Aspen 2014: Cases 1-4. John Hicks Texas Children s Hospital Baylor College of Medicine Houston, Tx. Case 1 History

Transcription

1 Aspen 2014: Cases 1-4 John Hicks Texas Children s Hospital Baylor College of Medicine Houston, Tx Case 1 History 2-month old full-term female presented with respiratory distress for 5 days with stridor. She was seen by her local PCP and started on oral steroids. There was also lethargy, and problems with feeding. Child was previously diagnosed with bronchiolitis. At that time, the differential diagnosis by her local PCP was reactive asthma-type cough, GERD, dysphagia/aspiration, laryngomalacia, tracheobronchomalacia. 1

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7 Diagnosis? 7

8 What is Filamin? Non-Muscle Actin Binding Protein, Discovered in kda Large Cytoplasmic Proteins Play Important Role in Cross-Linking Actin Filaments into Dynamic 3-Dimensional Structures Three Filamin Isoforms in Mammals - FLN A, B & C Filamins A (most abundant, X chromosome), B (non-muscle, chromosome 3) & C (adult cardiac, smooth & skeletal muscle, chromosome 7) Genomic Organization Highly Conserved Widely Expressed During Development FLNC More Restricted Expression in Skeletal and Cardiac Muscles in Adults 60 80% Homology Over Entire Sequence with Exception of 2 Hinged Regions - Greater Divergence Essential for Human Development: FLNA & FLNB Mutations Abnormal Development of Brain, Bone, Cardiovascular System & Other Organs 8

9 Filamin A: Protein Structure N-terminal: Actin-Binding Domain (ABD) - Long Rod-Like Domain of 24 Repeated, Anti-Parallel Sheets Two Flexible Loops (30 aa) Form Hinge Structures Dimerization of Filamin (C-Terminal) Allows Formation of V-shaped Flexible Structure for Essential Function Filamin A: Interactions 9

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11 Filamin Mutations & Disease Wide Range of Congenital Anomalies Mutations in Breast, Prostate & Colon Cancers FLNA Cause of Most Common Valvular Disorders & Dystrophies Complete Loss: Embryonic Lethal Filamin A mutations >50 Mutations Identified Some Diseases Associated with Mutations: Periventricular Nodular Heterotopia Periventricular Nodular Heterotoptia With Ehler-Danlos Syndrome Otopalatodigital Syndrome 1 and 2 Frontal Metaphyseal Dysplasia Melnick-Needles Syndrome Hydrocephalus Frontonasal Malformation Severe Mental Retardation and Syndactyly Nephrosis 11

12 Periventricular Nodular Heterotopia Malformation of Neuronal Migration Characterized by Nodules of Neurons in Inappropriate Location Adjacent to Wall of Lateral Vetricles May be Laminar or Nodular X-Linked Dominant Pattern. Affected Individuals Predominantly Heterozygous Females Males - Early Lethality Seizures (Focal Epilepsy: 90%) Dyslexia, Intelligence Ranges from Normal to Borderline Ehlers-Danlos Syndrome and PVH Ehlers-Danlos Syndrome Inherited Connective Tissue Disorders: Defect Synthesis of Collagen Mutations in Collagen Proteins (COL1A1, COL1A2) And/Or Enzymes in Processing/Synthesize Collagen (ADAMTS2, PLOD1) Most Forms Inherited in Autosomal Dominant Pattern Loose joints Fragile, small blood vessels Abnormal scar formation and wound healing Soft, velvety, stretchy skin that bruises easily Ehler-Danlos Syndrome & PVH Disruption in cell adhesion: common mechanism. Impaired cell adhesion strength/elasticity loss 12

13 Otopalatodigital Syndrome 1 and 2 OPD 1: Conduction Deafness, Cleft Palate, Characteristic Facial Malformations, Widely Spaced Eyes & Generalized Bone Dysplasia (Wide Broad Thumbs and Great Toes, Long Metacarpals, Partial Syndactyly, Severe Scoliosis & Congenital Dislocation of Hips and Knees) OPD2: Resembles OPD1, But More Severe Disorder with Microcephaly and Mental Retardation OPD1 Mostly in Males OPD2 Both Males and Females Frontal Metaphyseal Dysplasia Morphogenetic Defect of Bone Characterized by Striking Overgrowth of Frontal Facial Bones Deafness, Digital Anomalies and Osteodysplasia Males More Often Affected by FMD Females Usually Only Mildly Affected 13

