Vered Molho-Pessach1,2, Sivan Sheffer1, Rula Siam1, Spiro Tams3, Ihab Siam1, Rula Awwad4, Sofia Babay2, Julius Golender5, Natalia Simanovsky6, Yuval Ramot1,2, Abraham Zlotogorski1,2. 1. Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 2. Center for Genetic Diseases of the Skin and Hair, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 3. Faculty of Medicine, Palestinian Al Quds University, Abu Dis, Palestinian Authority. 4. Caritas Baby Hospital, Bethlehem, Palestinian Authority. 5. Department of Pediatric Cardiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 6. Department of Medical Imaging, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Abstract
BACKGROUND: Mutations in various desmosomal proteins were shown to cause inherited forms of cardiomyopathy. Carvajal syndrome (Online Mendelian Inheritance in Man [OMIM] 605676) is characterized by the association of dilated cardiomyopathy, striate palmoplantar keratoderma, and woolly hair. It is caused by homozygous as well as heterozygous mutations in DSP, which encodes the desmosomal plaque protein desmoplakin. An overlapping cardiocutaneous phenotype was also described with homozygous mutations in genes encoding two other desmosomal proteins; plakoglobin (Naxos disease; OMIM 601214) and desmocollin-2 (OMIM 610476). METHODS: We performed clinical and molecular workups in two consanguineous Arab Palestinian families manifesting an autosomal recessive pattern of inheritance of the above mentioned clinical findings. Whole exome sequencing was employed in the search for the causing mutation. RESULTS: Affected family members suffered from biventricular involvement and arrhythmogenic right ventricular dysplasia based on echocardiography and magnetic resonance imaging. One patient who underwent implantation of an implantable cardioverter-defibrillator (ICD) is still alive at the age of 59 years. Whole exome sequencing revealed two novel homozygous mutations in DSP, each affecting one family. CONCLUSIONS: The association of woolly hair with palmoplantar keratoderma in a child should lead to a cardiac workup in the search for those at increased risk for sudden cardiac death. Early diagnosis and ICD implantation may be lifesaving. Whole exome sequencing should be utilized for rapid genetic analysis since the cardiocutaneous phenotype may result from mutations in one of several genes.
BACKGROUND: Mutations in various desmosomal proteins were shown to cause inherited forms of cardiomyopathy. Carvajal syndrome (Online Mendelian Inheritance in Man [OMIM] 605676) is characterized by the association of dilated cardiomyopathy, striate palmoplantar keratoderma, and woolly hair. It is caused by homozygous as well as heterozygous mutations in DSP, which encodes the desmosomal plaque protein desmoplakin. An overlapping cardiocutaneous phenotype was also described with homozygous mutations in genes encoding two other desmosomal proteins; plakoglobin (Naxos disease; OMIM 601214) and desmocollin-2 (OMIM 610476). METHODS: We performed clinical and molecular workups in two consanguineous Arab Palestinian families manifesting an autosomal recessive pattern of inheritance of the above mentioned clinical findings. Whole exome sequencing was employed in the search for the causing mutation. RESULTS: Affected family members suffered from biventricular involvement and arrhythmogenic right ventricular dysplasia based on echocardiography and magnetic resonance imaging. One patient who underwent implantation of an implantable cardioverter-defibrillator (ICD) is still alive at the age of 59 years. Whole exome sequencing revealed two novel homozygous mutations in DSP, each affecting one family. CONCLUSIONS: The association of woolly hair with palmoplantar keratoderma in a child should lead to a cardiac workup in the search for those at increased risk for sudden cardiac death. Early diagnosis and ICD implantation may be lifesaving. Whole exome sequencing should be utilized for rapid genetic analysis since the cardiocutaneous phenotype may result from mutations in one of several genes.
Authors: Lynn M Boyden; Chen Y Kam; Angela Hernández-Martín; Jing Zhou; Brittany G Craiglow; Robert Sidbury; Erin F Mathes; Sheilagh M Maguiness; Debra A Crumrine; Mary L Williams; Ronghua Hu; Richard P Lifton; Peter M Elias; Kathleen J Green; Keith A Choate Journal: Hum Mol Genet Date: 2015-11-24 Impact factor: 6.150
Authors: Chen Yuan Kam; Adi D Dubash; Elisa Magistrati; Simona Polo; Karla J F Satchell; Farah Sheikh; Paul D Lampe; Kathleen J Green Journal: J Cell Biol Date: 2018-06-29 Impact factor: 10.539