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Situationskomedi, sitcom, är en typ av humoristisk dramaserie
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Situationskomedi – Wikipedia
pgifter utan källhänvisning kan ifrågasättas och tas bort utan att det behöver diskuteras på diskussionssidan. Uppslagsordet ”Sitcom” leder hit. För långfilmen med samma namn, se Sitcom (film). <span>Situationskomedi, sitcom, är en typ av humoristisk dramaserie, som först uppstod i radio, men idag framförallt sänds i tv. Situationskomediserierna kretsar vanligen kring en grupp fasta rollfigurer i en vardaglig miljö - hemmet, arbetsplatsen elle




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Moyamoya disease is a unique cerebrovascular entity characterized by progressive large intracranial artery narrowing and the development of prominent small vessel collaterals. The latter produces a characteristic smoky appearance on angiography, hence the name "moyamoya," a Japanese word meaning puffy, obscure, or hazy, like a puff of smoke in the air [1,2].
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opics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jul 2021. | This topic last updated: Oct 21, 2020. INTRODUCTION — <span>Moyamoya disease is a unique cerebrovascular entity characterized by progressive large intracranial artery narrowing and the development of prominent small vessel collaterals. The latter produces a characteristic smoky appearance on angiography, hence the name "moyamoya," a Japanese word meaning puffy, obscure, or hazy, like a puff of smoke in the air [1,2]. Moyamoya disease was first described in Japan in 1957. Many similar cases have subsequently been reported, mainly in Japan and other Asian countries. The disease is found less frequentl




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Moyamoya disease was first described in Japan in 1957. Many similar cases have subsequently been reported, mainly in Japan and other Asian countries. The disease is found less frequently in North America and Europe.
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aterals. The latter produces a characteristic smoky appearance on angiography, hence the name "moyamoya," a Japanese word meaning puffy, obscure, or hazy, like a puff of smoke in the air [1,2]. <span>Moyamoya disease was first described in Japan in 1957. Many similar cases have subsequently been reported, mainly in Japan and other Asian countries. The disease is found less frequently in North America and Europe. This topic will review the etiology and clinical aspects of moyamoya disease. Prognosis and treatment are discussed elsewhere. (See "Moyamoya disease: Treatment and prognosis".) CLASSIF




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The term "moyamoya" describes the specific angiographic findings of unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation (image 1).
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review the etiology and clinical aspects of moyamoya disease. Prognosis and treatment are discussed elsewhere. (See "Moyamoya disease: Treatment and prognosis".) CLASSIFICATION AND TERMINOLOGY ●<span>The term "moyamoya" describes the specific angiographic findings of unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation (image 1). ●Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no associated conditions. This may also be called primary or idi




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● Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no associated conditions. This may also be called primary or idiopathic moyamoya disease as well as the descriptive "spontaneous occlusion of the circle of Willis" [3,4].

● Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition as described below.

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scribes the specific angiographic findings of unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation (image 1). <span>●Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no associated conditions. This may also be called primary or idiopathic moyamoya disease as well as the descriptive "spontaneous occlusion of the circle of Willis" [3,4]. ●Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition as described below. (See 'Associated conditions' below.) These secondary forms of the condition have been termed "moyamoya phenomenon," "angiographic moyamoya," or "quasi-moyamoya disease" [3,5-7]. ETIOLOG




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Although the mode of inheritance is not established, one study suggested that familial moyamoya is an autosomal dominant disease with incomplete penetrance [20].
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17q25.3 is an important susceptibility factor for MMD in East Asian populations [8-16]. Several reports have also linked familial MMD to chromosomes 3p24.2, p26, 6q25, 8q23, and 12p12 [17-19]. <span>Although the mode of inheritance is not established, one study suggested that familial moyamoya is an autosomal dominant disease with incomplete penetrance [20]. The authors proposed that genomic imprinting and epigenetic modification may account for the predominantly maternal transmission and elevated female-to-male incidence ratio. (See 'Epide




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A later genome-wide association study confirmed the relationship of MMD and a previously reported locus on chromosome 17q25 [21]. The study also identified 10 novel risk loci, including the genes regulating homocysteine metabolism, loci related to large vessel disease, and loci that are highly expressed in the immune system.
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d female-to-male incidence ratio. (See 'Epidemiology' below and "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.) <span>A later genome-wide association study confirmed the relationship of MMD and a previously reported locus on chromosome 17q25 [21]. The study also identified 10 novel risk loci, including the genes regulating homocysteine metabolism, loci related to large vessel disease, and loci that are highly expressed in the immune system. Associated conditions — There are many conditions associated with MMS. They may be causative or syndromic. Some of the conditions reported to be associated with MMS include: ●Disease af




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● Disease affecting arteries around the circle of Willis

• Atherosclerosis [22]

• Radiation therapy to the base of the brain [23] (see "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects')

• Cranial trauma [24]

• Brain tumors [25-27]

• Meningitis [28]

• Other viral or bacterial infection (eg, Cutibacterium acnes, leptospirosis, HIV) [29-31]

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the immune system. Associated conditions — There are many conditions associated with MMS. They may be causative or syndromic. Some of the conditions reported to be associated with MMS include: <span>●Disease affecting arteries around the circle of Willis •Atherosclerosis [22] •Radiation therapy to the base of the brain [23] (see "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects') •Cranial trauma [24] •Brain tumors [25-27] •Meningitis [28] •Other viral or bacterial infection (eg, Cutibacterium acnes, leptospirosis, HIV) [29-31] ●Hematologic conditions •Sickle cell disease [32-34] •Beta thalassemia [35] •Fanconi anemia [36] •Hereditary spherocytosis [37] •Homocystinuria and hyperhomocysteinemia [38] •Factor XII




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● Hematologic conditions

• Sickle cell disease [32-34]

• Beta thalassemia [35]

• Fanconi anemia [36]

• Hereditary spherocytosis [37]

• Homocystinuria and hyperhomocysteinemia [38]

• Factor XII deficiency [39]

• Essential thrombocythemia [40]

• Protein S deficiency [41-43]

• Pyruvate kinase deficiency [44]

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ion", section on 'Cerebrovascular effects') •Cranial trauma [24] •Brain tumors [25-27] •Meningitis [28] •Other viral or bacterial infection (eg, Cutibacterium acnes, leptospirosis, HIV) [29-31] <span>●Hematologic conditions •Sickle cell disease [32-34] •Beta thalassemia [35] •Fanconi anemia [36] •Hereditary spherocytosis [37] •Homocystinuria and hyperhomocysteinemia [38] •Factor XII deficiency [39] •Essential thrombocythemia [40] •Protein S deficiency [41-43] •Pyruvate kinase deficiency [44] ●Vasculitis and autoimmune and multisystem diseases •Systemic lupus erythematosus [45] •Polyarteritis nodosa and postinfectious vasculopathy [46] •Graves disease and thyroiditis [47-50]




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● Vasculitis and autoimmune and multisystem diseases

• Systemic lupus erythematosus [45]

• Polyarteritis nodosa and postinfectious vasculopathy [46]

• Graves disease and thyroiditis [47-50]

• Sneddon syndrome and the antiphospholipid antibody syndrome [51,52]

• Anti-Ro and anti-La antibodies [53]

• Type 1 diabetes mellitus [50]

• Pulmonary sarcoidosis [54,55]

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itary spherocytosis [37] •Homocystinuria and hyperhomocysteinemia [38] •Factor XII deficiency [39] •Essential thrombocythemia [40] •Protein S deficiency [41-43] •Pyruvate kinase deficiency [44] <span>●Vasculitis and autoimmune and multisystem diseases •Systemic lupus erythematosus [45] •Polyarteritis nodosa and postinfectious vasculopathy [46] •Graves disease and thyroiditis [47-50] •Sneddon syndrome and the antiphospholipid antibody syndrome [51,52] •Anti-Ro and anti-La antibodies [53] •Type 1 diabetes mellitus [50] •Pulmonary sarcoidosis [54,55] ●Genetic and developmental disorders •Alagille syndrome [56,57] •Down syndrome [58,59] •Hypomelanosis of Ito [60] •Marfan syndrome [61] •Microcephalic osteodysplastic primordial dwarfis




