intramedullary tumor consistent with an intramedullary ependymoma (Image 13.2J). The spinal cord is indicated by the yellow arrows. Gross pathology of spinal cord in neurofibromatosis with multiple schwannomas (13.2N). 1. Evans DG. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. June 2009;4:16. 2. Lloyd SK, Evans DG. Neurofibromatosis type 2 (NF2): diagnosis and management. Handb Clin Neurol. 2013;115:957–967. Unless otherwise stated, all pathology images in this chapter are from the website http://medicine.stonybrookmedicine.edu/pathology/neuropathology and are reproduced with permission of the author, Roberta J. Seidman, MD, Associate Professor. Unauthorized reproduction is prohibited. 13.3 Sturge–Weber Syndrome An 8-year-old boy presented with mental retardation and seizures since infancy. He had a large “port-wine stain” on his upper face on the right side. Images 13.3A–13.3D: Axial CT images demonstrate the “tram-track” calcifications of Sturge–Weber syndrome. Image 13.3E: A port-wine stain in the distribution of the trigeminal nerve. Images 13.3F and 13.3G: Axial CT images demonstrate the remarkable degree of “tram-track” calcification possible in Sturge–Weber syndrome. Images 13.3H and 13.3I: Postcontrast axial T1-weighted images demonstrate bilateral occipital lobe leptomeningeal enhancement (red arrows) compatible with angiomatosis. There is also enhancement and hypertrophy of the choroid plexus bilaterally (yellow arrows). Images 13.3J and 13.3K: Anterior–posterior angiogram in the venous phase revealing that the surface medial and lateral convexity veins are absent, with exception of a single midfrontal convexity vein (red arrow) draining into the superior sagittal sinus (yellow arrow), a hallmark of Sturge–Weber syndrome. The contralateral side is normal for comparison. Image 13.3L: Axial T2-weighted image from a patient who underwent a right hemispherectomy to control seizures. 1. Sudarsanam A, Ardern-Holmes SL. Sturge-Weber syndrome: from the past to the present. Eur J Paediatr Neurol. May 2014;18(3):257–266. 2. Comi AM. Sturge-Weber syndrome and epilepsy: an argument for aggressive seizure management in these patients. Expert Rev Neurother. August 2007;7(8):951–956. 13.4 von Hippel–Lindau Syndrome A 13-year-old presented with dizziness and ataxia. Images 13.4A–13.4C: Postcontrast axial, coronal, and sagittal T1-weighted images demonstrate two right cerebellar hemangiomas in a patient with von Hippel–Lindau syndrome. An enhancing nodule is seen at the margin of the lesions (red arrows). Images 13.4D–13.4F: Postcontrast sagittal T1-weighted and T2-weighted and postcontrast axial T1-weighted images demonstrate innumerable spinal hemangiomas. Images 13.4G and 13.4H: Sagittal T2-weighted and postcontrast T1-weighted images of the cervical spine demonstrate a hemangioblastoma, which is again cystic with a solid nodule (red arrow). Image 13.4I: A retinal angiogram demonstrates an ocular hemangioma (image credit Dr. Stephen C. Pollack). Images 13.4J and 13.4K: Low and high power magnification reveals the vascularity of a hemangioblastoma (image credit Dr. Seema Shroff, Fellow, Neuropathology, NYULMC). 1. Friedrich CA. Von Hippel-Lindau syndrome. A pleomorphic condition. Cancer. December 1999;86:2478–2482. 2. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. June 2011;19(6):617–623. 3. Chou A Toon C, Pickett J, Gill AJ. von Hippel-Lindau syndrome. Front Horm Res. 2013;41:30–49. 13.5 Tuberous Sclerosis An 8-year-old child with MR developed intractable seizures and mental retardation. The examination showed subungual fibromas of toenails, adenoma sebaceum, and a Shagreen patch. The patient had autistic features and language delays, but no focal motor or sensory deficits. Images 13.5A and 13.5B: Axial FLAIR images demonstrate multiple cortical tubers (red arrows) and subependymal nodules (blue arrows) creating the “candle-guttering” sign. Images 13.5C and 13.5D: Gross pathology of cortical tubers (red arrow) and subependymal nodules (blue arrow). The cortex is thickened. Image 13.5E: Adenoma sebaceum (image credit Herbert L. Fred, MD, and Hendrik A. van Dijk). Image 13.5F: Ash leaf spots (image credit