Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March  17, 2010 — Thoracic disc disease and herniation is a common etiology for thoracic radiculopathy (Fig. 1). Symptomatic cases of thoracic disc herniation have been reported at almost all thoracic levels [9]. As in other spinal regions, MR imaging has all but replaced CT and myelography in the routine evaluation of thoracic disc disease. The lower thoracic spine (T8–T12 levels) is the most frequent site of occurrence, with the T11–T12 interspace accounting for 26–50% of all thoracic herniations [2–4]. Degeneration is favored as the prevailing cause for thoracic disc herniation, and the lower thoracic segments are most at risk because of the increased motion present at these levels [1]. Despite this degenerative etiology, thoracic disc disease is involved in only 0.15–4% of symptomatic disc herniations of the spine, and they represent <2% of all spinal disc surgeries performed [5,6]. The incidence of thoracic disc herniation is equal between men and women, and the age of onset is generally between the third and sixth decades of life [7].

Figure 1. A 55-year-old female patient with neck and upper chest pain and previous hardware fusion in the cervical spine. Sagittal (A) and axial (B,C) T2 weighted Mr imaging of the thoracic spine demonstrate a left paracentral disc herniation at the T7–8 level causing cord displacement and deformity. (Click for more details)

• Signs and symptoms

The symptoms associated with thoracic disc herniation are variable and usually include radicular symptoms such as variable pain, parasthesias, dysesthesias, allodynia, and loss of sensation in a segmental distribution across the anterior chest, thorax, and abdomen, depending on which nerve root(s) are affected. For example, T4 radiculopathies usually radiate to the nipple level; T6, the xiphoid; and T10, the umbilicus. First thoracic radiculopathy (T1) radiates into the median arm or ulnar aspect of the hand [8], and for our purposes will be covered in the cervical radiculopathy articles. Additionally, there may be localized axial pain at the level of spine pathology and thoracic radiculopathy. Diagnosis of some patients who report a deep aching-type pain is much more difficult because the pain can mimic other thoracic or abdominal problems such as angina, dyspepsia, or diverticular disease. It seems likely that some patients with atypical abdominal and chest pain have undiagnosed thoracic radiculopathy; however, the extent of this has never been adequately documented.

Physical examination is not a reliable way to diagnose thoracic radiculopathy. There may be localized spine and paraspinal tenderness, and sensory changes in a dermatomal pattern, but this is not universal. Unlike cervical or lumbosacral radiculopathies, there is no reliable way to test for muscle weakness in a myotomal pattern. The muscles that are likely to be affected (paraspinal, intercostal, and abdominal muscles) do not lend themselves to isolated muscle testing. Physical examination is critical, however, to rule out other causes of chest or abdominal pain and assess for myelopathy as discussed below.

There are also reports of thoracic disc herniations causing atypical symptoms. Two such cases involved patients with lower extremity leg pain mimicking that of lumbosacral disc disease and radiculopathy. The patients’ symptoms did not subside until a thoracic herniated nucleus pulposus (HNP) was identified and treated surgically at the involved T10 level [8,9]. Another case involved a patient with predominant shoulder pain and incomplete paraplegia. After an acromioplasty procedure for impingement syndrome failed to improve the patient’s shoulder symptoms, a large lower thoracic disc herniation was identified via MR imaging. Following surgical removal of the thoracic disc, the patient reported complete resolution of his shoulder pain symptoms and improvement in his paraplegia [10]. Thoracic discs generally herniate in a posterior-central or a posterior-lateral direction, and true lateral herniations are rare [11]. The incidence of asymptomatic thoracic disc herniation has been estimated at 37%, and the size of the herniation tends to fluctuate over time in patients who remain without symptoms [12].

The most serious of symptoms related to thoracic disc herniation and radiculopathy is the development of myelopathy. As in the cervical spine, thoracic myelopathy can result in irreversible neurologic dysfunction and threaten spinal cord tracts. It is often the result of spinal cord compression of a large central thoracic disc, a calcified thoracic HNP, an intradural herniation, or compromise of the spinal cord vascular supply [13]. Bladder dysfunction, a wide-based ataxic pattern of gait, and upper motor neuron signs such as positive Babinski sign, ankle clonus, and hyperreflexia should be sought for in a patient with suspected myelopathy. Mild lower extremity paraparesis is the most common symptom associated with thoracic disc herniation with myelopathy [14]. A thorough neurologic examination should be performed on all patients with suspected thoracic disc disease including tests usually reserved for patients with spinal cord injury such as Beevor’s sign and the cremasteric reflex. The coincidence of thoracic degenerative disc disease in a patient with pre-existing myelopathy can present with particularly complex symptoms (Fig. 2).

Figure 2. A 46-year-old female patient with multiple sclerosis presenting with right-sided midthoracic pain. T2-weighted sagittal (A) and axial (B,C) images of the cervical and thoracic spine. C2–5 region cord lesions caused by demyelinating disease are seen. A small right paracentral disc herniation is seen at the T8–9 level that was felt to be responsible for the patient’s acute symptoms. (Click for more details)

Thoracic spinal stenosis represents another, less common cause of thoracic radiculopathy with myelopathy. It may be defined as the narrowing of the anteroposterior (AP) diameter of the thoracic spinal canal to less than <10 mm. Scheuermann’s disease, achondroplasia, and epidural lipomatosis have been considered conditions that can contribute to, or cause, thoracic spinal stenosis. When present, thoracic spinal stenosis is highly associated with coexisting lumbar spinal stenosis [15].