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● Genetic and developmental disorders

• Alagille syndrome [56,57]

• Down syndrome [58,59]

• Hypomelanosis of Ito [60]

• Marfan syndrome [61]

• Microcephalic osteodysplastic primordial dwarfism type 2 [62]

• Multisystem disorder with short stature, hypergonadotropic hypogonadism, and dysmorphism [63,64]

• Neurofibromatosis type 1 [65-67]

• Noonan syndrome [68-70]

• Phakomatosis pigmentovascularis type IIIb [71]

• Prader-Willi syndrome [72]

• Pseudoxanthoma elasticum [73]

• Sturge-Weber syndrome [74]

• Tuberous sclerosis [75]

• Turner syndrome [76]

• Williams syndrome [77]

• Morning glory optic disc anomaly (image 2), usually in conjunction with other craniofacial abnormalities [

...
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e and thyroiditis [47-50] •Sneddon syndrome and the antiphospholipid antibody syndrome [51,52] •Anti-Ro and anti-La antibodies [53] •Type 1 diabetes mellitus [50] •Pulmonary sarcoidosis [54,55] <span>●Genetic and developmental disorders •Alagille syndrome [56,57] •Down syndrome [58,59] •Hypomelanosis of Ito [60] •Marfan syndrome [61] •Microcephalic osteodysplastic primordial dwarfism type 2 [62] •Multisystem disorder with short stature, hypergonadotropic hypogonadism, and dysmorphism [63,64] •Neurofibromatosis type 1 [65-67] •Noonan syndrome [68-70] •Phakomatosis pigmentovascularis type IIIb [71] •Prader-Willi syndrome [72] •Pseudoxanthoma elasticum [73] •Sturge-Weber syndrome [74] •Tuberous sclerosis [75] •Turner syndrome [76] •Williams syndrome [77] •Morning glory optic disc anomaly (image 2), usually in conjunction with other craniofacial abnormalities [78-80] (see "Congenital anomalies and acquired abnormalities of the optic nerve", section on 'Morning glory disc') ●Other vasculopathies and extracranial cardiovascular diseases •Coarctation o




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● Other vasculopathies and extracranial cardiovascular diseases

• Coarctation of the aorta [81]

• Congenital heart disease [82]

• Fibromuscular dysplasia [83]

• Renal artery stenosis [84]

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omaly (image 2), usually in conjunction with other craniofacial abnormalities [78-80] (see "Congenital anomalies and acquired abnormalities of the optic nerve", section on 'Morning glory disc') <span>●Other vasculopathies and extracranial cardiovascular diseases •Coarctation of the aorta [81] •Congenital heart disease [82] •Fibromuscular dysplasia [83] •Renal artery stenosis [84] ●Metabolic diseases •Type I glycogenosis [85,86] •Hyperphosphatasia [87] •Primary oxalosis [88] ●Renal disorders •Polycystic kidney disease [89-91] •Wilms tumor [84,92-104] Pathogenesis




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● Metabolic diseases

• Type I glycogenosis [85,86]

• Hyperphosphatasia [87]

• Primary oxalosis [88]

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ory disc') ●Other vasculopathies and extracranial cardiovascular diseases •Coarctation of the aorta [81] •Congenital heart disease [82] •Fibromuscular dysplasia [83] •Renal artery stenosis [84] <span>●Metabolic diseases •Type I glycogenosis [85,86] •Hyperphosphatasia [87] •Primary oxalosis [88] ●Renal disorders •Polycystic kidney disease [89-91] •Wilms tumor [84,92-104] Pathogenesis — The pathophysiologic processes leading to arterial stenosis and small vessel collateralizatio




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● Renal disorders

• Polycystic kidney disease [89-91]

• Wilms tumor [84,92-104]

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rta [81] •Congenital heart disease [82] •Fibromuscular dysplasia [83] •Renal artery stenosis [84] ●Metabolic diseases •Type I glycogenosis [85,86] •Hyperphosphatasia [87] •Primary oxalosis [88] <span>●Renal disorders •Polycystic kidney disease [89-91] •Wilms tumor [84,92-104] Pathogenesis — The pathophysiologic processes leading to arterial stenosis and small vessel collateralization involve vessel wall thickening and angiogenesis. A genetic susceptibility m




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Vascular changes in moyamoya are associated with evidence of increased angiogenesis-related factors, including endothelial colony-forming cells, various cytokines, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) [105-107].
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ssel collateralization involve vessel wall thickening and angiogenesis. A genetic susceptibility may be implicated in MMD, while underlying associated conditions trigger the development of MMS. <span>Vascular changes in moyamoya are associated with evidence of increased angiogenesis-related factors, including endothelial colony-forming cells, various cytokines, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) [105-107]. High levels of fibroblast growth factor, which may stimulate arterial growth, have been found in the vascular intima, media, and smooth muscle as well as cerebrospinal fluid among patie




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Multiple areas of cerebral infarction and focal cortical atrophy are commonly found. Although large vessel stenosis and occlusion are the hallmark of this disease, extensive territorial infarction is uncommon. The brain infarcts are generally small and located in the basal ganglia, internal capsule, thalamus, and subcortical regions [113]
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well as tissue damage related to the vascular abnormalities. ●Cerebrovascular disease – Brain tissue of patients with moyamoya usually reveals evidence of prior ischemic or hemorrhagic stroke. <span>Multiple areas of cerebral infarction and focal cortical atrophy are commonly found. Although large vessel stenosis and occlusion are the hallmark of this disease, extensive territorial infarction is uncommon. The brain infarcts are generally small and located in the basal ganglia, internal capsule, thalamus, and subcortical regions [113]. However, the cause of death in most autopsy cases is intracerebral hemorrhage [94]. The hemorrhage is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or peri




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However, the cause of death in most autopsy cases is intracerebral hemorrhage [ 94]. The hemorrhage is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or periventricular region. Bleeding into the intraventricular space is frequently observed.
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f this disease, extensive territorial infarction is uncommon. The brain infarcts are generally small and located in the basal ganglia, internal capsule, thalamus, and subcortical regions [113]. <span>However, the cause of death in most autopsy cases is intracerebral hemorrhage [94]. The hemorrhage is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or periventricular region. Bleeding into the intraventricular space is frequently observed. ●Vascular stenosis – Pathologic vascular lesions appear in the large vessels of the circle of Willis and in the small collateral vessels [95]. The terminal portions of the internal caro




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Pathologic vascular lesions appear in the large vessels of the circle of Willis and in the small collateral vessels [95]. The terminal portions of the internal carotid arteries as well as the proximal middle and anterior cerebral arteries are most commonly involved [114]. Some patients may have unilateral stenosis at presentation, although progression to bilateral involvement may occur [115,116]. Less frequently, the posterior circulation is affected, especially the posterior cerebral artery.
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ge is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or periventricular region. Bleeding into the intraventricular space is frequently observed. ●Vascular stenosis – <span>Pathologic vascular lesions appear in the large vessels of the circle of Willis and in the small collateral vessels [95]. The terminal portions of the internal carotid arteries as well as the proximal middle and anterior cerebral arteries are most commonly involved [114]. Some patients may have unilateral stenosis at presentation, although progression to bilateral involvement may occur [115,116]. Less frequently, the posterior circulation is affected, especially the posterior cerebral artery. In the affected large arteries, variable stenosis or occlusion is associated with intimal fibrocellular thickening, tortuosity or duplication of the internal elastic lamina, and attenua




