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Introduction: Neurocutaneous diseases
S e m i n a r s in
Pediatric Neurology Introduction: Neurocutaneous Diseases HE PACE HAS been rapid. In 1987, three of the genes for neurocutaneous disorders were mapped--the first of two tuberous sclerosis complex (TSC) genes, TSC1, on chromosome 9, the neurofibromatosis 1 (NF1) gene on chromosome 17, and the neurofibromatosis 2 (NF2) gene on chromosome 22. In 1992, a second TSC gene, TSC2, was mapped to chromosome 16 using a marker for polycystic kidney disease type 1. Since then, progress has been feverish. Although NF1 and NF2 are two diseases each caused by a different gene, TSC1 and TSC2 are separate genes that cause the same disorder. Traditionally, neurocutaneous diseases (also called phakomatoses) have included five entities: neurofibromatosis, tuberous sclerosis complex, ataxia telangiectasia, Sturge-Weber syndrome, and von Hippel-Lindau. All except SturgeWeber are genetic syndromes. However, depending on a person's orientation, a panoply of disorders can be considered neurocutaneous. Several examples follow: neurological infections with skin lesions, such as Lyme's disease; metabolic disorders, such as Fabry's disease with angiokeratomas; cortical dysgeneses with typical skin involvement, such as incontinentia pigmenti; various syndromes, such as hypomelanosis of Ito; and the list goes on. Purists might quibble with inclusion of von HippelLindau, which has no skin abnormality, but otherwise, the unifying feature of this large group of disorders is involvement of both nervous system and skin. For this issue on neurocutaneous diseases, I selected disorders based partly on the traditional viewpoint, and also because I knew of authors who could provide informative, balanced viewpoints that would be useful to the clinician. The topics selected for this issue are the first three from the traditional group: neurofibromatosis (NF), TSC,
T
and ataxia telangiectasia. Increasing involvement by parents and families, advances in imaging techniques, and molecular discoveries are some of the factors that have led to startling insights regarding pathogenesis, and have spurred clinical investigations, sometimes with the goal of understanding phenotype-genotype correlations, that provided more in-depth understanding of diagnosis and treatment. Initially, I considered listing the interesting, important, or surprising features of each article. The lists became too long. Instead, this listing of five tidbits from each article should encourage you to read the articles in depth.
Neurofibromatosis 1 in Childhood by Kathryn N. North: 9 Common complications of NF1 are learning disabilities, scoliosis, and optic nerve gliomas. 9 The absence of cafe au l a i t spots, axillary freckling, cutaneous neurofibromas, and Lisch nodules excludes NF1 with greater than 95% certainty in individuals over age 5 years. 9 Optic nerve tumors become symptomatic by age 6 years. 9 MRI T2 hyperintensities of NF1 disappear during late teenage years and the twenties. 9 Plexiform neurofibromas are the variety that can become malignant.
The Diagnosis and Management of Neurofibromatosis 2 in Childhood by Mia MacCollin and Victor-Felix Mautner: 9 Most patients with NF2 are symptomatic by adolescence. 9 Patients with NF2 have an increased risk of drowning due to underwater disorientation. 9 Subtle skin tumors and posterior subcapsular cataracts are clues to diagnosis.
Seminars in Pediatric Neurology, Vol 5, No 4 (December), 1998: pp 229-230
229
230
9 Meningiomas or schwannomas in children are commonly indicators of NF2. 9 An internal auditory canal (IAC) protocol is necessary for adequate magnetic resonance imaging.
Diagnosis and Management of Tuberous Sclerosis Complex by David Neal Franz: 9 A child with neonatal rhabdomyoma of the heart is likely to have TSC. 9 MRI FLAIR images can identify brain lesions that were previously imperceptible. 9 Among the newer agents, vigabatrin (possibly FDA-approved by press time) may be especially effective for seizures caused by TSC. Lamotrigine use can be complicated by potentially severe rash, and topiramate may cause kidney stones, but both can be used effectively for seizures of TSC. 9 Autism may occur in the absence of mental retardation, seizures, or large numbers of tubers. 9 Serial imaging (kidney and brain) remains controversial, but Dr. Franz provides a rational scheme.