14 Melnick-Needles Syndrome OPD2-Like Features: Malformed Skull and Craniofacial Structures In Addition, Irregular Rib Constrictions, Deformed Clavicles, Scapula and Pelvis, and Curved/Bowed Long Bones Mostly Affects Females Male Offspring of Affected Women Usually Die Shortly After Birth Wide Range of Defects in Kidneys, Urethra and Atrioventricular Canal, and Complete Intestinal Malrotation 14

15 Case 2 History 12 year-old previously healthy male who presented with several week history of right flank pain, leg pain, and walking with a limp, which was attributed to a soccer injury. He noted pink-tinged urine a few times over the past several weeks, but did not tell his parents about this. CT showed a right retroperitoneal 20 cm mass. 15

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20 Immunostains??? Immunostains Negative Stains: Desmin, Myogenin, MSA, MyoD1 Chromogranin, S100 Synaptophysin CD99 ALK-1 EMA, PanCytokeratin CD34 MUC1 Collagen Type IV Positive Stains: SMA (low expression) INI1 (retained nuclear) Beta-Catenin (cytoplasmic) Vimentin 20

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24 Cytogenetics & Molecular Genetics Karyotype: 46,XY RT-PCR Translocations Negative for: Ewing Sarcoma Synovial Sarcoma Alveolar Rhabdomyosarcoma Low-Grade Fibromyxoid Sarcoma/Sclerosing Epithelioid Fibrosarcoma Diagnosis? 24

25 Wait... One More Immunostain What Antibody??? CCNB3 25

26 BCOR-CCNB3 Translocation BCOR-CCNB3 Sarcoma Undifferentiated/Unclassified Sarcomas Constitute Group of Rare Mesenchymal Tumors Lacking Any Evident Line of Differentiation BCOR-CCNB3 Fusion Gene: Chromosome X Paracentric inversion Recently Described in Ewing-Like Translocation- Negative Sarcomas Arising in Bone & Soft Tissue 26

27 BCOR-CCNB3 Sarcoma: IHC & Gene Profiling BCOR-CCNB3 Sarcoma Recurrent Paracentric Inversion on Chromosome X: BCOR-CCNB3 Fusion Gene in ~4% (24/594) of Undifferentiated Ewing-Like Sarcomas Lacking EWSR1 Rearrangements Gene Expression Profiling of BCOR-CCNB3 Sarcomas Distinct from Ewing Sarcoma BCOR-CCNB3 Fusion Protein Drives Cell Proliferation 10 Additional BCOR-CCNB3 Sarcoma Cases Reported Frequent Occurrence in Long Bones of Adolescents and Young Adults Strong Male Predilection (3.4M: 1.0F). Potentially Less Aggressive Clinical Course 27

28 Tumor Pathogenesis of BCOR CCNB3 Gene: Meiotic Cyclin Restricted to Spermatocytes BCOR Gene Encodes Nuclear Co-Repressor of BCL6 & Regulates Mesenchymal Stem Cell Function Through Epigenetic Modification of Histone Methylation BCOR-CCNB3 Fusion Gene Function - Consistent with BCOR Promoter Activity in Putative Mesenchymal Progenitor Cells BCOR Identified as N-terminal Partner (BCOR-RARA) in Acute Promyelocytic Leukemia & C-terminal Partner (ZC3H7B-BCOR) in Endometrial Stromal Sarcoma and Ossifying Fibromyxoid Tumor BCOR: Alternative Mechanisms for Oncogenesis in Different Tumor Types Case 3 History 16 year-old Asian-American male with chronic skin disorder and recently noticed nodular lesion with ulceration of overlying skin, associated with fever and exudate. He has been treated recently for skin infection that has not resolved. 28

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