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One of the hallmarks of moyamoya is the presence of a collateral meshwork of overgrown and dilated small arteries, the moyamoya vessels, that branch from the circle of Willis (image 3).
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osis or occlusion is associated with intimal fibrocellular thickening, tortuosity or duplication of the internal elastic lamina, and attenuation of the media [92,117-119]. ●Collateral vessels – <span>One of the hallmarks of moyamoya is the presence of a collateral meshwork of overgrown and dilated small arteries, the moyamoya vessels, that branch from the circle of Willis (image 3). The pathology of the smaller perforating vessels in moyamoya is variable. Morphometric analysis suggests that some are dilated with relatively thin walls, while others are stenotic with




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Leptomeningeal vessels are another source of collaterals in moyamoya. As a result of intracranial internal carotid artery stenosis, leptomeningeal anastomoses may develop from the three main cerebral arteries (middle, anterior, and posterior). These collaterals result from dilatation of preexisting arteries and veins. In addition, transdural anastomoses, termed vault moyamoya, may develop from extracranial arteries such as the middle meningeal and superficial temporal arteries [96].
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ens of aneurysms showed disappearance of internal elastic lamina and media [93]. These findings are similar to those of the berry aneurysms commonly observed in primary subarachnoid hemorrhage. <span>Leptomeningeal vessels are another source of collaterals in moyamoya. As a result of intracranial internal carotid artery stenosis, leptomeningeal anastomoses may develop from the three main cerebral arteries (middle, anterior, and posterior). These collaterals result from dilatation of preexisting arteries and veins. In addition, transdural anastomoses, termed vault moyamoya, may develop from extracranial arteries such as the middle meningeal and superficial temporal arteries [96]. ●Aneurysms – Cerebral aneurysms have been associated with moyamoya in a number of reports [97-101]. Aneurysms can develop at vessel branching points in the circle of Willis or along col




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In patients with moyamoya disease, stenosis due to fibrocellular intimal thickening may also affect the extracranial and systemic arteries, including the cervical carotid, renal, pulmonary, and coronary vessels [92,103].
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idal arteries, or other peripheral collateral arteries [102]. These small vessel aneurysms are the major cause of parenchymal (intracerebral) hemorrhage in moyamoya. ●Extracranial involvement – <span>In patients with moyamoya disease, stenosis due to fibrocellular intimal thickening may also affect the extracranial and systemic arteries, including the cervical carotid, renal, pulmonary, and coronary vessels [92,103]. Involvement of the renal arteries has been most frequently reported. In one study of 86 patients with moyamoya disease, six had renal artery stenosis, two had associated renovascular hy




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Involvement of the renal arteries has been most frequently reported. In one study of 86 patients with moyamoya disease, six had renal artery stenosis, two had associated renovascular hypertension, and one had a renal artery aneurysm [84]. Similarly, in a later study of 73 consecutive patients with moyamoya disease, four had renal artery stenosis [121].
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isease, stenosis due to fibrocellular intimal thickening may also affect the extracranial and systemic arteries, including the cervical carotid, renal, pulmonary, and coronary vessels [92,103]. <span>Involvement of the renal arteries has been most frequently reported. In one study of 86 patients with moyamoya disease, six had renal artery stenosis, two had associated renovascular hypertension, and one had a renal artery aneurysm [84]. Similarly, in a later study of 73 consecutive patients with moyamoya disease, four had renal artery stenosis [121]. EPIDEMIOLOGY Incidence and prevalence — The relative prevalence of moyamoya disease (MMD) and moyamoya syndrome (MMS) vary geographically. MMD is more common in East Asian countries tha




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There is a female predominance, with a female-to-male ratio of 1.9.

● A family history of MMD is present in 10 to 12 percent of patients.

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he following observations have been made [124-127]: ●The annual incidence of moyamoya is 0.35 to 0.94 per 100,000 population. ●The prevalence of moyamoya is 3.2 to 10.5 per 100,000 population. ●<span>There is a female predominance, with a female-to-male ratio of 1.9. ●A family history of MMD is present in 10 to 12 percent of patients. Using hospital admissions data, a United States study found an incidence of 0.57 per 100,000 persons/year [128]. Among ethnic groups in California, the moyamoya incidence rate for Asian




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● The prevalence of moyamoya is 3.2 to 10.5 per 100,000 population.
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Korea [114,122,123]. In epidemiologic surveys conducted in Japan, the following observations have been made [124-127]: ●The annual incidence of moyamoya is 0.35 to 0.94 per 100,000 population. <span>●The prevalence of moyamoya is 3.2 to 10.5 per 100,000 population. ●There is a female predominance, with a female-to-male ratio of 1.9. ●A family history of MMD is present in 10 to 12 percent of patients. Using hospital admissions data, a United States




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Data from a nationwide registry in Japan, with 2545 cases of MMD, showed a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second broader peak at approximately 40 years of age [127]
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he incidence of MMS in Japan is approximately 10 times lower than MMD [129,130]. Age distribution — MMD and MMS both occur in children and adults; presentation in infancy is uncommon [131,132]. <span>Data from a nationwide registry in Japan, with 2545 cases of MMD, showed a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second broader peak at approximately 40 years of age [127]. A cohort study of 802 patients with MMD from China also demonstrated a bimodal age distribution, with a major peak at 5 to 9 years of age and another peak at 35 to 39 years of age [133




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The most common initial presentation of moyamoya is ischemic stroke [134-138]. Transient ischemic attack (TIA) is also a frequent initial presentation and may be recurrent [134,138].
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moya has varying clinical presentations; the expression of disease and the age at presentation are influenced by regional and ethnic differences. Ischemic stroke and transient ischemic attack — <span>The most common initial presentation of moyamoya is ischemic stroke [134-138]. Transient ischemic attack (TIA) is also a frequent initial presentation and may be recurrent [134,138]. In one retrospective series from the United States, 61 percent of 31 adults with moyamoya disease (MMD) or moyamoya syndrome (MMS) presented with ischemic symptoms; in those with stroke




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In one retrospective series from the United States, 61 percent of 31 adults with moyamoya disease (MMD) or moyamoya syndrome (MMS) presented with ischemic symptoms; in those with stroke, the predominant pattern was a border zone pattern of infarction [137].
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c attack — The most common initial presentation of moyamoya is ischemic stroke [134-138]. Transient ischemic attack (TIA) is also a frequent initial presentation and may be recurrent [134,138]. <span>In one retrospective series from the United States, 61 percent of 31 adults with moyamoya disease (MMD) or moyamoya syndrome (MMS) presented with ischemic symptoms; in those with stroke, the predominant pattern was a border zone pattern of infarction [137]. In another retrospective study, 21 German patients with MMD all presented with ischemic events, including 16 who were adults at symptom onset [136]. In children, symptomatic episodes of




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Patients with moyamoya present infrequently with seizures, often secondary to ischemic damage [145]. The rate of epilepsy may be more frequent in children than in adults [142].
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ented with ICH or intraventricular hemorrhage, small aneurysms in the periventricular area have been reported (image 4). Patients may also present with subarachnoid hemorrhage [144]. Seizures — <span>Patients with moyamoya present infrequently with seizures, often secondary to ischemic damage [145]. The rate of epilepsy may be more frequent in children than in adults [142]. Other presentations ●Headache – Headache is common in patients with moyamoya [146]. In one cohort of patients, migraine symptoms were more common than tension-type headache symptoms [14




