DIAGNOSIS AND MANAGEMENT ISSUES IN NF 1 & NF 2 AND OTHER GENETIC BRAIN TUMORS INTRODUCTION n The neurofibromatosis (NF) is a heterogenous of group of disorder characterized by abnormal skin pigmentation and numerous neuro- ectodermal tumors. n Several types of NF are described, two distinct forms usually covers most. These two forms share some similarities but are distinct entities caused by genes on different chromosomes . Introduction contd.. n Phakomatomatosis (greek root phakos=birthmark) are a group of hereditary disorders with cutaneous, ocular and neurological manifestation; these include neurofibromatosis, tuberous sclerosis complex, von Hippel-Lindau disease and the neurocutaneous angiomatosis. n The variable expression and overlap of many of these disorders can make diagnosis difficult. Evaluations of multiple systems and multiple family members is best accomplished by a multidisciplinary group, including geneticist, ophthalmologist, dermatologist, neurologist and neurosurgeon. Diagnosis and treatment should be designed for the affected patient and his family members in a way to avoid fragmentation of medical care. HISTORICAL PERSPECTIVE n Sporadic description of multiple dermal tumors “wart man”, and a likely diagnosis of NF1, appeared in 17th & 18th centuries (Monstrorum historia 1642). n In 1849, Robert Smith from Dublin medical school reported the clinical and autopsy finding of two cases of NF . n Friedrich Daniel von Recklinghausen, a student of Virchow, in 1882 credited with the first thorough description of NF . n Marie, Bernard and Chauffard (1896) described the significance of café-au-lait spots. Lisch (1937) drew attention of pigmented iris nodules and Crowie (1964) described axillary frecklings. n Term phakomatosis coined by van der Hoeve in 1920. HISTORY Contd.. n Thomson in 1900 described familial basis of the disorder. Preiser and Davenport (1918) described autosomal dominant inheritance of the condition. n Ricardi (1982) followed by Evans (1992) described about NF2 . n Based on the public attention & interest on NF1 from the movie ‘the elephant man’ , National Neuro-Fibromatosis Foundation (NNFF) conceptualized and setup. n In 1987, diagnostic criteria were laid down for NF1 & NF2 by National Institutes of Health Consensus development conference . GENETIC AND CLINICAL FEATURES OF PHAKOMATOSIS DISORDER GENETICS NEUROLOGICAL FEATURE GENERAL FEATURES Neurofibromatosis-1 Autosomal Spinal NF, pelxiform NF, Skin neurofibromas, café dominant (17q) Optic glioma, cerebral and au lait spots, posterior fossa glioma, intertriginous freckles, macrocephaly, hydrocephalus, iris hamartoma, scoliosis, cranial and vertebral pheochromocytoma, dysplasia, learning disorders hemihypertrophy, and seizures. neurofibrosarcoma. Neurofibromatosis-2 Autosomal Bilateral acoustic schwannoma, Posterior subcapsular dominant (22q) meningioma, spinal cataract. schwannoma, ependymoma ,astrocytoma Tuberous sclerosis Autosomal Subependymal nodules & giant Ash-leaf spot, shagreen cpmplex dominant(9q, cell astrocytoma, cortical patches, adenoma 11q,12q,14) tubers, seizures, mental sebaceum, subungual retardation. fibromas, tooth pitting, cardiac rhabdomyoma. Von Hippel-Lindau Autosomal Hemangioblastoma of the Retinal disease dominant (3p) cerebellum,spinal cord or brain hemangioblastoma, renal stem. cyst/carcinoma, pheochromocytoma GENETIC AND CLINICAL FEATURES OF PHAKOMATOSIS Ataxia- Autosomal Ataxia, dysarthria, choreo- Telangiectasia, telangiectasia dominant athetosis, polyneuropathy, leukemia, lymphoma, (11q) cebellar & spinal Ca breast, radiation degeneration, intellectual hypersensitivity, impairment immunodeficiency Sturge-Weber Somatic Parieto-occipetal angioma , Hemangioma of retina, syndrome mutation seizures facial angioma Klippel-Trenaunay- Somatic Spinal angioma. Dermatomal Weber syndrome mutation hemangioma. Rendu-Osler-Weber Autosomal CNS angioma and Epistaxis, gastric syndrome dominant hemorrhage hemorrhage. Wyburn-Mason Uncertain AVM of midbrain, mental Facial nevi syndrome changes. Fabry’s disease X-linked Painful polyneuropathy, Telangiectasia of leg & recessive stroke. abdomen, renal failure, hypertension, MI. GENETIC PATHOGENESIS NF1: n Neurofibromatosis-1 gene is inherited in autosomal dominant pattern with high penetrance but variable and unpredictable expression. n Prevalence – 1:4000 live births, 50% with +ve family history. n Gene responsible is located in pericentric region of chromosome 17(long arm). n NF1 gene is a tumor-suppressor gene. Neurofibromin, a NF1 gene product, interact with ras p21 oncogene to produce an inactive state and limits cell growth. A mutated neurofibromin molecule could not control cell growth thereby resulting in accelerated cell proliferation. GENETIC PATHOGENESIS NF2: n Inherited in autosomal dominant pattern n Incidence of the disease is about 1 in 40,000. 