References

1. Mcinerney J, Ball PA. The pathophysiology of thoracic disc disease. Neurosurg Focus. 2000;9(4):1-8
2. Blumenkopf B. Thoracic intervertebral disc herniations: diagnostic value of magnetic resonance imaging. Neurosurgery. 1988;23:36-40
3. Tahmouserie A. Herniated thoracic intervertebral disc, an unusual presentation. Case report. Neurosurgery. 1980;7:623-625
4. Videman T, Battie MS, Gill K, et al. Magnetic resonance imaging findings and their relationships in the thoracic and lumbar spine. Spine. 1995;20:928-935
5. Alvarez O, Roque CT, Pampeti M. Multilevel thoracic disc herniations: CT and MR studies. J Comp Assist Tomog. 1988;12:649-652
6. Acre CA, Dohrmann G. Thoracic disc herniation. Improved diagnosis with computed tomographic scanning and a review of the literature. Surg Neurol. 1985;23:356-361
7. Brown CW, Deffer Jr. PA, et al. The natural history of thoracic disc herniation. Spine. 1992;17(Suppl 6):S97-S102
8. Lyu RK, Chang HS. Thoracic disc herniation mimicking acute lumbar disc disease. Spine. 1999;24(19):2066-2067
9. Knoller SM, Haag M. Paralysis of the foot as the first symptom of herniated thoracic disc. Zentrabl Neurochir. 1999;60(4):191-195
10. Wilke A, Wolf U. Thoracic disc herniation: a diagnostic challenge. Man Therapy. 2000;5(3):181-184
11. Stillerman CB, Chen TC, et al. Experience in the surgical management of 82 symptomatic herniated thoracic discs and a review of the literature. J Neurosurg. 1988;88:623-633
12. Wood KB, Blair JM. The natural history of asymptomatic thoracic disc herniations. Spine. 1997;22:525-530
13. Epstein NE, Syrquin MS. Intradural disc herniations of the cervical, thoracic, and lumbar spine: report of three cases and a review of the literature. J Spinal Disord. 1990;12:396-403
14. Vanichkachorn JS, Vaccaro AR. Thoracic disc disease: diagnosis and treatment. J Am Acad Orthop Surg. 2000;8:159-169
15. Epstein NE, Schwall G. Thoracic spinal stenosis: diagnostic and treatment challenges. J Spinal Disord. 1994;7:259-269
16. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.2a April 2010 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 13, 2010 — The phakomatoses are a set of inherited neurologic disorders that were grouped together by van der Hoeve in 1932 [1]. The grouping included neurofibromatosis (NF), tuberous sclerosis (now called tuberous sclerosis complex, TSC), and von Hippel-Lindau syndrome (VHL). The original basis for the aggregation was that each disorder produces spotty manifestations. Much has been learned about these disorders in the decades since van der Hoeve. It is now known that these are three separate conditions with little in common clinically, each the result of a change in a distinct gene. NF and TSC, in fact, are themselves genetically heterogeneous: NF now can be split into three disorders, neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis, and TSC into two disorders, TSC1 and TSC2. Nevertheless, there is still some utility to the phakomatosis concept. First, it calls attention to a set of disorders that share a tendency toward development of tumors of the nervous system, associated with other multisystem features. Second, although the genes are different, they all act through a tumor suppressor mechanism. This article considers each of the phakomatoses, including major clinical features and current understanding of pathogenetic mechanisms (Table 1). (Click to download table 1. In PDF format)

• The tumor suppressor concept

The modern understanding of the phakomatoses, and of cancer genetics in general, can be traced to the tumor suppressor hypothesis formulated by Knudson [2]. The notion was originally invoked to explain the more rapid onset of tumors in individuals with hereditary retinoblastoma than in sporadic cases. It was postulated that sporadic tumors require two hits to occur to produce the tumor, whereas hereditary tumors require only a single hit. Over the years, it has become clear that these hits correspond with mutations in specific genes, known collectively as tumor suppressor genes. Mutation leading to loss of function is found in both alleles in tumor cells, indicating that the genes act in a recessive manner at the cellular level. Sporadic tumors occur when first one allele and then the other is mutated. Because this process requires two rare events in the same cell lineage, sporadic tumors tend to be rare. In contrast, if an individual inherits a mutation in one allele, only a single event—mutation of the remaining intact allele—needs to occur to produce a tumor. These individuals have a high likelihood of developing tumors, may develop multiple tumors, and have an earlier age of onset than sporadically affected individuals. Inheritance in these individuals is dominant, because inheritance of only single mutant allele conveys susceptibility. The tumor suppressor concept is illustrated in Fig. 1.

Figure 1. Tumor suppressor concept. Both copies of a tumor suppressor gene are mutated in a tumor (far right, mutation shown as solid box). For an individual in the general population, mutation of both copies of a gene requires two independent mutations occurring successively in the same cell lineage, a rare occurrence. An individual with an inherited predisposition, such as a phakomatosis, has a single mutant allele in all cells (center panel). This mutation may be inherited from a parent (top) or acquired as a new mutation in a sperm or egg or even postzygotically (bottom). In either case, such an individual is heterozygous for the mutation in most or all somatic cells and will develop a tumor whenever the wild-type allele acquires a mutation in an appropriate cell type. (Click to enlarge figure)

Tumor suppressor genes play a variety of roles in controlling cell replication. They include genes involved in DNA repair, control of the cell cycle, and control of intracellular signaling. The mutations in tumors tend to involve loss of function (eg, frameshifts, stop mutations, deletions). Missense mutations can also occur if they affect amino acids that are critical for function. As a group, disorders resulting from tumor suppressor mutations tend to be associated with a wide variety of different mutations, because there usually are many ways to disrupt the function of a gene product. This variability creates a challenge in establishing DNA-based diagnostic testing, because it is usually necessary to scan a large gene thoroughly for mutations. The testing is expensive and prone to missing a proportion of pathogenic changes.