Renal Angiomyolipomas, Cysts, and Cancer in Tuberous Sclerosis Complex by Hartmut P.H. Neumann, Georg Schwarzkopf, and Elizabeth Petri Henske: 9 Renal disease, especially in TSC adults, is a leading cause of both morbidity and death. 9 Kidney lesions include angiomyolipomas (AMLs), cysts, and renal cell carcinomas. 9 Fat density is characteristic of an AML on CT scan, but renal cell carcinomas do not have fat. 9 Bilateral AMLs occurring with renal cysts is a pattern highly characteristic of TSC. 9 Loss of heterozygosity for either a TSC1 or TSC2 gene marker occurs frequently (60%) in AMLs associated with TSC or associated with isolated pulmonary lymphangiomyomatosis, but in only 10% of sporadic AMLs.
INTRODUCTION
Parallels Between Tuberous Sclerosis Complex and Neurofibromatosis I: Common Threads in the Same Tapestry by David H. Gutmann: 9 The products and their genes: neurofibromin (neurofibromatosis gene), hamartin (TSC 1 gene), and tuberin (TSC2 gene). 9 In different families, TSC may be caused by mutations of either the TSC1 or the TSC2 genes. 9 Both neurofibromin and tuberin have s~quence similarities to GTPase activating proteins (GAPs), and both function as tumor suppressors. 9 Neurofibromin is a negative regulator of ras, and tuberin of rapl. 9 Both ras & rapl affect the MAP kinase signaling pathway, a pathway important to cell growth or to arrest of cell growth. If this seems confusing, clarify it by looking at Dr. Gutmann's diagrams.
Ataxia Telangiectasia by T h o m a s O. Crawford: 9 The gene for ataxia telangiectasia may be involved in cell-cycle regulation (compare with tuberin & neurofibromin). Cerebellar Purkinje cells are selectively depleted or abnormal. Alpha fete-protein level is almost always elevated to two times the upper limit. Ataxia is the first manifestation, but telangiectasia is delayed by 4 to 5 years. Fatal bacterial pneumonia is related to hypogammaglobulinemia but probably also to silent aspiration. Mundane aspects of medical practice may lull the practitioner into apathy, but the challenges, complexity, and fascination of these patients renew enthusiasm. Raymond S. Kandt, MD
Guest Editor
Pediatric Neurology Introduction: Neurocutaneous Diseases HE PACE HAS been rapid. In 1987, three of the genes for neurocutaneous disorders were mapped--the first of two tuberous sclerosis complex (TSC) genes, TSC1, on chromosome 9, the neurofibromatosis 1 (NF1) gene on chromosome 17, and the neurofibromatosis 2 (NF2) gene on chromosome 22. In 1992, a second TSC gene, TSC2, was mapped to chromosome 16 using a marker for polycystic kidney disease type 1. Since then, progress has been feverish. Although NF1 and NF2 are two diseases each caused by a different gene, TSC1 and TSC2 are separate genes that cause the same disorder. Traditionally, neurocutaneous diseases (also called phakomatoses) have included five entities: neurofibromatosis, tuberous sclerosis complex, ataxia telangiectasia, Sturge-Weber syndrome, and von Hippel-Lindau. All except SturgeWeber are genetic syndromes. However, depending on a person's orientation, a panoply of disorders can be considered neurocutaneous. Several examples follow: neurological infections with skin lesions, such as Lyme's disease; metabolic disorders, such as Fabry's disease with angiokeratomas; cortical dysgeneses with typical skin involvement, such as incontinentia pigmenti; various syndromes, such as hypomelanosis of Ito; and the list goes on. Purists might quibble with inclusion of von HippelLindau, which has no skin abnormality, but otherwise, the unifying feature of this large group of disorders is involvement of both nervous system and skin. For this issue on neurocutaneous diseases, I selected disorders based partly on the traditional viewpoint, and also because I knew of authors who could provide informative, balanced viewpoints that would be useful to the clinician. The topics selected for this issue are the first three from the traditional group: neurofibromatosis (NF), TSC,
T
and ataxia telangiectasia. Increasing involvement by parents and families, advances in imaging techniques, and molecular discoveries are some of the factors that have led to startling insights regarding pathogenesis, and have spurred clinical investigations, sometimes with the goal of understanding phenotype-genotype correlations, that provided more in-depth understanding of diagnosis and treatment. Initially, I considered listing the interesting, important, or surprising features of each article. The lists became too long. Instead, this listing of five tidbits from each article should encourage you to read the articles in depth.