50% are inherited & rest due to de novo mutations. n Defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22 band q11-13.1 which have tumor-suppressive function. The mutated NF II gene is presumed to result in either a failure to synthesize Merlin or the production of a defective peptide that lacks the normal tumor-suppressive effect. GENETIC PATHOGENESIS www.peds.ufl.edu www.absoluteastronomy.com/topics/5-HTTLPR CRITERIA FOR DIAGNOSIS OF NEUROFIBROMATOSIS SOURCE- Neurofibromatosis, conference statement. National Institutes of Health Consensus Development Conference Neurofibromatosis 1 : Presence of two or more of the following- n Six or more café-au-lait macules whose greatest diameter >5mm in pre-peubertal age and >15mm in postpubertal patients. n Two or more neurofibromas of any type or one plxiform neurofibroma. n Freckling in the axillary or inguinal region. n Optic glioma n Two or more Lisch nodules (iris). n Sphenoid dysplasia, thinning of long bone cortex, with or without pseudo-arthrosis. n A parent, sibling or child with NF1 according to the above criteria. NEUROFIBROMATOSIS TYPE 1 n BRAIN TUMORS- Glioma of optic pathway (esp pilocytic astrocytoma 15%), rarely acoustic neuroma & meningioma. n OTHER CRANIAL ABNORMALITY- Hydrocephalus (tumor or aqueductal stenosis), idiopathic macrocephaly, cranial dysplasia (sphenoid wing aplasia, parieto-occipetal defect), speech impediments (50%), learning disability (25%), mental retardation (8.4%) & seizure (5%). n SPINAL ANOMALY- Intra and extradural neurofibroma (MC), spinal meningocele, rarely spinal astrocytoma / meningioma, scalloping of vertebral body(10%), kyphoscoliosis, idiopathic vertebral displasia including atlanto-axial dislocation. LAB. EVALUATION FOR NF1 n Protein truncation assay (PTA), which identifies a proportion of individuals with NF1, has been developed. Complete gene sequencing can be done . The detection rate using PTA varies from 65-70% in those who clearly have NF1 by clinical criteria. For patients with a single clinical finding, such as multiple café-au-lait spots in the absence of a positive family history, PTA (when positive) can be helpful. n Sequencing of the neurofibromin gene has detection rate of 95%. n Prenatal period- In a family with multiple affected members, linkage analysis can track the NF1 gene through the generations to determine which chromosome 17 region the fetus received. n Identification of the mutation in the affected parent would permit prenatal diagnosis via amniocentesis or chorionic villus sample (CVS). IMAGING EVALUATION IN NF 1 n Plain X ray - modeling defects, bony erosion, scoliosis. n MRI head- preferred diagnostic modality. Unidentified bright spots (UBO) seen on T2-weighted images generally do not enhance, represent benign hamartomas. Rarely, hydrocephalus / Chiari type 1 malformation/brain tumors are seen. n MRI is also useful in evaluating mediastinal masses, spinal cord tumors, deep plexiform neurofibromas, neurofibromas of the brachial or sacral plexus, as well as abdominopelvic lesions. n PET- F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) may be used to stage and follow up MPNST. OTHER EVALUATION METHOD IN NF 1 n EEG - Seizures are reported more often in patients with NF1 than in the general population (4-7%). n Slit-lamp examination - who have only a single clinical criterion such as multiple café-au-lait spots. CRITERIA FOR DIAGNOSIS OF NEUROFIBROMATOSIS SOURCE- Neurofibromatosis, conference statement. National Institutes of Health Consensus Development Conference Neurofibromatosis 2: Presence of one of the following- th n Bilateral 8 nerve masses. th n A parent, sibling or child with NF2 and either unilateral 8 nerve masses n Or any two of the following- neurofibroma, meningioma, glioma, Schwannoma, juvenile posterior subcapsular lenticular opacity. NEUROFIBROMATOSIS TYPE 2 n INTRACRANIAL TUMORS- Bilateral acoustic schwannomas, meningioma. n INTRASPINAL TUMORS- neurofibroma (aka dumbell tumor), meningioma, ependymoma, low grade astrocytoma. EVALUATION IN NF 2 n Detection rates for molecular-based testing approaches 65%. n For families in which no mutation can be identified in a known affected individual, linkage analysis or indirect genetic testing methods may be utilized. n For a parent who has NF2, prenatal testing can be done on amniocytes or chorionic villi. EVALUATION IN NF 2 n Radiography- Plain films of the spine may be helpful in evaluating scoliosis. n MRI- Mainstay for diagnosis and screening of CNS and spinal cord tumors. At risk individuals may be monitored for CNS tumors beginning in their teens, with annual MRIs of the head.