All of these principles apply to the phakomatoses. Each condition is caused by mutation in a distinct tumor suppressor gene. In each case, tumors have mutations in both alleles. Affected individuals inherit one mutant allele from a parent or have spontaneous mutation of an allele in a sperm or egg cell. Multiple independent tumors arise from separate events in which the remaining wild-type allele is mutated. Several of the conditions include nontumor manifestations as well as tumor (eg, learning disabilities in NF1). These manifestations result from dysfunction in some cell types because of haploinsufficiency—reduced levels of expression of the relevant gene because of heterozygosity for a mutation. All of the phakomatoses exhibit an appreciable rate of spontaneous mutation, probably because the mutational mechanism is relatively nonstringent (ie, any mutation that causes loss of function, regardless of where it occurs in the gene, will lead to the disorder). Also, some individuals exhibit mosaicism for a mutation; that is, they contain a mixture of mutant and nonmutant cells. Mosaicism occurs when the first hit occurs somatically. Clinical manifestations in such individuals may be limited to a restricted region of the body (segmental involvement) or may be generalized but milder than in nonmosaic individuals. Germline mosaicism, in which the mutation is confined to multiple sperm or egg cells, can lead to recurrence in a sibling even though neither parent shows signs of the disorder.

References

1. van der Hoeve J. Eye symptoms in phakomatoses. Trans Ophthalmol Soc U K. 1932;52:380-401
2. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68:820-823
3. Korf B. Neurofibromas and malignant tumors of the peripheral nervous system. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: phenotype, natural history, and pathogenesis. Baltimore: Johns Hopkins 1999:142-161
4. Dugoff L, Sujansky E. Neurofibromatosis type 1 and pregnancy. Am J Med Genet. 1996;66:7-10
5. Korf BR. Plexiform neurofibromas. Am J Med Genet. 1999;89(1):31-37
6. Carey JC, Laub JM, Hall BD. Penetrance and variability in neurofibromatosis: a genetic study of 60 families. Birth Defects: Orig Artic Ser. 1979;15(5B):271-281
7. Huson SM, Harper PS, Compston DAS. Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain. 1988;111:1355-1381
8. Korf BR. Diagnostic outcome in children with multiple cafe au lait spots. Pediatrics. 1992;90(6):924-927
9. Stumpf DA, Alksne JF, Annegers JF, Brown SS, Conneally PM, Housman D, et al. Neurofibromataosis. Arch Neurol. 1988;45:575-578
10. Moreno JC, Mathoret C, Lantieri L, Zeller J, Revuz J, Wolkenstein P. Carbon dioxide laser for removal of multiple cutaneous neurofibromas. Br J Dermatol. 2001;144(5):1096-1098
11. Needle MN, Cnaan A, Dattilo J, Chatten J, Phillips PC, Shochat S, et al. Prognostic signs in the surgical management of plexiform neurofibroma: The Children’s Hospital of Philadelphia experience, 1974–1994. J Pediatr. 1997;131(5):678-682
12. Crawford AH, Schorry EK. Neurofibromatosis in children: the role of the orthopaedist. J Am Acad Orthop Surg. 1999;7(4):217-230
13. North KN, Riccardi V, Samango-Sprouse C, Ferner R, Moore B, Legius E, et al. Cognitive function and academic performance in neurofibromatosis 1: consensus statement from the NF1 cognitive disorders task force. Neurology. 1997;48(4):1121-1127
14. Rasmussen SA, Yang Q, Friedman J. Mortality in neurofibromatosis 1: an analysis using US death certificates. Am J Human Genet. 2001;68:1110-1118
15. Evans DGR, Baser ME, Friedman JM, McGaughran J, Timms B, Moran A. Malignant peripheral nerve sheath tumors in neurofibromatosis 1. J Hum Genet. 2002;39(5):311-314
16. Mautner VF, Friedrich RE, Von Deimling A, Hagel C, Korf B, Knofel MT, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma. Neuroradiology. 2003;45(9):618-625

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 13, 2010 — TSC is an autosomal dominant disorder with complete penetrance and population prevalence around 1:6000. It is a complex, highly variable, multisystem disorder, with prominent effects on the skin, nervous system, heart, kidneys, eyes, and lungs [1,2]. Two distinct genes, TSC1 and TSC2, account for an essentially identical disorder. (Click to download a case record in PDF format…688 KB) (Click to download a case record in PDF format)

The central nervous system pathology of TSC includes areas of cortical dysplasia and subependymal nodules. Dysplastic regions show disorganized cellular architecture and the presence of large cells with properties of incompletely differentiated neurons [3]. There may be many such areas, which are visible by MR imaging [4–7], including prenatal MR imaging in some instances [8]. The neurologic correlate of cerebral dysplasia in TSC is the occurrence of seizures and developmental impairment [9,10]. Patients with onset of seizures in early childhood are at greatest risk of developmental delay. Seizures can take many forms, including infantile spasms. Subependymal nodules tend to calcify and therefore are visible on CT scans. In some cases, these nodules may expand, forming a giant cell astrocytoma [11,12]. These tumors typically occur near the foramen of Munro and can cause obstructive hydrocephalus.