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Headache is common in patients with moyamoya [146]. In one cohort of patients, migraine symptoms were more common than tension-type headache symptoms [147].
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oyamoya present infrequently with seizures, often secondary to ischemic damage [145]. The rate of epilepsy may be more frequent in children than in adults [142]. Other presentations ●Headache – <span>Headache is common in patients with moyamoya [146]. In one cohort of patients, migraine symptoms were more common than tension-type headache symptoms [147]. ●Other neurologic symptoms – There are case reports of patients with moyamoya who develop dystonia, chorea, or dyskinesia, but these appear to be uncommon manifestations [148-150]. ●Asy




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There are case reports of patients with moyamoya who develop dystonia, chorea, or dyskinesia, but these appear to be uncommon manifestations [148-150].
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dache – Headache is common in patients with moyamoya [146]. In one cohort of patients, migraine symptoms were more common than tension-type headache symptoms [147]. ●Other neurologic symptoms – <span>There are case reports of patients with moyamoya who develop dystonia, chorea, or dyskinesia, but these appear to be uncommon manifestations [148-150]. ●Asymptomatic disease – Moyamoya can be found incidentally in asymptomatic patients undergoing screening imaging for other conditions or because of family history [151,152]. A nationwid




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Patterns of infarction may be suggestive of moyamoya, but these features are not specific for this condition. In a retrospective series of 32 adults with first-ever ischemic stroke, patients with early-stage MMD had ischemic lesions involving only deep subcortical structures, while those with advanced stage had predominantly cortical lesions [155].
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subcortical regions (image 5). Ischemic injury distal to the stenotic or occluded moyamoya vessel is common in superficial and deep border zone regions most susceptible to hypoperfusion [154]. <span>Patterns of infarction may be suggestive of moyamoya, but these features are not specific for this condition. In a retrospective series of 32 adults with first-ever ischemic stroke, patients with early-stage MMD had ischemic lesions involving only deep subcortical structures, while those with advanced stage had predominantly cortical lesions [155]. In patients with intracerebral hemorrhage (ICH), bleeding occurs in deep structures such as the basal ganglia, thalamus, and/or ventricular system. Bleeding in the cortical and subcorti




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Dilated collateral vessels in the basal ganglia or thalamus can be demonstrated as multiple punctate flow voids, a finding that is considered virtually diagnostic of moyamoya (image 6) [161].
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or for subsequent intracerebral hemorrhage (hazard ratio 2.89; 95% CI 1.001-13.24) [159]. Additional MRI findings have been implicated in identifying vascular changes consistent with moyamoya: ●<span>Dilated collateral vessels in the basal ganglia or thalamus can be demonstrated as multiple punctate flow voids, a finding that is considered virtually diagnostic of moyamoya (image 6) [161]. ●The "ivy sign" refers to focal, tubular, or serpentine hyperintensities on fluid-attenuated inversion recovery (FLAIR) or contrast-enhanced T1 images in the subarachnoid spaces that re




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The "ivy sign" refers to focal, tubular, or serpentine hyperintensities on fluid-attenuated inversion recovery (FLAIR) or contrast-enhanced T1 images in the subarachnoid spaces that represent slow, retrograde collateral flow through engorged pial vessels via leptomeningeal anastomoses (image 7) [162-164].
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●Dilated collateral vessels in the basal ganglia or thalamus can be demonstrated as multiple punctate flow voids, a finding that is considered virtually diagnostic of moyamoya (image 6) [161]. ●<span>The "ivy sign" refers to focal, tubular, or serpentine hyperintensities on fluid-attenuated inversion recovery (FLAIR) or contrast-enhanced T1 images in the subarachnoid spaces that represent slow, retrograde collateral flow through engorged pial vessels via leptomeningeal anastomoses (image 7) [162-164]. Observational data of 48 patients with ischemic symptoms and MMD showed the extent of the ivy sign was associated with a reduction in cerebral vascular reserve assessed by single-photon




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The "brush sign" refers to prominent hypointensity in medullary veins draining areas of impaired cerebral perfusion on susceptibility-weighted imaging (SWI), a high spatial resolution 3D-gradient echo MRI technique that accentuates paramagnetic properties of blood products such as deoxyhemoglobin
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fic for MMS/MMD and has been reported in association with large-vessel stenosis or occlusions, where it is referred to as FLAIR vascular hyperintensities or the hyperintense vessel sign [166]. ●<span>The "brush sign" refers to prominent hypointensity in medullary veins draining areas of impaired cerebral perfusion on susceptibility-weighted imaging (SWI), a high spatial resolution 3D-gradient echo MRI technique that accentuates paramagnetic properties of blood products such as deoxyhemoglobin. In a group of 33 patients, the brush sign was identified more often in moyamoya patients with TIA and infarction than in asymptomatic patients. This sign was also more prominent in tho




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Like the ivy sign, the "brush sign" is not specific for moyamoya and has been identified in patients with subacute stroke from many causes [168].
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entified more often in moyamoya patients with TIA and infarction than in asymptomatic patients. This sign was also more prominent in those with impaired cerebrovascular reserve (image 8) [167]. <span>Like the ivy sign, the "brush sign" is not specific for moyamoya and has been identified in patients with subacute stroke from many causes [168]. ●Post-contrast enhancement within the arterial wall may be seen using high-resolution MRI [169]. One study of 24 patients with moyamoya who underwent high-resolution vessel wall imaging




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The diagnosis of moyamoya disease (MMD) is made by identifying the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries and proximal circle of Willis vessels, along with the presence of prominent collateral vessels (image 5). Moyamoya syndrome (MMS) is diagnosed by identifying these characteristic angiographic features in the setting of an associated condition.
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h hyperventilation was reported to be safe in one series of 127 children [172], rare reports link hyperventilation to limb-shaking TIA and episodes of chorea and dystonia [175-177]. DIAGNOSIS — <span>The diagnosis of moyamoya disease (MMD) is made by identifying the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries and proximal circle of Willis vessels, along with the presence of prominent collateral vessels (image 5). Moyamoya syndrome (MMS) is diagnosed by identifying these characteristic angiographic features in the setting of an associated condition. (See 'Associated conditions' above.) Indications for vascular imaging — The possibility of MMD disease should be considered in: ●Children or young adults with repeated symptoms of ische




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The possibility of MMD disease should be considered in:

● Children or young adults with repeated symptoms of ischemic attacks resulting from low perfusion in the same arterial territory.

● Patients who lack common factors for primary intracerebral hemorrhage (ICH) but present with intracerebral hemorrhage in brain regions supplied by small vessels that branch from the circle of Willis (eg, caudate, thalamus, or intraventricular hemorrhage within the lateral ventricles).

● Children or young adults with ischemic or hemorrhagic stroke who may lack common cerebrovascular risk factors. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis'.)

● Patients who undergo magnetic resonance imaging (MRI), particularly in the context of evaluation for cerebral ischemia, which shows associated findings such as dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," the "brush sign," or enhancement of the arterial wall (See 'Neuroimaging' above.)