Herbert L. Fred, MD, and Hendrik A. van Dijk). Image 13.5G: Ungual fibromas (image credit Dr. David G. Cogan). Image 13.5H: A shagreen’s patch. Images 13.5I and 13.5J: Axial CT images demonstrate many calcified subependymal nodules and lesions within the brain parenchyma. Images 13.5K–13.5M: Postcontrast axial, coronal, and sagittal T1-weighted images demonstrate a large SEGA in the left frontal horn and third ventricle with cystic portions extending into the right basal ganglia. Image 13.5N: Gross pathology of a SEGA (image credit The Armed Forces Institute of Pathology). Images 13.5O and 13.5P: Coronal and axial T1-weighted images of the abdomen and pelvis showing massive renal enlargement due to innumerable angiomyolipomas. Images 13.5Q and 13.5R: Right and left renal angiograms demonstrate abnormal vessels associated with angiomyolipomas. Image 13.5S: Axial chest CT image demonstrates severe cystic lung disease consistent with lymphangiomyomatosis. 1. Grajkowska W, Kotulska K, Jurkiewicz E, Matyja E. Brain lesions in tuberous sclerosis complex. Review. Folia Neuropathol. 2010;48(3):139–149. 2. Borkowska J, Schwartz RA, Kotulska K, Jozwiak S. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. January 2011;50(1):13–20. 3. Fallah A, Rodgers SD, Weil AG, et al. Resective epilepsy surgery for tuberous sclerosis in children: determining predictors of seizure outcomes in a multicenter retrospective cohort Study. Neurosurgery. October 2015;77(4):517–524. Unless otherwise stated, all pathology images in this chapter are from the website http://medicine.stonybrookmedicine.edu/pathology/neuropathology and are reproduced with permission of the author, Roberta J. Seidman, MD, Associate Professor. Unauthorized reproduction is prohibited.
Case History
Diagnosis: Neurofibromatosis Type 1
Introduction
NF1 (von Recklinghausen disease) is an autosomal-dominant condition caused by decreased production of the protein neurofibromin, which has a putative tumor suppressor function.
The NF1 gene has been localized to the long arm of chromosome 17; a more severe phenotype has been observed in a subset of patients with a complete gene deletion. Only one NF1 gene need be deleted or mutated to produce the condition.
Mutations in another gene (SPRED1) have been identified in a subset of patients described to have an NF-like syndrome, also known as Legius syndrome. These patients do not develop neurofibromas or Lisch nodules, unlike NF1.
Clinical Presentation
NF1 presents with a variable combination of cutaneous findings, benign neurofibromas, visual disturbances due to optic pathway gliomas, and abnormalities of the skeletal system. Patients develop symptoms by the age of 5.
Additional features include learning disabilities in about half of the patients, scoliosis, behavioral disturbances, hypertension, pheochromocytomas, hypoglycemia, iris fibromas glaucoma, seizures in 10% of patients, gliomas in the brain and brainstem, and glomus tumors. Congenital pseudoarthrosis and bowing of tibial bones can be evident at birth.
Radiographic Appearance and Diagnosis
The diagnosis requires the presence of at least two of seven criteria to confirm the presence of neurofibromatosis, type 1. The seven clinical criteria used to diagnose NF1 are as follows:
Optic pathway gliomas often originate from the optic nerve, but may grow along the length of the visual pathways including the optic chiasm and tract. They homogeneously enhance with the administration of contrast, and there is often significant mass effect on adjacent structures. They are hyperintense on T2-weighted images.
The dermatological and ocular manifestations of NF1 are shown (see Images 13.1E–13.1G).
Plexiform neurofibromas appear as large masses on peripheral nerves.
Thinning of the long bones is visible on plain radiographs.
Another common finding is numerous foci of abnormal hyperintensity on T2-weighted images that are concentrated in the basal ganglia, cerebellum, and brainstem. These are referred to as “unidentified objects” or “UBOs.” These lesions may represent areas of proliferation of glial cells. They may spontaneously resolve, but may be a marker for cognitive impairment.
