CHRONIC LUNG DISEASE IN CUTIS LAXA by Rachel Ellen Westman BS, University of Idaho, 2009 Submitted to the Graduate Faculty of Graduate School of Public Health in partial fulfillment of the requirements for the degree of Master of Science University of Pittsburgh 2011 UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH This thesis was presented by Rachel E. Westman It was defended on April 13, 2011 and approved by Thesis Advisor: Zsolt Urban PhD, Associate Professor, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh Committee Member: Robin Grubs PhD, CGC, Assistant Professor, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh Committee Member: Juliann McConnell, MS, CGC, Pediatric Genetics Counselor, Children’s Hospital of Pittsburgh Committee Member: John Wilson PhD, Assistant Professor, Department of Biostatistics Graduate School of Public Health, University of Pittsburgh ii Copyright © by Rachel E. Westman 2011 iii CHRONIC LUNG DISEASE IN CUTIS LAXA Rachel E. Westman, M.S. University of Pittsburgh, 2011 BACKGROUND: Cutis laxa (CL) is a group of disorders characterized by loose, inelastic, and redundant skin. The different types of CL are distinguished by clinical features, inheritance, and molecular findings. The objective of this study was to characterize the pulmonary phenotype of the different types of CL based on age of onset (congenital, acquired/late-onset, or unknown) and mutational status. The first aim of this study was to collect clinical data to better define the pulmonary involvement in cutis laxa. The second aim was to determine if heterozygous carriers of recessive types of cutis laxa are susceptible to chronic lung disease. METHODS: Clinical questionnaires, medical histories, and pulmonary function tests (PFTs) were used to collect clinical data on patients with a confirmed or suspected diagnosis of CL and unaffected first- degree relatives with a known mutation (carriers). The clinical data was then compared between the groups categorized by age of onset and between those with known mutations (mutational status). RESULTS: The clinical questionnaires and medical histories of 83 CL patients with 8 acquired/late-onset, 52 congenital, and 23 of unknown etiology and 5 carriers were analyzed. In addition, mutations have been identified in 27 of the 83 patients in ELN, FBLN4, FBLN5, ATP6V0A2, or LTBP4, and the 5 carriers had mutations in either FBLN4 or LTBP4. The most common respiratory responses amongst the patients included pneumonia (24.1%), tachypnea (15.7%), and emphysema (12.0%). The only statistically significant finding was dyspnea in acquired/late-onset patients. Of those with a known mutation, 15 reported pulmonary involvement, with 10 of these individuals having at least one LTBP4 mutation. For the 13 PFTs iv collected, the 10 CL patients ranged from normal lung function to very severe obstruction, and 3 carriers were deemed to have normal function. An important new finding was the presence of pulmonary obstructive disease in those with ATP6V0A2 mutations. CONCLUSION: These results demonstrate a high prevalence and significant heterogeneity of pulmonary complications in CL. Further research is needed to determine any correlation between specific pulmonary findings and genotypes. PUBLIC HEALTH SIGNIFICANCE: Chronic lung disease is a common cause of morbidity in the general population. Uncovering the genetic basis of chronic lung disease in inherited syndromes has the potential to identify key molecular targets for improved diagnosis and treatment of common respiratory ailments. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XIII 1.0 INTRODUCTION ........................................................................................................ 1 2.0 BACKGROUND .......................................................................................................... 3 2.1 TYPES OF CUTIS LAXA .................................................................................. 3 2.1.1 Occipital Horn Syndrome (OHS) ................................................................ 3 2.1.2 Autosomal Dominant Cutis Laxa (ADCL) ................................................. 4 2.1.3 Autosomal Recessive Cutis Laxa Type 1 (ARCL1) ................................... 8 2.1.3.1 Mutations in FBLN4 ............................................................................. 9 2.1.3.2 Mutations in FBLN5 ........................................................................... 10 2.1.4 Autosomal Recessive Cutis Laxa Type 2 (ARCL2) ................................. 12 2.1.4.1 Autosomal Recessive Cutis Laxa Type 2A ........................................ 