Figure 1. Subependymal giant cell astrocytoma. Tumor cells that achieve truly giant proportions, often polygonal in contour and closely apposed in lobular array, are responsible for this neoplasm’s name (but not evident in all cases). (Click to enlarge figure)

Table 1. Brain Tumor Associated Genetic Syndromes (Click for more details)

The characteristic skin lesions of TSC include hypopigmented macules, subcutaneous collagenous plaques, angiofibromas, and periungual fibromas [13]. These lesions are important cosmetically and in establishing the diagnosis. Glial nodules that arise within the eyes are also useful for diagnosis and usually do not impair vision [14]. Infants with TSC may have cardiac rhabdomyomas [15], which often are asymptomatic but can present with obstruction or arrhythmia. Rhabdomyomas tend to regress over time. In some instances, they have been identified by prenatal ultrasound [16,17], enabling prenatal diagnosis. The major renal lesions are angiomyolipomas and cysts [18]. The former may be asymptomatic or can cause bleeding or renal failure. Renal failure occurs only when patients have large gene deletions that encompass both the TSC2 gene and the neighboring PKD1 (adult polycystic kidney disease gene) on chromosome 16 [19,20]. Women with TSC are at risk for a life-threatening pulmonary complication, lymphangiomyomatosis [21].

TSC is diagnosed using clinical criteria [22]. Major features are angiofibroma, forehead plaque, periungual fibroma, more than three hypopigmented macules, Shagreen patch, multiple retinal hamartomas, giant cell astrocytoma, subependymal nodules, cortical tuber, cardiac rhabdomyoma, renal angiomyolipoma, and lymphangiomyomatosis. Minor features are dental enamel pits, hamartomatous rectal polyps, bone cysts, white matter migration lines, gingival fibromas, retinal achromic patch, confetti skin lesions, and renal cysts. Definitive diagnosis requires two major features or one major and two minor features. Individuals with one major and one minor feature are designated as probable TSC. Those with one major or two or more minor features are said to have possible TSC. Genetic testing is beginning to emerge as an adjunct to diagnosis, but the existence of two TSC genes and a wide diversity of mutations in each makes mutation detection challenging [23].

Figure 2.  Neuroimages revealing a Subependymal Giant Cell Astrocytoma near the right foramen of Monro. This postcontrast injection MRI demonstrates the subependymal giant cell astrocytoma’s typically intraventricular location near the foramen of Monro (with resulting obstructive hydrocephalus), as well as its characteristic circumscription. This example was not associated with other features of tuberous sclerosis. (Click to enlarge figure)

Management of individuals with TSC consists of surveillance to recognize treatable complications. Antiepileptic therapy is indicated for those with seizures. Renal lesions are monitored by ultrasound, CT scanning, or MR imaging, and surgery is offered for symptomatic tumors. Cardiac tumors may require surgery or may regress spontaneously. Individuals with TSC should be offered counseling, both to understand the natural history of the disorder and to understand the genetic risks.

Two distinct genes, designated TSC1 and TSC2, have been identified that are responsible for TSC in different individuals. TSC1 is located on chromosome 9 and encodes a protein referred to as hamartin [24]. TSC2 is located on chromosome 16 and encodes tuberin [25]. In the cell, tuberin and hamartin form a complex involved in the control of cell division [26]. Their intimate association probably explains the similar phenotype associated with mutation at either locus. Although the phenotypes cannot be easily distinguished, it seems that more individuals with the disorder have the mutation at TSC2 than at TSC1, and the TSC2 phenotype may be more severe [27,28]. Somatic mosaicism for TSC gene mutations has been described [29].

Figure 3. Postmortem specimens showing cortical tubers in (A) and subependymal tubers in (B) (Click to enlarge figure)