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e (MMS) is diagnosed by identifying these characteristic angiographic features in the setting of an associated condition. (See 'Associated conditions' above.) Indications for vascular imaging — <span>The possibility of MMD disease should be considered in: ●Children or young adults with repeated symptoms of ischemic attacks resulting from low perfusion in the same arterial territory. ●Patients who lack common factors for primary intracerebral hemorrhage (ICH) but present with intracerebral hemorrhage in brain regions supplied by small vessels that branch from the circle of Willis (eg, caudate, thalamus, or intraventricular hemorrhage within the lateral ventricles). ●Children or young adults with ischemic or hemorrhagic stroke who may lack common cerebrovascular risk factors. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis'.) ●Patients who undergo magnetic resonance imaging (MRI), particularly in the context of evaluation for cerebral ischemia, which shows associated findings such as dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," the "brush sign," or enhancement of the arterial wall (See 'Neuroimaging' above.) Diagnostic criteria — Definitive diagnosis of moyamoya requires neurovascular imaging. Diagnostic criteria for MMD proposed by a Japanese research committee include the following major




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Definitive diagnosis of moyamoya requires neurovascular imaging. Diagnostic criteria for MMD proposed by a Japanese research committee include the following major requirements [6]:

● Stenosis or occlusion at the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries

● Abnormal vascular networks in the basal ganglia; these networks can also be diagnosed by the presence of multiple flow voids on brain MRI

● Angiographic findings are present bilaterally; cases with unilateral angiographic findings are considered probable

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ings such as dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," the "brush sign," or enhancement of the arterial wall (See 'Neuroimaging' above.) Diagnostic criteria — <span>Definitive diagnosis of moyamoya requires neurovascular imaging. Diagnostic criteria for MMD proposed by a Japanese research committee include the following major requirements [6]: ●Stenosis or occlusion at the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries ●Abnormal vascular networks in the basal ganglia; these networks can also be diagnosed by the presence of multiple flow voids on brain MRI ●Angiographic findings are present bilaterally; cases with unilateral angiographic findings are considered probable For the diagnosis of MMD, underlying associated conditions (suggestive instead of MMS) are excluded. (See 'Further evaluation' below.) Angiography — Stenotic distal internal carotid or




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There are three clinically and genetically distinct forms of neurofibromatosis: neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis. NF1, previously known as von Recklinghausen disease, is the most common type.
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opics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jul 2021. | This topic last updated: Jan 08, 2021. INTRODUCTION — <span>There are three clinically and genetically distinct forms of neurofibromatosis: neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis. NF1, previously known as von Recklinghausen disease, is the most common type. The hallmarks of NF1 are multiple café-au-lait macules and neurofibromas. The condition is called segmental NF1 when clinical features are limited to one area of the body due to somatic




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The condition is called segmental NF1 when clinical features are limited to one area of the body due to somatic mosaicism of a pathogenic variant in the NF1 gene.
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and 2 (NF1 and NF2) and schwannomatosis. NF1, previously known as von Recklinghausen disease, is the most common type. The hallmarks of NF1 are multiple café-au-lait macules and neurofibromas. <span>The condition is called segmental NF1 when clinical features are limited to one area of the body due to somatic mosaicism of a pathogenic variant in the NF1 gene. The pathogenesis, clinical features, and diagnosis of NF1 are reviewed here. Management and prognosis are discussed separately (see "Neurofibromatosis type 1 (NF1): Management and progn




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The incidence of segmental NF1 is unknown, but the prevalence is estimated at 1:36,000 to 1:40,000 [3].
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ce of approximately 1:2600 to 3000 individuals [1]. Approximately one-half of the cases are familial (inherited) [1] The de novo mutations occur primarily in paternally derived chromosomes [2]. <span>The incidence of segmental NF1 is unknown, but the prevalence is estimated at 1:36,000 to 1:40,000 [3]. A study of death certificates in the United States revealed a mean age at death for persons with NF1 at 54.4 years and median at 59 years, well below population norms (70.1 and 74 years




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NF1 is an autosomal-dominant genetic disorder with an incidence of approximately 1:2600 to 3000 individuals [1]. Approximately one-half of the cases are familial (inherited) [1] The de novo mutations occur primarily in paternally derived chromosomes [2].
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d prognosis"). The other two forms of neurofibromatosis, NF2 and schwannomatosis, are also discussed in detail separately. (See "Neurofibromatosis type 2" and "Schwannomatosis".) EPIDEMIOLOGY — <span>NF1 is an autosomal-dominant genetic disorder with an incidence of approximately 1:2600 to 3000 individuals [1]. Approximately one-half of the cases are familial (inherited) [1] The de novo mutations occur primarily in paternally derived chromosomes [2]. The incidence of segmental NF1 is unknown, but the prevalence is estimated at 1:36,000 to 1:40,000 [3]. A study of death certificates in the United States revealed a mean age at death f




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Pathogenic variants in the NF1 gene result in loss of production or reduced function of protein, causing the wide spectrum of clinical findings, including NF1-associated tumors [7]. Penetrance, or the likelihood that the individual carrying the variant will manifest the disorder, is complete
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a number of signaling pathways that include the stem cell factor (SCF)/c-kit signaling, mammalian (mechanistic) target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) pathways. <span>Pathogenic variants in the NF1 gene result in loss of production or reduced function of protein, causing the wide spectrum of clinical findings, including NF1-associated tumors [7]. Penetrance, or the likelihood that the individual carrying the variant will manifest the disorder, is complete. NF1 is highly variable in its expression, however (ie, the severity of and specific manifestations of the disorder vary among affected individuals within the same family and from one f




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NF1 is highly variable in its expression, however (ie, the severity of and specific manifestations of the disorder vary among affected individuals within the same family and from one family to another) [ 8].
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sing the wide spectrum of clinical findings, including NF1-associated tumors [7]. Penetrance, or the likelihood that the individual carrying the variant will manifest the disorder, is complete. <span>NF1 is highly variable in its expression, however (ie, the severity of and specific manifestations of the disorder vary among affected individuals within the same family and from one family to another) [8]. Somatic mutation or loss of heterozygosity at the NF1 locus, in combination with a germline NF1 mutation, leads to complete loss of neurofibromin expression that is seen in NF1 lesions




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It is possible that haploinsufficiency (ie, heterozygosity for a pathogenic variant with an intact second allele) accounts for some aspects of the phenotype, such as neurocognitive problems.
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mutation, leads to complete loss of neurofibromin expression that is seen in NF1 lesions such as pseudoarthrosis [9] and neurofibromas [10]. NF1 therefore functions as a tumor suppressor gene. <span>It is possible that haploinsufficiency (ie, heterozygosity for a pathogenic variant with an intact second allele) accounts for some aspects of the phenotype, such as neurocognitive problems. Segmental NF1 is caused by somatic mosaicism due to a postzygotic mutation in the NF1 gene [11]. This results in some cells having two normal NF1 genes and other cells containing a path




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The typical order of appearance of clinical manifestations is café-au-lait macules, axillary and/or inguinal freckling, Lisch nodules (iris hamartomas), and neurofibromas [14]. Osseous dysplasias, if present, usually appear during the patient's first year after birth, and symptomatic optic pathway glioma (OPG) usually occurs by the time the patient is three years of age (table 1).
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tion in all cells and will not have segmental disease. Rare individuals have been described who have only germline mosaicism without apparent somatic features [12,13]. CLINICAL MANIFESTATIONS — <span>The typical order of appearance of clinical manifestations is café-au-lait macules, axillary and/or inguinal freckling, Lisch nodules (iris hamartomas), and neurofibromas [14]. Osseous dysplasias, if present, usually appear during the patient's first year after birth, and symptomatic optic pathway glioma (OPG) usually occurs by the time the patient is three years of age (table 1). Other tumors and neurologic complications typically begin to appear after the first year of life. Hypertension may occur in childhood. Malignant transformation of tumors may also occur




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Café-au-lait macules are flat, uniformly hyperpigmented macules that appear during the first year after birth and usually increase in number during early childhood (picture 1).
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irst year of life. Hypertension may occur in childhood. Malignant transformation of tumors may also occur in childhood but more often occurs in adolescence and adulthood. Café-au-lait macules — <span>Café-au-lait macules are flat, uniformly hyperpigmented macules that appear during the first year after birth and usually increase in number during early childhood (picture 1). The number of café-au-lait macules then stabilizes over time. Up to 15 percent of the normal population has one to three café-au-lait macules; however, the presence of six or more café-