12 2.1.4.2 Autosomal Recessive Cutis Laxa Type 2B (ARCL2B), Geroderma Osteodysplastic (GO), & Wrinkly Skin Syndrome (WSS)............................. 13 2.1.5 De Barsy Syndrome .................................................................................... 17 2.1.6 Urban-Rifkin Davis Syndrome (URDS) ................................................... 18 2.1.7 Macrocephaly, Alopecia, Cutis Laxa and Scoliosis (MACS) Syndrome 19 2.1.8 Acquired Cutis Laxa ................................................................................... 20 2.2 CHRONIC PULMONARY DISEASE ............................................................ 23 vi 2.2.1 Chronic Obstructive Pulmonary Disease (COPD) ................................... 23 2.2.1.1 Emphysema .......................................................................................... 24 2.2.1.2 Chronic Bronchitis .............................................................................. 24 2.2.1.3 Other Chronic Pulmonary Diseases .................................................. 25 2.3 CUTIS LAXA & OBSTRUCTIVE PULMONARY DISEASE ..................... 26 2.3.1 Elastin Threshold Hypothesis .................................................................... 26 2.3.2 Cutis Laxa & Pulmonary Disease .............................................................. 28 3.0 SPECIFIC AIMS ........................................................................................................ 29 3.1 SPECIFIC AIM 1: DEFINE THE NATURAL HISTORY OF PULMONARY PHENOTYPES ASSOCIATED WITH CL. ......................................... 29 3.2 SPECIFIC AIM 2: DETERMINE IF HETEROZYGOTE CARRIERS OF SEVERE RECESSIVE CL MUTATIONS ARE SUSCEPTIBLE TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). ................................................... 29 4.0 METHODS ................................................................................................................. 30 4.1 CLINIC PROTOCOL ....................................................................................... 30 4.1.1 Recruitment ................................................................................................. 30 4.1.2 Screening ...................................................................................................... 31 4.1.3 Informed Consent Process ......................................................................... 31 4.1.4 Research Activities ...................................................................................... 32 4.1.4.1 Research Clinic Involvement for Affected Individuals ................... 32 4.1.4.2 Non-Research Clinic Involvement for Affected Individuals ........... 34 4.1.4.3 Research Activities for Unaffected First Degree Relatives ............. 34 4.1.5 Follow-up ..................................................................................................... 35 vii 4.1.6 Mutational Analysis .................................................................................... 35 4.2 PULMONARY DATA ....................................................................................... 36 4.2.1 Patient Classifications ................................................................................. 36 4.2.1.1 Onset Classification ............................................................................. 36 4.2.1.2 Cutis Laxa Type .................................................................................. 37 4.2.2 Clinical Questionnaires & Medical Histories ........................................... 38 4.2.3 Pulmonary Function Tests (PFTs) ............................................................ 40 4.2.3.1 Pulmonary Function Classification ................................................... 40 4.3 STATISTICAL ANALYSIS ............................................................................. 42 5.0 RESULTS ................................................................................................................... 43 5.1 GENERAL PULMONARY RESPONSES ...................................................... 43 5.2 ONSET CLASSIFICATION AND PULMONARY RESPONSES ............... 46 5.3 MUTATIONAL ANALYSIS ............................................................................ 48 5.3.1 Mutational Analysis and Pulmonary Responses ...................................... 52 5.4 PULMONARY FUNCTION TEST (PFT) RESULTS ................................... 54 6.0 DISCUSSION ............................................................................................................. 56 6.1 GENERAL PULMONARY RESPONSES ...................................................... 57 6.2 ONSET CLASSIFICATION & PULMONARY INVOLVEMENT ............. 59 6.3 CL TYPES & PULMONARY INVOLVEMENT .........................................