The pathological findings of a neurofibroma are shown in Image 13.1O.
Treatment
Symptomatic skin neurofibromas can be treated with simple excision, carbon dioxide laser ablation, and electrocautery. Partial surgical excision of plexiform neurofibromas may be attempted, but total excision is often not possible. Resection of optic pathway gliomas may be attempted if only one nerve is affected, though there will be permanent visual loss in that eye.
Orthopedic surgery may be needed to correct limb overgrowth.
References
Case History
Diagnosis: Neurofibromatosis Type 2
Introduction
Neurofibromatosis type 2 (NF2) is characterized by the growth of multiple, nonmalignant brain tumors. It is caused by a defect on chromosome 22 that gives rise to a product called merlin or schwannomin. It is a member of the ezrin, radixin, moesin (ERM) family of cytoskeleton–membrane linker proteins. The NF2 mutation is about 98% penetrant.
It affects about 1 in 60,000 people. Half of the cases are sporadic, and half are inherited in an autosomal-dominant fashion.
Clinical Presentation
Bilateral vestibular schwannomas are the hallmark of the disease, seen in over 90% of patients. The most common clinical presentation is slowly progressive, bilateral hearing loss in older children and young adults. Almost all patients are affected by the age of 30 years.
Schwannomas of other cranial nerves are seen most commonly in the trigeminal nerve. Multiple meningiomas are also characteristic and may present with seizures, headaches, or focal neurological symptoms from compression of the underlying brain or spinal cord.
Nearly half of the patients have spinal lesions, which present with a slowly progressive myelopathy.
More than 90% of patients have an opacity of the lens known as a juvenile subcapsular cataract.
In contrast to NF1, skin lesions are not common.
The formal diagnostic criteria for NF2 require one of the following clinical presentations:
Bilateral vestibular schwannomas
Unilateral vestibular schwannoma and any two of the following: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacity
A first-degree relative with NF2 and either a unilateral vestibular schwannoma or any two of the following: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacity
Multiple meningiomas and either a unilateral vestibular schwannoma or any two of the following: schwannoma, glioma, neurofibroma, cataract
Radiographic Appearance and Diagnosis
Imaging will often reveal bilateral vestibular schwannomas. These are extraaxial, enhancing masses that originate in the internal auditory canal and project into the cerebellopontine angle often with significant mass effect on the brainstem and cerebellum. Schwannomas can be seen on other cranial nerves as well, most commonly the trigeminal nerve.
Diagnostic technologies such as MRI and CT can reveal tumors as small as a few millimeters in diameter, thus allowing early treatment.
Meningiomas are extraaxial, homogeneously enhancing masses that frequently have a dural tail and externally compress the brain and spinal cord.
Lesions of the spinal canal include extramedullary lesions (meningiomas and schwannomas) and intramedullary lesions (astrocytomas or ependymomas).
Treatment
At present, treatments are aimed at controlling the symptoms.
Surgical resection of symptomatic tumors is the mainstay of treatment. However, many tumors are not resectable due to their location and only partial removal of tumors is possible. Surgical removal of the tumors may result in hearing loss.
Radiation therapy (radiosurgery).
Watchful waiting—if tumors are not progressing rapidly or if the patient has other serious medical issues.
Genetic counseling is important as well.
References
Case History
Diagnosis: Sturge–Weber Syndrome
Introduction
Sturge–Weber syndrome is characterized by angiomas of the meninges, eye, face, and brain. It is unique among the neurocutaneous disorders in that it is sporadic, without a hereditary component.
Clinical Presentation
Patients present with seizures that usually start in infancy. There is often a port-wine stain birthmark, caused by an overgrowth of capillaries, usually in the ophthalmic nerve distribution. Malformation of blood vessels in the pia mater causes failure of venous drainage. This, in turn, leads to neuronal loss and calcification in the cerebral cortex ipsilateral to the birthmark. In most patients, the findings are unilateral. Stroke-like episodes, hemiparesis, visual field defects, headaches, and cognitive dysfunction are commonly encountered.
Ocular manifestations: glaucoma, buphthalmos, tomato-catsup fundus, iris heterochromia, tortuous retinal vessels, myopia, strabismus, amblyopia, visual field defects, conjunctival and choroid hemangiomas.