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The number of café-au-lait macules then stabilizes over time. Up to 15 percent of the normal population has one to three café-au-lait macules; however, the presence of six or more café-au-lait macules is highly suggestive of NF1 [ 15,16].
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u-lait macules — Café-au-lait macules are flat, uniformly hyperpigmented macules that appear during the first year after birth and usually increase in number during early childhood (picture 1). <span>The number of café-au-lait macules then stabilizes over time. Up to 15 percent of the normal population has one to three café-au-lait macules; however, the presence of six or more café-au-lait macules is highly suggestive of NF1 [15,16]. One retrospective study used age and number/type of café-au-lait macules at the time of presentation to determine the risk of having NF1 [17]. Younger age at presentation (≤29 months) a




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Freckling in the axillary or inguinal regions (Crowe sign) is a diagnostic criterion distinct from café-au-lait macules. The freckles are smaller in size than café-au-lait macules, appear later, and usually occur in clusters in skin folds rather than randomly (picture 2 and picture 3).
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h the diagnostic criteria specify examination in ordinary room lighting. (See "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp examination (black light)'.) Freckling — <span>Freckling in the axillary or inguinal regions (Crowe sign) is a diagnostic criterion distinct from café-au-lait macules. The freckles are smaller in size than café-au-lait macules, appear later, and usually occur in clusters in skin folds rather than randomly (picture 2 and picture 3). Freckling occurs mostly in regions of skin apposition, especially the axillary and inguinal areas. Freckling usually is not apparent at birth but often appears by age three to five year




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Freckling occurs mostly in regions of skin apposition, especially the axillary and inguinal areas. Freckling usually is not apparent at birth but often appears by age three to five years, typically first in the inguinal region [15]. Freckling may also occur in other intertriginous areas, such as the neckline or inframammary areas in women. In some individuals, freckling may occur elsewhere on the body and may be diffuse. One or two small freckles or the presence of a café-au-lait macule in a skin fold does not fulfill the diagnostic criterion for skin fold freckling.
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from café-au-lait macules. The freckles are smaller in size than café-au-lait macules, appear later, and usually occur in clusters in skin folds rather than randomly (picture 2 and picture 3). <span>Freckling occurs mostly in regions of skin apposition, especially the axillary and inguinal areas. Freckling usually is not apparent at birth but often appears by age three to five years, typically first in the inguinal region [15]. Freckling may also occur in other intertriginous areas, such as the neckline or inframammary areas in women. In some individuals, freckling may occur elsewhere on the body and may be diffuse. One or two small freckles or the presence of a café-au-lait macule in a skin fold does not fulfill the diagnostic criterion for skin fold freckling. Lisch nodules — Lisch nodules are raised, tan-colored hamartomas of the iris and represent a specific finding for NF1. They do not affect vision in any manner. Lisch nodules are useful




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Lisch nodules are raised, tan-colored hamartomas of the iris and represent a specific finding for NF1. They do not affect vision in any manner. Lisch nodules are useful both in establishing a diagnosis of NF1 in a child and determining whether a parent is affected. These lesions are detected in fewer than 10 percent of affected children younger than six years of age but are seen in greater than 90 percent of adults [19,20].
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the body and may be diffuse. One or two small freckles or the presence of a café-au-lait macule in a skin fold does not fulfill the diagnostic criterion for skin fold freckling. Lisch nodules — <span>Lisch nodules are raised, tan-colored hamartomas of the iris and represent a specific finding for NF1. They do not affect vision in any manner. Lisch nodules are useful both in establishing a diagnosis of NF1 in a child and determining whether a parent is affected. These lesions are detected in fewer than 10 percent of affected children younger than six years of age but are seen in greater than 90 percent of adults [19,20]. They may be seen with a direct ophthalmoscope if the nodules are large or numerous and the iris is light in color, but the slit lamp is a more reliable way to distinguish Lisch nodules




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They may be seen with a direct ophthalmoscope if the nodules are large or numerous and the iris is light in color, but the slit lamp is a more reliable way to distinguish Lisch nodules from iris nevi, which are not associated with NF1 ( picture 4) [21].
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g whether a parent is affected. These lesions are detected in fewer than 10 percent of affected children younger than six years of age but are seen in greater than 90 percent of adults [19,20]. <span>They may be seen with a direct ophthalmoscope if the nodules are large or numerous and the iris is light in color, but the slit lamp is a more reliable way to distinguish Lisch nodules from iris nevi, which are not associated with NF1 (picture 4) [21]. Tumors — Persons with NF1 develop both benign and malignant tumors at increased frequency throughout life [22]. Neurofibromas are the most common type of benign tumor that develops in p




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Persons with NF1 develop both benign and malignant tumors at increased frequency throughout life [22]. Neurofibromas are the most common type of benign tumor that develops in persons with NF1. OPGs are the predominant type of intracranial neoplasms, but other central nervous system (CNS) and non-CNS tumors can occur.
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ge or numerous and the iris is light in color, but the slit lamp is a more reliable way to distinguish Lisch nodules from iris nevi, which are not associated with NF1 (picture 4) [21]. Tumors — <span>Persons with NF1 develop both benign and malignant tumors at increased frequency throughout life [22]. Neurofibromas are the most common type of benign tumor that develops in persons with NF1. OPGs are the predominant type of intracranial neoplasms, but other central nervous system (CNS) and non-CNS tumors can occur. One retrospective French study included 88 children (3 months to 17 years old) and 16 adults (19 to 52 years old) with NF1 who developed CNS tumors over a period between 1982 and 2000 [




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Discrete cutaneous neurofibromas are the most common type. They consist of soft, fleshy, sessile or pedunculated tumors [31]. They move with the skin on examination and are not tender. Some are located within the dermis and can be palpated as a soft spot in the skin, often with an overlying violaceous discoloration. These cutaneous lesions usually begin to appear just before or during adolescence, although small lesions can be seen in younger children, especially if the skin is viewed with side lighting. They tend to increase in size and number with age and vary in number from just a few to thousands, with the highest density occurring over the trunk.
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In a report of 247 pregnancies in 105 women, growth of new lesions and enlargement of existing lesions were reported in 60 and 55 percent of cases, respectively [30]. Cutaneous neurofibromas — <span>Discrete cutaneous neurofibromas are the most common type. They consist of soft, fleshy, sessile or pedunculated tumors [31]. They move with the skin on examination and are not tender. Some are located within the dermis and can be palpated as a soft spot in the skin, often with an overlying violaceous discoloration. These cutaneous lesions usually begin to appear just before or during adolescence, although small lesions can be seen in younger children, especially if the skin is viewed with side lighting. They tend to increase in size and number with age and vary in number from just a few to thousands, with the highest density occurring over the trunk. Cutaneous neurofibromas are benign and do not carry a risk of malignant transformation, but they often represent a major cosmetic problem in adults. Pruritus associated with accelerated




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Nodular neurofibromas are discrete lesions that may grow under the skin, where they appear as firm, rubbery masses that may be tender, or occur deeper inside the body (image 1). Some can enlarge to the point where they compress surrounding structures or cause pain, but they do not tend to invade surrounding tissues like plexiform neurofibromas. They may take up 18-fluorodeoxyglucose, as occurs in MPNST [36], and may have pathologic features including nuclear atypia, some mitotic activity, and dense cellularity, referred to as "atypical neurofibroma" or "atypical neurofibromatous neoplasms of uncertain biologic potential" (ANNUBP) [37].
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common feature of malignant transformation of an existing plexiform neurofibroma is a painful, expanding lesion. (See 'Malignant peripheral nerve sheath tumors' below.) Nodular neurofibromas — <span>Nodular neurofibromas are discrete lesions that may grow under the skin, where they appear as firm, rubbery masses that may be tender, or occur deeper inside the body (image 1). Some can enlarge to the point where they compress surrounding structures or cause pain, but they do not tend to invade surrounding tissues like plexiform neurofibromas. They may take up 18-fluorodeoxyglucose, as occurs in MPNST [36], and may have pathologic features including nuclear atypia, some mitotic activity, and dense cellularity, referred to as "atypical neurofibroma" or "atypical neurofibromatous neoplasms of uncertain biologic potential" (ANNUBP) [37]. Atypical neurofibromas have homozygous deletion of cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) in addition to loss of both NF1 alleles [38-40] and may be premalignant lesions. Opt