References

1. Franz DN. Diagnosis and management of tuberous sclerosis complex. Semin Pediatr Neurol. 1998;5(4):253-268
2. Webb DW, Osborne JP. Tuberous sclerosis. Arch Dis Child. 1995;72:471-474
3. Crino PB, Trojanowski JQ, Dichter MA, Eberwine J. Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology. Proc Natl Acad Sci U S A. 1996;93(24):14152-14157
4. Christophe C, Sekhara T, Rypens F, Ziereisen F, Christiaens F, Dan B. MRI spectrum of cortical malformations in tuberous sclerosis complex. Brain Dev. 2000;22(8):487-493
5. Mizuno S, Takahashi Y, Kato Z, Goto H, Kondo N, Hoshi H. Magnetic resonance spectroscopy of tubers in patients with tuberous sclerosis. Acta Neurol Scand. 2000;102(3):175-178
6. Sener RN. Tuberous sclerosis: diffusion MRI findings in the brain. Eur Radiol. 2002;12(1):138-143
7. Thibaut H, Parizel PM, Van Goethem J, De Schepper AM. Tuberous sclerosis: CT and MRI characteristics. Eur J Radiol. 1993;16:176-179
8. Levine D, Barnes P, Korf B, Edelman R. Tuberous sclerosis in the fetus: second-trimester diagnosis of subependymal tubers with ultrafast MR imaging. AJR Am J Roentgenol. 2000;175(4):1067-1069
9. Husain AM, Foley CM, Legido A, Chandler DA, Miles DK, Grover WD. Tuberous sclerosis complex and epilepsy: prognostic significance of electroencephalography and magnetic resonance imaging. J Child Neurol. 2000;15(2):81-83
10. Curatolo P, Verdecchia M, Bombardieri R. Tuberous sclerosis complex: a review of neurological aspects. Eur J Paediatr Neurol. 2002;6(1):15-23
11. Cuccia V, Zuccaro G, Sosa F, Monges J, Lubienieky F, Taratuto AL. Subependymal giant cell astrocytoma in children with tuberous sclerosis. Childs Nerv Syst. 2003;19(4):232-243
12. O’Callaghan FJ, Lux A, Osborne J. Early diagnosis of subependymal giant cell astrocytoma in children with tuberous sclerosis. J Neurol Neurosurg Psychiatry. 2000;68(1):118
13. Webb DW, Clarke A, Fryer A, Osborne JP. The cutaneous features of tuberous sclerosis: a population study. Br J Dermatol. 1996;135(1):1-5
14. Rowley SA, O’Callaghan FJ, Osborne JP. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br J Ophthalmol. 2001;85(4):420-423
15. DiMario FJ, Diana D, Leopold H, Chameides L. Evolution of cardiac rhabdomyoma in tuberous sclerosis complex. Clin Pediatr (Phila). 1996;35(12):615-619
16. Axt-Fliedner R, Qush H, Hendrik HJ, Ertan K, Lindinger A, Mausle R, et al. Prenatal diagnosis of cerebral lesions and multiple intracardiac rhabdomyomas in a fetus with tuberous sclerosis. J Ultrasound Med. 2001;20(1):63-67
17. Bader RS, Chitayat D, Kelly E, Ryan G, Smallhorn J, Hornberger LK. Fetal rhabdomyoma: prenatal diagnosis, clinical outcome, and incidence of associated tuberous sclerosis complex. J Am Coll Cardiol. 2003;41(6Suppl B):483-484
18. Cook JA, Oliver K, Mueller RF, Sampson J. A cross sectional study of renal involvement in tuberous sclerosis. J Med Genet. 1996;33(6):480-484
19. Harris PC. The TSC2/PKD1 contiguous gene syndrome. Contrib Nephrol. 1997;122:76-82
20. Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease–a contiguous gene syndrome. Nat Genet. 1994;8:328-332
21. Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc. 2000;75(6):591-594
22. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998;13(12):624-628
23. Niida Y, Lawrence-Smith N, Banwell A, Hammer E, Lewis J, Beauchamp RL, et al. Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. Hum Mutat. 1999;14(5):412-422
24. Van Slegtenhorst M, De Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277(5327):805-808
25. The European Chromosome 16 Tuberous Sclerosis Consortium . Identification and characterisation of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1-11
26. Krymskaya VP. Tumour suppressors hamartin and tuberin: intracellular signalling. Cell Signal. 2003;15(8):729-739
27. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet. 2001;68(1):64-80
28. Ali JB, Sepp T, Ward S, Green AJ, Yates JR. Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis. J Med Genet. 1998;35(12):969-972
29. Verhoef S, Bakker L, Tempelaars AM, Hesseling-Janssen AL, Mazurczak T, Jozwiak S, et al. High rate of mosaicism in tuberous sclerosis complex. Am J Hum Genet. 1999;64(6):1632-1637
30. Brain developmental disorders: Disorders of neuronal differentiation [Full text]
31. Brain tumors associated with genetic disorders (Familial tumor syndromes) [Full text]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 13, 2010 —  The hallmark feature of VHL is the occurrence of hemangioblastomas, tumors consisting mainly of vascular elements [1]. The most common locations are the cerebellum, spinal cord, and retina. Although nonmalignant, they are space-occupying and therefore may be symptomatic. Lesions are readily visible by MR imaging, which is used for detection and surveillance. Other major features of the disorder are renal cysts [1], which may progress to renal cell carcinoma; cysts of the pancreas or epididymus; endolymphatic sac tumors that cause deafness [3]; and, in some families, pheochromocytoma [4]. VHL is autosomal dominant with complete penetrance and has population prevalence estimated at 1:60,000.

The VHL gene is located on chromosome 3 [5]. It encodes a protein that is involved in the regulation of a cellular pathway that responds to hypoxemia [6]. Loss of function of VHL leads to promiscuous activation of this pathway and consequent stimulation of angiogenesis, resulting in hemangioblastomas. Unlike the genes for the other phakomatoses, the VHL gene is relatively small (2 exons), making the task of mutation analysis easier. There is an important genotype–phenotype correlation, in that only certain types of mutation have been found in families with pheochromocytoma [7,8].

