United State Canadian Specialty Conference Pediatric Pathology February 26, 2011 David Parham, MD University of Oklahoma Case 1 Case 1: Clinical history 2 year, 3 month old African American male admitted for apneic episodes during sleep. On physical examination, vital signs included a heart rate of 123 beats/min, respiratory rate 32 breaths/min, and blood pressure 100/70 mm Hg. The only physical finding of note was a liver border 2-3 cm below the right costal margin. Special studies Echocardiography revealed: cardiomegaly left ventricular diastolic and systolic dysfunction biatrial dilatation pulmonary venous and venocaval diastolic flow reversal moderate tricuspid stenosis tricuspid regurgitation a small pericardial effusion. Cardiac catheterization found markedly elevated right and left ventricular pressures. 1
Echocardiography http://emedicine.medscape.com/article/895392-overview http://cardiophile.org/wp-content/uploads/2008/04/emf2.jpg Therapy Following biopsy and diagnosis, heart transplantation was performed, with removal of an explant consisting of right and left ventricle and the lower portions of dilated right and left atria. Case history and special stains courtesy of Dr. Ali Saad, Arkansas Children s Hospital. Illustration of gross specimen Marked dilation of RA 2
Low power view of myocardium High power view: Brightly eosinophilic myocyte inclusions Blow-up of image: inclusions appear submembranous 3
Trichrome: strong staining of inclusions Elastic stain: no abnormalities Congo Red: no evidence of amyloid 4
PAS: no evidence of glycogen Desmin: heterogenous staining Desmin: strong staining in inclusions 5
Desmin: staining of cross striations and submembranous material Actin: no abnormal staining Diagnosis: desmin-related restrictive cardiopathy Confirmed by electron microscopy and consultation by Dr. Debra Kearney at Texas Children s Hospital 6
Forms of cardiomyopathy Normal Dilated Hypertrophic Restrictive Restrictive cardiomyopathy (RCM) Key features Increased stiffness of the ventricles Compromised diastole filling Preserved systolic function Coronal CT:marked atrial dilatation http://circ.ahajournals.org/cgi/content-nw/full/98/14/1457/f1 7
Gross image of RCM associated with troponin gene mutation http://heart.bmj.com/content/94/10/1257/f1.large.jpg Treatment of RCM Symptomatic treatment Cardiac transplantation Causes of RCM Source: Wikipedia Primary Löffler's syndrome endocardial fibroelastosis Secondary infiltrative cardiac amyloidosis haemochromatosis sarcoidosis interstitial postradiation fibrosis 8
Miscellaneous Connective tissue disease (scleroderma, Churg- Strauss syndrome, reactive arthritis, ) Metabolic disease (cystinosis, Gaucher's disease, hemochromatosis, Fabry's disease) Neoplasms and pseudoneoplasms (lymphoma, hypereosinophilic syndrome, carcinoid, Structural genetic abnormalities (pseudoxanthoma elasticum, Noonan's syndrome, Werner's syndrome) Idiopathic Mutations in sarcomeric protein genes Desmin Cardiac troponin T and I (TNNI3) Alpha cardiac actin αb-crystallin (desmin-related molecule) Unknown desmin-related genes dystrophin desmin myosin actin αb-crystallin From Delakis et al: NEJM 2000; 342:770-780. 9
Desmin-related cardiomyopathy Clinical symptoms Arrhythmia A-V block and associated syncope Atrial fibrillation Cardiac failure Restrictive cardiomyopathy Dilated cardiomyopathy (1-2% of dilated DCM) Left ventricular non-compaction Desmin-related cardiomyopathy Mutations in desmin gene (chromosome 2q35) In frame obliterations in 1B domain (p.r173_e179 deletion) Highly conserved end of alpha-helical rod domain (E413K mutation) Affected intramolecular interactions per modeling and electrostatic calculation) IVS2-2A splice site mutation (separate reports in Russia and Italy) caused skipping of exon 3 Heterozygous missense mutation in exon 3 (E245D) Mutations in desmin Top: Exon composition of desmin coding region Bottom: structural organization of desmin protein domains (green) orange = deletion sites From Vrabie et al: Acta Neuropathologica 109:411-417 10
Desmin-related cardiomyopathy EM findings are diagnostic Subsarcolemmal desmin-reactive aggregates Accumulations of granular and filamentous material Can be found in skeletal muscle and heart Desmin-related cardiomyopathy Inheritance pattern Generally autosomal dominant Occasionally sporadic or autosomal recessive Desmin-associated cardiomyopathy pedigree Zhang J, Kumar A, Stalker HJ, Virdi G, Ferrans VJ, Horiba K, Fricker FJ, Wallace MR. Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy. Clin Genet 2001: 59: 248 256. Munksgaard, 2001 11
A EM of desmin-related RCM Bertini et al: Acta Neuropathologica 1991;81:632-640 B * * Accumulation of osmiophilic granular and filamentous material in intermyofibrillar (A) and subsarcolemmal (B) foci. Note streaming of Z disks (*). EM of desmin-related RCM Bertini et al: Acta Neuropathologica 1991;81:632-640 On higher magnification the material has a granular and filamentous structure similar to Z disks Cytoplasmic bodies with amorphous central core surrounded by filaments EM of desmin-related RCM Bertini et al: Acta Neuropathologica 1991;81:632-640 Granular and filamentous osmiophilic material near the intercalated disks. 12
ImmunoEM Anti-desmin conjugated with gold particles adheres to the granular material (from Zhang J et al.,clin Genet 2001: 59: 248 256. Desmin-related cardiomyopathy Associated clinical findings Muscle weakness-peripheral myopathy Clinical disease Subclinical pathology Symmetric weakness and atrophy of muscles of the face, trunk, shoulder girdle, and extremities Myofibrillar or multicore myopathy on biopsy Intestinal myopathy (rare) Desmin-associated myopathy: skeletal muscle findings Myocyte inclusion bodies, H and E From Vrabie et al: Acta Neuropathologica 109:411-417 13
Desmin-associated myopathy: skeletal muscle findings Rimmed myocyte vacuoles, Gomori stain From Vrabie et al: Acta Neuropathologica 109:411-417 Desmin-associated myopathy: skeletal muscle findings Accumulation of desmin, particularly subsarcolemmal From Vrabie et al: Acta Neuropathologica 109:411-417 Desmin-associated myopathy: skeletal muscle findings EM: subplasmalemmal granular material From Vrabie et al: Acta Neuropathologica 109:411-417 14
Desmin-related cardiomyopathy Reports of: Sensory motor polyneuropathy Giant axons EM: Accumulation of neurofilaments (another intermediate filament) and neurotubules, axonal spheroids Coronary artery desmin inclusions Pes cavus (high arch) Desmin-related neuropathy Axonal spheroid filled with neurofilamentous aggregate Bertini et al: Acta Neuropathologica 1991;81:632-640 Acknowledgements Dr. Ali Saad, Arkansas Children s Hospital Dr. Van Savell, Driscoll Children s Hospital Dr. Debra Kearney, Texas Children s Hospital 15