Radiographic Appearance and Diagnosis
Skull radiography shows classic double-lined gyriform pattern of calcifications paralleling cerebral convolutions referred to as “tram-track” or “railroad-track” calcifications.
Head CT and brain MRI typically reveal parietooccipital calcifications in a gyriform distribution. Most commonly the posterior portion of the brain is affected, and the frontal lobes are spared. However, in severe cases, all four lobes of the brain are involved. There may be cortical atrophy, abnormal draining veins, and an enlarged choroid plexus with prominent contrast enhancement.
CT or MRI may show hemiatrophy of the cerebral hemisphere; changes similar to those of the Dyke–Davidoff–Masson syndrome, including cerebral hemiatrophy with ipsilateral calvarial diploic space enlargement, may be seen in Sturge–Weber syndrome.
With the addition of contrast, leptomeningeal enhancement and choroid plexus hypertrophy are commonly seen.
On catheter angiograms, superficial cortical veins are absent and the deep venous drainage is enlarged and abnormal.
Treatment
Seizures: Antiseizure medications, focal cortical resection, corpus callosotomy or vagal nerve stimulator (VNS). Hemispherectomy (anatomic hemispherectomy vs functional hemispherectomy vs hemidecortication) is recommended when seizures are intractable or when there is evidence of progressive cortical damage. VNS can be performed in patients who are not good candidates for other surgeries.
Cutaneous: dye laser anticoagulation.
Eyes: glaucoma surgery, radiotherapy for choroidal hemangiomas.
References
Case History
Diagnosis: von Hippel–Lindau Syndrome
Introduction
von Hippel–Lindau (VHL) syndrome is caused by an autosomal-dominant mutation in the VHL gene, which acts as a tumor suppressor. It is characterized by multiple hemangiomas of the eye and central nervous system (CNS). Hemangioblastomas are noninfiltrative masses formed by the overgrowth of capillaries. They are the most common primary infratentorial neoplasm in adults. About 20% of all hemangioblastomas occur as part of VHL syndrome.
It occurs in about 1 in 35,000 to 1 in 50,000 persons.
Clinical Presentation
Patients present with symptoms of increased intracranial pressure (ICP) and cerebellar dysfunction. These include headache, ataxia, nausea, vomiting, and vertigo. If there is hemorrhage into the tumor, patients may experience sudden and severe neurological symptoms. Spinal hemangioblastomas present with a progressive myelopathy and are highly specific for VHL.
Retinal hemangiomas are a core feature of the disease and can cause visual loss.
On histology, hemangiomas are highly vascular tumors.
Other features include cysts of the pancreas, kidneys, liver, and reproductive organs. Clear-cell renal cell carcinomas, pancreatic neuroendocrine tumors, and pheochromocytomas also occur at an increased frequency. These tumors are a frequent cause of death for patients with VHL.
Approximately 10% of patients develop endolymphatic sac tumors, which can lead to sudden and severe hearing loss.
Radiographic Appearance
Hemangioblastomas are cystic masses with an enhancing nodule at the margin of the lesion 50% of the time. The contents of the cyst are isodense to cerebrospinal fluid (CSF) on all sequences. In the other 50% of cases, they are solidly enhancing masses.
Seventy-five percent occur in the cerebellum, most often in the vermis, while the remainder occur in the spinal cord or medulla. Supratentorial hemangioblastomas are very rare.
Treatment
It is important to screen patients with VHL for retinal angiomas, hemangioblastomas, renal carcinomas, and pheochromocytomas. Hemangioblastomas are benign, and surgery is curative if the entire tumor can be removed. The tumor will recur if resection is not complete. Treatment of retinal angiomas and renal carcinomas can reduce disability and increase life expectancy.
References
Case History
Diagnosis: Tuberous Sclerosis Complex
Introduction
Tuberous sclerosis complex (TSC) is a neurocutaneous disorder characterized by hamartomas in the brain, skin, heart, lung, liver, and kidney.
TSC is an autosomal-dominant disorder affecting children and adults; it results from mutations in one of two genes, TSC1 (encoding hamartin) or TSC2 (encoding tuberin).