1. Conway JE, Chou D, Clatterbuck RE, Brem H, Long DM, Rigamonti D. Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease. Nsurg. 2001;48(1):55-62
2. Chauveau D, Duvic C, Chretien Y, Paraf F, Droz D, Melki P, et al. Renal involvement in von Hippel-Lindau disease. Kidney Int. 1996;50(3):944-951
3. Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, et al. Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA. 1997;277(18):1461-1466
4. Hes FJ, Hoppener JW, Lips CJ. Clinical review 155: Pheochromocytoma in Von Hippel-Lindau disease. J Clin Endocrinol Metab. 2003;88(3):969-974
5. Latif F, Tory K, Gnarra J, Yao M, Duh F-M, Orcutt ML, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260:1317-1320
6. Kaelin Jr WG. The von Hippel-Lindau gene, kidney cancer, and oxygen sensing. J Am Soc Nephrol. 2003;14(11):2703-2711
7. Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, et al. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66-75
8. Friedrich CA. Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet. 2001;10(7):763-767

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 13, 2010 — NF2 is about 10-fold less common than NF1 but shares the features of autosomal dominant inheritance, complete penetrance, and a propensity toward the development of tumors of the nerve sheath. The most typical tumor of NF2, however, is the schwannoma, although neurofibromas may occur more rarely [1]. Virtually all individuals with NF2 eventually develop bilateral vestibular schwannomas [2]. Other cranial nerves, especially the fifth nerve, may also be involved. Schwannomas can occur along spinal nerves and cause cord compression, and also can occur along peripheral nerves. Dermal tumors are much less common in NF2 than in NF1, but plaquelike dermal schwannomas can appear. (Click for more details) (Click to download a case record in PDF format)

Figure 1. Subcutaneous and cutaneous lesions in a young man with NF2; note paucity of cafe-au-lait spots. Right neck mass in patient with NF2. Facial asymmetry, OS proptosis and exotropia as well as several subcutaneous lesions on the forehead and face in a 20 year old male with NF2. (Click to magnify figure)

The other major tumor associated with NF2 is the meningioma. Meningiomas may occur throughout the central nervous system and can cause major morbidity. Ependymomas also are seen, but, in contrast with meningiomas, these tumors are often asymptomatic.

The only major nontumor manifestation of NF2 is cataracts, which tend to be posterior subcapsular cataracts or cortical wedge opacities [3]. Unlike NF1, learning disabilities are not a component of NF2; nor are skeletal dysplasias or major pigmentary changes.

Diagnosis of NF2 is based on clinical criteria [4]. The defining feature is the presence of bilateral vestibular schwannomas. Although these tumors may occur early in life, their onset is often delayed. In their absence, individuals with an affected first-degree relative may be diagnosed on the basis of two or more NF2-associated tumors, such as meningioma, schwannoma, ependymoma, or neurofibroma. Individuals with unilateral vestibular schwannoma and two of these tumors also are likely to be affected and should be followed.

Figure 2. Meningioma to the left of midline. [left image] Multiple meningiomas (on the left) on the surface of brain [middle image]. Bilateral acoustic neuromas [right image] (Click to magnify figure)

Figure 3. Bilateral acoustic neuromas (A), right sided acoustic neuromas (B), Multiple meningiomas, (C) (Click to magnify figure)

Figure 4. Grade II spinal astrocytoma in a patient with NF2. (a) Sagittal T2-weighted MR image (3,500/100) of the cervical spine. A focal abnormality at the C7 level demonstrates slight hyperintensity (arrow) with focal cord engorgement. (b) Sagittal nonenhanced T1-weighted image (400/11). There are no signal abnormalities in the cord, but a mild focal engorgement is seen again at the C7 level (arrow). (c) Sagittal contrast-enhanced T1-weighted image (400/11) shows multiple enhancing tumors (small white arrows) in proximity within the cord parenchyma. A small mass posterior to the cerebellar vermis is thought to represent an intracranial meningioma (black arrow). The linear enhancing structure on the ventral aspect of the cord and medulla represents a draining vein (large white arrows). (d) Transverse contrast-enhanced T1-weighted image (400/15) demonstrates the central location of one intramedullary enhancing tumor (arrow). (Click to magnify figure)

Management of NF2 focuses on early detection of treatable lesions [5]. The hearing status of affected individuals and those at risk based on family history should be closely monitored by audiometry and brainstem auditory–evoked responses. Screening for vestibular tumors using MR imaging should begin in adolescence. The typical treatment for symptomatic lesions is surgery, although stereotactic radiation therapy has also been used [6]. Given the bilaterality of vestibular schwannomas, the treatment plan needs to be carefully formulated by clinicians with experience in treating NF2, with the goal of preserving hearing as long as possible. Management of other symptomatic tumors is currently surgical.

Figure 5. Spinal nerve sheath tumor in a patient with NF2, (a) Sagittal T2-weighted MR image (3,500/100) of the cervical and upper thoracic spine. A rounded extraaxial mass is depicted in the spinal canal at the level of T3 and compresses the cord (black arrow). Two small focal hyperintense areas (white arrows) are also identified in the cord near the central canal at the C3 and C5-C6 levels. (b) Sagittal contrast-enhanced T1-weighted image (500/8). Mass lesion (black arrow) at T3 demonstrates homogeneous enhancement and represents an NST. Two additional lesions (white arrows) identified within the cord are also enhanced; they represent intramedullary tumors. (Click to magnify figure)

Figure 6. Spinal ependymoma in a patient with NF2. (a) Sagittal intermediate-weighted MR image (2,500/20) of the cervical spine. Several hyperintense tumors (arrows) are present at the level of the medulla, C3-C4, C6 to C7, T1, T3, and T5. The tumor at the C6-C7 level is large and partially cavitary, and it produces cord engorgement. Less obvious cord engorgement is also caused by the tumors at the C3-C4 and T3 levels. (b) Sagittal nonenhanced T1-weighted image clearly demonstrates the cavitary tumor at the C6-C7 level. Two of the solid tumors at the C3-C4 and T3 levels appear slightly hyperintense with respect to the normal cord (arrows). (c) Sagittal contrast-enhanced T1-weighted image. All intramedullary tumors are enhanced. (Click to magnify figure)

The NF2 gene is located on chromosome 22 and encodes a protein [7,8] referred to as merlin or schwannomin. Merlin is a cytoskeletal protein that seems to be involved in the regulation of cell growth, although the details of how it participates in the pathogenesis of lesions associated with NF2 are unclear [9]. The NF2 gene functions as a tumor suppressor, however, with evidence of loss of function of both alleles in NF2-associated tumors [10]. Mutation analysis is feasible for confirmation of diagnosis, although currently available testing does not detect all possible mutations. Some genotype–phenotype correlations have been established; specifically, truncating mutations tend to be associated with a more severe phenotype than whole-gene deletions or missense mutations [11,12]. Instances of somatic mosaicism have been reported [13,14].