Neurofibromatosis 1 in Childhood by Kathryn N. North: 9 Common complications of NF1 are learning disabilities, scoliosis, and optic nerve gliomas. 9 The absence of cafe au l a i t spots, axillary freckling, cutaneous neurofibromas, and Lisch nodules excludes NF1 with greater than 95% certainty in individuals over age 5 years. 9 Optic nerve tumors become symptomatic by age 6 years. 9 MRI T2 hyperintensities of NF1 disappear during late teenage years and the twenties. 9 Plexiform neurofibromas are the variety that can become malignant.
The Diagnosis and Management of Neurofibromatosis 2 in Childhood by Mia MacCollin and Victor-Felix Mautner: 9 Most patients with NF2 are symptomatic by adolescence. 9 Patients with NF2 have an increased risk of drowning due to underwater disorientation. 9 Subtle skin tumors and posterior subcapsular cataracts are clues to diagnosis.
Seminars in Pediatric Neurology, Vol 5, No 4 (December), 1998: pp 229-230
229
230
9 Meningiomas or schwannomas in children are commonly indicators of NF2. 9 An internal auditory canal (IAC) protocol is necessary for adequate magnetic resonance imaging.
Diagnosis and Management of Tuberous Sclerosis Complex by David Neal Franz: 9 A child with neonatal rhabdomyoma of the heart is likely to have TSC. 9 MRI FLAIR images can identify brain lesions that were previously imperceptible. 9 Among the newer agents, vigabatrin (possibly FDA-approved by press time) may be especially effective for seizures caused by TSC. Lamotrigine use can be complicated by potentially severe rash, and topiramate may cause kidney stones, but both can be used effectively for seizures of TSC. 9 Autism may occur in the absence of mental retardation, seizures, or large numbers of tubers. 9 Serial imaging (kidney and brain) remains controversial, but Dr. Franz provides a rational scheme.
Renal Angiomyolipomas, Cysts, and Cancer in Tuberous Sclerosis Complex by Hartmut P.H. Neumann, Georg Schwarzkopf, and Elizabeth Petri Henske: 9 Renal disease, especially in TSC adults, is a leading cause of both morbidity and death. 9 Kidney lesions include angiomyolipomas (AMLs), cysts, and renal cell carcinomas. 9 Fat density is characteristic of an AML on CT scan, but renal cell carcinomas do not have fat. 9 Bilateral AMLs occurring with renal cysts is a pattern highly characteristic of TSC. 9 Loss of heterozygosity for either a TSC1 or TSC2 gene marker occurs frequently (60%) in AMLs associated with TSC or associated with isolated pulmonary lymphangiomyomatosis, but in only 10% of sporadic AMLs.
INTRODUCTION
Parallels Between Tuberous Sclerosis Complex and Neurofibromatosis I: Common Threads in the Same Tapestry by David H. Gutmann: 9 The products and their genes: neurofibromin (neurofibromatosis gene), hamartin (TSC 1 gene), and tuberin (TSC2 gene). 9 In different families, TSC may be caused by mutations of either the TSC1 or the TSC2 genes. 9 Both neurofibromin and tuberin have s~quence similarities to GTPase activating proteins (GAPs), and both function as tumor suppressors. 9 Neurofibromin is a negative regulator of ras, and tuberin of rapl. 9 Both ras & rapl affect the MAP kinase signaling pathway, a pathway important to cell growth or to arrest of cell growth. If this seems confusing, clarify it by looking at Dr. Gutmann's diagrams.
Ataxia Telangiectasia by T h o m a s O. Crawford: 9 The gene for ataxia telangiectasia may be involved in cell-cycle regulation (compare with tuberin & neurofibromin). Cerebellar Purkinje cells are selectively depleted or abnormal. Alpha fete-protein level is almost always elevated to two times the upper limit. Ataxia is the first manifestation, but telangiectasia is delayed by 4 to 5 years. Fatal bacterial pneumonia is related to hypogammaglobulinemia but probably also to silent aspiration. Mundane aspects of medical practice may lull the practitioner into apathy, but the challenges, complexity, and fascination of these patients renew enthusiasm. Raymond S. Kandt, MD
Guest Editor