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Plexiform neurofibromas may be located superficially and associated with overgrowth of skin and soft tissues (picture 5), may be located deep inside the body, or may have both superficial and deep components. Cutaneous involvement tends to be diffuse, with no discernible nerve fibers, although small plaques of cutaneous plexiform tumors may have palpable cords of thickened nerves. Deeper plexiform neurofibromas tend to appear as thickened nerves and can grow into a complex mass consisting of a network of enlarged nerves.
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, but they often represent a major cosmetic problem in adults. Pruritus associated with accelerated growth of neurofibromas may be a prominent and distressing symptom. Plexiform neurofibromas — <span>Plexiform neurofibromas may be located superficially and associated with overgrowth of skin and soft tissues (picture 5), may be located deep inside the body, or may have both superficial and deep components. Cutaneous involvement tends to be diffuse, with no discernible nerve fibers, although small plaques of cutaneous plexiform tumors may have palpable cords of thickened nerves. Deeper plexiform neurofibromas tend to appear as thickened nerves and can grow into a complex mass consisting of a network of enlarged nerves. The lesions are usually congenital and tend to grow most rapidly during childhood [32]. Whole-body imaging reveals plexiform neurofibromas in approximately 50 percent of patients with N




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OPGs occur in approximately 15 percent of children younger than six years of age with NF1 [41]. They rarely occur in older children and adults [42,43]. OPGs are typically low-grade pilocytic astrocytomas [42,43]. They can arise anywhere along the anterior visual pathway to the optic radiations and involve the optic nerves, chiasm, and postchiasmal optic tracts (image 2).
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rofibromas have homozygous deletion of cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) in addition to loss of both NF1 alleles [38-40] and may be premalignant lesions. Optic pathway gliomas — <span>OPGs occur in approximately 15 percent of children younger than six years of age with NF1 [41]. They rarely occur in older children and adults [42,43]. OPGs are typically low-grade pilocytic astrocytomas [42,43]. They can arise anywhere along the anterior visual pathway to the optic radiations and involve the optic nerves, chiasm, and postchiasmal optic tracts (image 2). A retrospective magnetic resonance imaging (MRI) study of 562 adults and children with NF1 revealed an overall prevalence of optic pathway tumors of 9.3 percent [44]. (This may have bee




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Detecting precocious puberty early in patients with NF1 is important because it may indicate the presence of a clinically significant OPG, although abnormal puberty can occur in the absence of OPG. In addition, treatment can minimize the complications of accelerated linear bone growth and premature development of secondary sexual characteristics. One of the earliest signs of precocious puberty is accelerated linear growth, which highlights the importance of maintaining accurate growth charts using standards for children with NF1
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Premature or delayed puberty due to OPGs — Children with tumors involving the optic chiasm occasionally present with either premature or delayed puberty caused by hypothalamic involvement [23]. <span>Detecting precocious puberty early in patients with NF1 is important because it may indicate the presence of a clinically significant OPG, although abnormal puberty can occur in the absence of OPG. In addition, treatment can minimize the complications of accelerated linear bone growth and premature development of secondary sexual characteristics. One of the earliest signs of precocious puberty is accelerated linear growth, which highlights the importance of maintaining accurate growth charts using standards for children with NF1 [53,54]. (See "Definition, etiology, and evaluation of precocious puberty" and 'Growth' below.) Other central nervous system neoplasms — In addition to OPGs, individuals with NF1 are at




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In addition to OPGs, individuals with NF1 are at an increased risk for developing other CNS neoplasms, particularly low-grade astrocytomas and brainstem gliomas [23,42,55-58]. The most frequent clinical presentation is that of increased intracranial pressure, although lesions are often asymptomatic and are noted as incidental findings if brain imaging is performed. Patients with symptoms are more likely to progress and require treatment [58].
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rate growth charts using standards for children with NF1 [53,54]. (See "Definition, etiology, and evaluation of precocious puberty" and 'Growth' below.) Other central nervous system neoplasms — <span>In addition to OPGs, individuals with NF1 are at an increased risk for developing other CNS neoplasms, particularly low-grade astrocytomas and brainstem gliomas [23,42,55-58]. The most frequent clinical presentation is that of increased intracranial pressure, although lesions are often asymptomatic and are noted as incidental findings if brain imaging is performed. Patients with symptoms are more likely to progress and require treatment [58]. Brainstem gliomas in patients with NF1 may be asymptomatic and not require therapy [59]. Patients who present with symptomatic brainstem gliomas are more likely to have higher-grade tum




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Malignant peripheral nerve sheath tumors — MPNSTs, previously called neurofibrosarcomas, usually arise within preexisting plexiform or nodular neurofibromas. The primary care provider should be alert to the possibility of this highly malignant tumor, particularly in teenagers and young adults. The first presentation of malignant transformation often is development of significant and constant pain, change in consistency from soft to hard, or rapid growth of a nodule within an existing plexiform neurofibroma [60,61].
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[WHO] grade II or III) requiring treatment [57]. Soft tissue sarcomas — Patients with NF1 are at an increased risk of developing soft tissue sarcomas, such as MPNSTs and rhabdomyosarcoma (RMS). <span>Malignant peripheral nerve sheath tumors — MPNSTs, previously called neurofibrosarcomas, usually arise within preexisting plexiform or nodular neurofibromas. The primary care provider should be alert to the possibility of this highly malignant tumor, particularly in teenagers and young adults. The first presentation of malignant transformation often is development of significant and constant pain, change in consistency from soft to hard, or rapid growth of a nodule within an existing plexiform neurofibroma [60,61]. MRI findings suggestive of malignant change include large size, depth below the fascial layer, and necrosis [62]. Positron emission tomography (PET) imaging with 18-fluorodeoxyglucose m




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Rhabdomyosarcoma — RMS is encountered more frequently in persons with NF1 than in the general population [68]. RMS in association with NF1 tends to present at an early age, often arises in a genitourinary site, and is usually of the embryonal histologic subtype [68].
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eral nerve tumors", section on 'Malignant peripheral nerve sheath tumors' and "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Malignant peripheral nerve sheath tumors'.) <span>Rhabdomyosarcoma — RMS is encountered more frequently in persons with NF1 than in the general population [68]. RMS in association with NF1 tends to present at an early age, often arises in a genitourinary site, and is usually of the embryonal histologic subtype [68]. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis".) Gastrointestinal stromal tumors — Persons with NF1 are also at an increased r




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Gastrointestinal stromal tumors — Persons with NF1 are also at an increased risk of developing soft tissue sarcomas that arise within the stromal compartment of the gastrointestinal tract, termed gastrointestinal stromal tumors (GISTs) [69-72]. In the setting of NF1, GISTs frequently occur in the small intestine (more than 70 percent), are often multiple, and have a different molecular pathology from sporadic GISTs in persons who do not have NF1.
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ses in a genitourinary site, and is usually of the embryonal histologic subtype [68]. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis".) <span>Gastrointestinal stromal tumors — Persons with NF1 are also at an increased risk of developing soft tissue sarcomas that arise within the stromal compartment of the gastrointestinal tract, termed gastrointestinal stromal tumors (GISTs) [69-72]. In the setting of NF1, GISTs frequently occur in the small intestine (more than 70 percent), are often multiple, and have a different molecular pathology from sporadic GISTs in persons who do not have NF1. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".) Glomus tumors — Glomus tumors arise in the tips of the fingers and toes under the nail bed (i