Figure 7. Multiple spinal meningiomas in a patient with NF2. Sagittal contrast-enhanced T1-weighted MR image (550/22) of the cervical spine. Extramedullary enhancing dural-based tumors (meningiomas) are seen at the C2 and C7-T1 levels (black solid arrows). The tumor at the C7-T1 level results in cord compression. In addition, an enhancing intramedullary tumor (white solid arrows) at the T3-T4 level causes focal cord engorgement. An associated syrinx (open arrow) is seen in a small segment of the cord proximal to this tumor. (Click to magnify figure)

• Schwannomatosis

Schwannomatosis is a relatively recently described entity that is now regarded as a distinct form of neurofibromatosis [15,16]. Affected individuals have multiple schwannomas but do not have vestibular schwannomas. Also, they differ from NF2 patients in that individuals with schwannomatosis do not develop other tumors of the central nervous system, such as meningioma or ependymomas. Nevertheless, distinguishing those with schwannomatosis from those with NF2 can be difficult, particularly at a young age when vestibular tumors have not yet have developed. Although most cases occur sporadically, autosomal dominant transmission of schwannomatosis may occur. Penetrance is incomplete, in contrast with NF1 or NF2. The gene for schwannomatosis has not been identified [17]. Analysis of tumors has revealed acquired mutations of both alleles of the NF2 gene, but these mutations differ from tumor to tumor in the same individual [18]. The genetic mechanism that underlies schwannomatosis is therefore unknown at present, and genetic testing is not possible for diagnostic purposes.

References

1. Evans DG, Sainio M, Baser ME. Neurofibromatosis type 2. J Med Genet. 2000;37(12):897-904
2. Evans DG, Lye R, Neary W, Black G, Strachan T, Wallace A, et al. Probability of bilateral disease in people presenting with a unilateral vestibular schwannoma. J Neurol Neurosurg Psychiatry. 1999;66(6):764-767
3. Pearson-Webb MA, Kaiser-Kupfer MI, Eldridge R. Eye findings in bilateral acoustic (central) neurofibromatosis: association with presenile lens opacities and cataracts but absence of Lisch nodules. N Engl J Med. 1986;315:1553-1554
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The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

March 9, 2010 — NF1 is the most common of the phakomatoses, occurring in approximately 1 in 3500 individuals worldwide. Its manifestations may also be the most wide ranging. The hallmark pathologic lesion is the neurofibroma, a benign tumor of the nerve sheath [3]. Neurofibromas may occur anywhere in the body, either as focal nodules or encompassing multiple nerve fascicles (plexiform neurofibroma). Focal neurofibromas occur in the skin, where they can cause major disfigurement, or internally, where they can lead to nerve compression or invade the spinal canal. For the most part, focal neurofibromas are not present in young children but begin to appear in the preadolescent years and then unpredictably throughout life. Puberty and pregnancy are times when neurofibromas commonly appear or grow, suggesting a hormonal influence [4]. Plexiform neurofibromas, in contrast, tend to be congenital and often grow during the early years of life, sometimes causing soft tissue enlargement leading to hypertrophy [5]. Plexiform neurofibromas can be deeply rooted and hence difficult to remove surgically. Plexiform neurofibromas may cause major cosmetic disfigurement or functional impairment. (Click to download a case record in PDF format…557 KB)

Figure 1. Multiple cutaneous neurofibromas (Click to magnify figure)

NF1 is an unpredictable and protean disorder [6,7]. The presenting sign is usually the occurrence of multiple café-au-lait macules, noticed in the early months of life [8]. Six or more such spots larger than 5 mm before puberty or larger than 15 mm after puberty constitutes a diagnostic criterion [9]. Skin-fold freckles appearing between 3 and 5 years of age constitutes a second criterion. Other diagnostic criteria are the occurrence of iris Lisch nodules (melanocytic hamartomas), which are commonly present in adults with NF1; optic glioma; characteristic skeletal dysplasia (orbital or tibial dysplasia); two or more neurofibromas or one plexiform neurofibroma; and an affected first-degree relative. The presence of two or more features establishes the clinical diagnosis of NF1, but diagnosis often requires observation over a period of time, because many of the features are age dependent. Genetic testing is becoming available and is discussed later.

Figure 2. Lisch nodules (Click to magnify figure)

Management of NF1 is currently limited to surveillance for treatable complications, anticipatory guidance, and genetic counseling. Treatment consists mostly of surgical removal of symptomatic neurofibromas. Dermal tumors can be removed by plastic surgery or other techniques, such as CO2 laser [10] or electrodessication. It is usually impossible to resect plexiform neurofibromas fully, but judicious debulking can be helpful. Recurrence tends to be correlated with degree of resection [11]. Children with tibial bowing can be managed with bracing to avoid the risk of fracture [12]. Learning disabilities and attention deficit disorder are common and respond to standard interventions [13].