Major Features of TSC
Facial angiofibromas or forehead plaque.
Nontraumatic ungual or periungual fibroma.
Hypomelanotic macules (>3).
Shagreen patch (connective tissue nevus).
Multiple retinal nodular hamartoma.
Cortical tuber: When cerebellar cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of tuberous sclerosis (TS).
Subependymal nodules (SEN).
Subependymal giant cell astrocytoma (SEGA).
Cardiac rhabdomyoma, single or multiple.
Lymphangioleiomyomatosis: When both lymphangioleiomyomatosis (LAM) and renal angiomyolipomas (AMLs) are present, other features of TS should be present before a definite diagnosis is assigned. As many as 60% of women with sporadic LAM (and not TSC) may have renal or other AMLs.
Renal AML: When both LAM and renal AMLs are present, other features of TS should be present before a definite diagnosis is assigned (see previous remarks).
Minor Features of TSC
Multiple randomly distributed pits in dental enamel.
Hamartomatous rectal polyps: Histological confirmation is suggested.
Bone cysts: Radiographic confirmation is sufficient.
Cerebral white matter radial migration lines: Radiographic confirmation is sufficient. One panel member felt strongly that three or more radial migration lines should constitute a major sign.
Gingival fibromas.
Nonrenal hamartoma: Histological confirmation is suggested.
Retinal achromic patch.
“Confetti” skin lesions.
Multiple renal cysts.
Diagnostic Criteria for TSC
Definite TSC—Two major features or one major feature plus two or more minor features.
Possible TSC—Either one major feature or two or more minor features.
Clinical Presentation
TSC is characterized by a variable combination of mental retardation, autism, seizures, and a wide variety of dermatological abnormalities.
The kidneys, heart, eyes, lungs, and eyes may be affected by hamartomas.
Renal: autosomal-dominant polycystic kidney disease, isolated renal cyst(s), AMLs, which are more common in women and may develop later in adulthood, and renal carcinoma.
Cardiac: rhabdomyomas, which cause cardiac output failure.
Pulmonary: multifocal micronodular pneumocyte hyperplasia (MMPH), pulmonary cysts, and LAM; LAM is inexorably progressive and more common in women.
Ocular: retinal astrocytomas, hypopigmented areas of retina, iris, and even eyelashes.
Hepatic: Cysts, typically asymptomatic and nonprogressive.
Radiographic Appearance
Radiographically, TS is characterized by:
Cortical tubers, which are thought to be due to either poor myelination or dysplasia of the white matter. On CT images, the tubers are often calcified. On T2-weighted images, they appear as hyperdensities of the cortex and subcortical white matter. Tubers are characterized by dysplastic glial and neuronal elements and disorganized cortical lamination.
Subependymal nodules (SENs). These are projections into the walls of the lateral ventricles said to have a “candle-guttering” appearance. They are shown in Images 13.5A and 13.5B.
Subependymal giant cell astrocytomas (SEGAs). The generally benign SENs can degenerate into SEGAs in 5% to 10% of cases. SEGAs are benign tumors that arise from the subependyma and project into the lateral ventricle often abutting the septum pellucidum. They have variable signals on both CT and MRI depending on the degree of calcification. They are often clinically silent, but if large enough may lead to obstructive hydrocephalus and increased ICP.
Cerebral aneurysms: These have been reported intracranially as well as in the aorta and axillary arteries.
Extraneurological manifestations of TS include AMLs, which are benign tumors of the kidney composed of blood vessels, smooth muscle cells, and fat cells.
LAM is a proliferation of disorderly smooth muscle growth throughout the lungs and pulmonary vasculature.
Treatment
Seizures: antiseizure medications; note that vigabatrin (Sabril) is considered a first-line therapy for infantile spasms; ketogenic diet.
m-TOR inhibitors: rapamycin or sirolimus or everolimus (Afinitor) is used to treat various hamartomas or SEGAs.
Surgery: surgical resection of tumors affecting various organs if symptomatic; focal cortical resection, corpus callosotomy, VNS, removal of SEGAs, shunt surgery for obstructive hydrocephalus.
Facial angiofibromas: laser therapy, topical rapamycin.
References
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