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Glomus tumors — Glomus tumors arise in the tips of the fingers and toes under the nail bed (image 3) and present with pain, tenderness, and sensitivity to cold. They are associated with NF1 [73] and are important to recognize because the pain is readily relieved by surgical removal of the tumor.
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ultiple, and have a different molecular pathology from sporadic GISTs in persons who do not have NF1. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".) <span>Glomus tumors — Glomus tumors arise in the tips of the fingers and toes under the nail bed (image 3) and present with pain, tenderness, and sensitivity to cold. They are associated with NF1 [73] and are important to recognize because the pain is readily relieved by surgical removal of the tumor. Other tumors — NF1 patients have an increased risk of certain other malignancies, such as juvenile myelomonocytic leukemia and pheochromocytoma, although genetic etiologies other than N




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Other tumors — NF1 patients have an increased risk of certain other malignancies, such as juvenile myelomonocytic leukemia and pheochromocytoma, although genetic etiologies other than NF1 are more common causes of these malignancies.
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d present with pain, tenderness, and sensitivity to cold. They are associated with NF1 [73] and are important to recognize because the pain is readily relieved by surgical removal of the tumor. <span>Other tumors — NF1 patients have an increased risk of certain other malignancies, such as juvenile myelomonocytic leukemia and pheochromocytoma, although genetic etiologies other than NF1 are more common causes of these malignancies. Women with NF1, particularly those under 50 years of age, are at increased risk of breast cancer [74]. Breast cancers tend to be estrogen receptor negative and human epidermal growth fa




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Bone abnormalities in NF1 include pseudoarthrosis and bone dysplasia, which are part of the United States National Institutes of Health (NIH) Consensus Conference criteria for the disease, as well as short stature, scoliosis, nonossifying fibromas, sphenoid dysplasia, and osteoporosis [76,77].
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gher rates in patients with NF1 is uncertain [27]. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Juvenile myelomonocytic leukemia'.) Bone abnormalities — <span>Bone abnormalities in NF1 include pseudoarthrosis and bone dysplasia, which are part of the United States National Institutes of Health (NIH) Consensus Conference criteria for the disease, as well as short stature, scoliosis, nonossifying fibromas, sphenoid dysplasia, and osteoporosis [76,77]. (See 'Diagnostic criteria' below and 'Plexiform neurofibromas' above.) Long bone dysplasia and pseudoarthrosis — Long bone dysplasia presents in infants or young children as anterolater




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Other bone lesions — Other skeletal lesions include vertebral defects, such as scalloping caused by dural ectasia, nonossifying fibromas within long bones, and sphenoid wing dysplasia, which may present as facial asymmetry. Rarely, a bone defect can occur in the lambdoidal suture, which is easily palpable [80,81].
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e (1.7:1). NF1 is the most common cause of long bone pseudoarthrosis, accounting for 50 to 80 percent of cases; therefore, evaluation for NF1 should be performed in a child with this condition. <span>Other bone lesions — Other skeletal lesions include vertebral defects, such as scalloping caused by dural ectasia, nonossifying fibromas within long bones, and sphenoid wing dysplasia, which may present as facial asymmetry. Rarely, a bone defect can occur in the lambdoidal suture, which is easily palpable [80,81]. Growth — Children with NF1 frequently have short stature. In a database of 569 White North American patients with NF1, 13 percent had a height ≥2 standard deviations below the populatio




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Scoliosis occurs in 10 to 25 percent of persons with NF1 [78,84,85]. This condition frequently becomes apparent at 6 to 10 years of age or in early adolescence. Scoliosis in children with NF1 most commonly affects the thoracic spine and tends to be sharply angulated and dystrophic. Sometimes there is an associated paraspinal plexiform neurofibroma.
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ough NF1 in the mother was associated with a decrease in birth weight [83]. (See "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature".) Scoliosis — <span>Scoliosis occurs in 10 to 25 percent of persons with NF1 [78,84,85]. This condition frequently becomes apparent at 6 to 10 years of age or in early adolescence. Scoliosis in children with NF1 most commonly affects the thoracic spine and tends to be sharply angulated and dystrophic. Sometimes there is an associated paraspinal plexiform neurofibroma. (See "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis".) Osteoporosis — Persons with NF1 have lower bone density per age compared with general population c




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Osteoporosis — Persons with NF1 have lower bone density per age compared with general population controls [76]. The severity of decreased bone density can range from osteopenia to osteoporosis. The etiology of this decrease in bone density is unknown.
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o be sharply angulated and dystrophic. Sometimes there is an associated paraspinal plexiform neurofibroma. (See "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis".) <span>Osteoporosis — Persons with NF1 have lower bone density per age compared with general population controls [76]. The severity of decreased bone density can range from osteopenia to osteoporosis. The etiology of this decrease in bone density is unknown. A survey from Finland revealed an increased risk of fractures in both children and adults over the age of 40 years with NF1 (threefold and fivefold increased relative risk, respectively




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Neurologic disorders include cognitive deficits, learning disabilities, headaches, and seizures. Gross and fine motor developmental delays are also seen. Macrocephaly is a common feature. Dural ectasia along the spine can result in symptoms such as pain resulting from nerve root compression [87].
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he age of 40 years with NF1 (threefold and fivefold increased relative risk, respectively) compared with population controls of similar age and sex distribution [86]. Neurologic abnormalities — <span>Neurologic disorders include cognitive deficits, learning disabilities, headaches, and seizures. Gross and fine motor developmental delays are also seen. Macrocephaly is a common feature. Dural ectasia along the spine can result in symptoms such as pain resulting from nerve root compression [87]. Cognitive deficits and learning disabilities — Cognitive deficits, learning disabilities, and autism spectrum disorders occur with higher frequency in children with NF1 [88,89]. A study




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The diagnostic criteria developed by the United States National Institutes of Health (NIH) Consensus Conference in 1987 [152] and updated in 1997 [153] are based upon specific clinical features of NF1 (table 2). According to these criteria, at least two of the following clinical features must be present to make the diagnosis of NF1:

● Six or more café-au-lait macules >5 mm in diameter in prepubertal and >15 mm in diameter in postpubertal individuals. For each lesion, the longest diameter is measured. Ordinary room light (not a Wood's lamp) is used.

● Two or more neurofibromas of any type or one plexiform neurofibroma (picture 6).

● Freckling in the axillary or inguinal regions.

● Optic glioma.

● Two or more Lisch nodules (iris hamartomas).

● A distinctive bony lesion, such as sphenoid dysplasia or thickening of the long bone cortex with or without pseudoarthrosis.

● A first-degree relative (parent, sibling, or offspring) with NF1 based upon the above criteria.

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luation should be performed to identify Lisch nodules and early signs of optic pathway glioma (OPG). (See 'Clinical manifestations' above and 'Diagnostic criteria' below.) Diagnostic criteria — <span>The diagnostic criteria developed by the United States National Institutes of Health (NIH) Consensus Conference in 1987 [152] and updated in 1997 [153] are based upon specific clinical features of NF1 (table 2). According to these criteria, at least two of the following clinical features must be present to make the diagnosis of NF1: ●Six or more café-au-lait macules >5 mm in diameter in prepubertal and >15 mm in diameter in postpubertal individuals. For each lesion, the longest diameter is measured. Ordinary room light (not a Wood's lamp) is used. ●Two or more neurofibromas of any type or one plexiform neurofibroma (picture 6). ●Freckling in the axillary or inguinal regions. ●Optic glioma. ●Two or more Lisch nodules (iris hamartomas). ●A distinctive bony lesion, such as sphenoid dysplasia or thickening of the long bone cortex with or without pseudoarthrosis. ●A first-degree relative (parent, sibling, or offspring) with NF1 based upon the above criteria. The NIH diagnostic criteria are both highly specific and sensitive in all but the youngest children [14], with 97 percent of affected persons meeting the diagnostic criteria by eight ye