Life expectancy in NF1 is reduced on average, although many experience a normal lifespan [14]. Mortality associated with the disorder is usually caused by malignancy or vascular problems. The risk of NF-associated malignancy is estimated at 10% [15]. The major tumor type is malignant peripheral nerve sheath tumor, usually arising from a plexiform neurofibroma. These tumors present clinically with sudden growth or pain, usually in the second through fourth decades. Although there may be imaging signs suggesting malignancy, such as hemorrhage or cystic components [16], the diagnosis is often difficult because an affected individual is likely to have multiple benign tumors. Increased metabolic activity detected by positron emission tomography scanning may help distinguish benign from malignant lesions [17]. Other nonneural malignancies that are increased in frequency in NF1 include leukemia, particularly juvenile myelomonocytic leukemia, and rhabdomyosarcoma [18].

NF1 is also associated with an increased risk of glioma. The most common lesion is the optic glioma [19]. Evidence of optic glioma can be recognized by imaging in approximately 15% of children with NF1, typically before 6 years of age [20,21]. Tumors can occur in the orbit, the chiasm, or both, and can be unilateral or bilateral. Associated symptoms include proptosis, pain, visual impairment, constricted visual fields, or neuroendocrine disturbance (for chiasmatic tumors). Neuroendocrine disturbance most often takes the form of precocious puberty. Optic gliomas are commonly asymptomatic, in spite of progression visualized by imaging, and growth may be self limiting. As a consequence, treatment is reserved for those with progressive symptomatic lesions. Radiation therapy has been all but abandoned in young children with optic gliomas because of the high risk of vascular dysplasias, malignancies, and cognitive deficits. Chemotherapy with vincristine and carboplatinum is now used as a first-line therapy for those with symptomatic optic glioma [22].

Figure 3. Left optic nerve glioma with thickening of the nerve and proptosis, Unidentified bright object (UBO) within the brain parenchyma, Radial and ulnar bowing and obliteration of the intramedullary spaces. (Click to magnify figure)

Because optic gliomas often do not require therapy, there has been controversy regarding whether asymptomatic children with NF1 should be screened by brain MR imaging. Proponents note that such screening identifies children at greater risk and allows for close follow-up [23]. Others argue that asymptomatic lesions will not be treated, so it is more efficient to monitor first for signs and symptoms, offering imaging to those with a suspicion of harboring an active lesion [24].

Gliomas can occur elsewhere in the brain or spinal cord. Most often these (like optic gliomas) are pilocytic astrocytomas, and most are relatively slow growing. Gliomas in individuals with NF1 tend to be more indolent in their progression than their counterparts in non–NF1-affected individuals. Gliomas need to be distinguished from areas of enhanced T2 signal intensity seen by MR imaging, which are common in children with NF1 and tend to disappear with time [25,26]. These NF spots are not space occupying and do not cause distinct neurologic signs. The overall number of such spots may correlate with the occurrence of learning disabilities, however [27–30].

Nontumor manifestations of NF1 may contribute significantly to morbidity. Skeletal dysplasia, most often involving long bones, especially the tibia, can lead to fracture and pseudoarthrosis [12]. This dysplasia is a congenital problem, so a child found not to have tibial bowing is not at risk. Approximately 50% of children with NF1 have learning disabilities [31]. There is no NF-specific pattern, and there may be associated attention deficit disorder and neuromotor developmental delays. Early recognition of learning disabilities is important to implement customized educational plans.

NF1 is an autosomal dominant disorder with complete penetrance and a high rate of new mutation. An affected individual has a 50% risk of transmitting the disorder to any offspring, with no way to predict severity. Approximately 50% of cases arise from a new mutation, in which case both parents are free of clinical signs. Somatic mosaicism may present as segmental NF, in which the features are confined to a restricted region of the body, or as mild NF [32,33]. Germline mosaicism has been reported [34], which means that recurrence risk for an unaffected couple is slightly higher than the general population risk.

The gene for NF1 resides on chromosome 17 and encodes a protein referred to as neurofibromin [35]. Neurofibromin includes a guanosine triphosphate (GTPase)-activating protein domain that regulates the conversion of Ras-GTP to Ras-GDP, thereby exerting an effect to control signal transduction within the cell [36]. The NF1 gene functions as a tumor suppressor, so that mutation of both alleles is required to unleash tumor growth. Affected individuals are heterozygous, leading to a high frequency of tumors caused by somatic mutation of the wild-type allele. It is not clear whether nontumor manifestations, such as learning disabilities, also occur because of a tumor suppressor mechanism or whether these result from haploinsufficiency of NF1 function in heterozygous cells.

The discovery of the NF1 gene has shed light on the pathogenesis of the disorder and is beginning to affect clinical management. Genetic testing for purposes of diagnosis, including prenatal diagnosis, is now possible [37]. The gene is large, and mutations are widely scattered along the gene, so a multitiered approach has been most successful. Clinical trials are beginning, using drugs that may impact the function of the Ras pathway and other drugs such as angiogenesis inhibitors [38]. Clinical trials for NF1 are listed by the National Neurofibromatosis Foundation at www.nf.org/clinical_trials . One of the major targets of treatment has been the plexiform neurofibroma. Volumetric MR imaging may provide a means of measuring the rate of change in the size of these large and irregular lesions [39].

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40. Neurofiromatosis type  I [Full text]