Синдром Карвахаль: краткий обзор и клинический случай кардиомиопатии, ассоциированной с компаунд гетерозиготными мутациями гена десмоплакина

Мутации в генах, кодирующих десмосомальные белки, являются причиной широкого спектра заболеваний с аномалиями кожи, волос и сердца; в 45-50% случаев эти мутации детерминируют развитие аритмогенной правожелудочковой кардиомиопатии. Сегодня известно более 120 аутосомно-доминантных и аутосомно-рецессивных мутаций гена десмоплакина (DSP), вызывающих кожно-кардиальную патологию. В статье представлен впервые выявленный в Восточной Европе (Беларусь) редкий клинический случай синдрома Карвахаль (OMIM 605676), ассоциированного с компаунд гетерозиготными мутациями, с классической триадой признаков (фенотип дилатационной кардиомиопатии, кератодермия и шерстисто-курчавые волосы). Краткий литературный обзор проблемы и вопросы дифференциальной диагностики представлены в статье в виде сравнительного анализа синдрома Карвахаль с фенотипически сходной патологией — синдромом Наксос, обусловленным мутациями в гене, кодирующем другой десмосомальный белок — плакоглобин (синдром Наксос, OMIM 601214), и приводящими к развитию аритмогенной правожелудочковой кардиомиопатии.

1. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated ardiomyopathy J. Am. Acad. Dermatol. 1998;39:418-21. doi:10.1016/S0190-9622(98)70317-2.

2. Nehme N, El Malti R, Roux-Buisson N, et al. Evidence for genetic heterogeneity in Carvajal syndrome. Cell Tissue Res. 2012;348(2):261-4. doi:10.1007/s00441-012-1351-6.

3. Boule S, Fressart V, Laux D, et al. Expanding the phenotype associated with a desmoplakin dominant mutation: Carvajal/Naxos syndrome associated with leukonychia and oligodontia. Int. J. Cardiol. 2012;161:50-2. doi:10.1016/j.ijcard.2012.06.068.

4. Protonotarios N, Tsatsopoulou A. Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy. Cardiovasc Path. 2004; 13(4): 185-94. doi: 10.1016/j.carpath.2004.03.609.

5. Protonotarios N, Tsatsopoulou A, Anastasakis A, et al. Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin. J Am Coll Cardiol. 2001;38:1477-84.

6. Rickelt S, Pieperhoff S. Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases. Cell Tissue Res. 2012;348:325-33. doi:10.1007/s00441-012-1365-0.

7. Baykan A, Olgar S, Argun M, et al. Different clinical presentations of Naxos disease and Carvajal syndrome: Case series from a single tertiary center and review of the literature. Anatol J Cardiol. 2015;15(5):404-8. doi:10.5152/akd.2014.5413.

8. Malcic I, Kniewald H, Jelic A, et al. Carvajal syndrome — rare entity of cardiocutaneous syndrome in a child from the Mediterranean part of Croatia — report on a new mutation of a desmoplakin gene. Cardiol Young. 2015;25(S 1):86. doi:10.1017/S1047951115000529.

9. Mahoney MG, Sadowski S, Brennan D, et al. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. J Invest Dermatol. 2010;130:968-78. doi :10.1038/jid.2009.357.

10. Yesudian PD, Cabral RM, Ladusans E, et al. Novel compound heterozygous mutations in the desmoplakin gene cause hair shaft abnormalities and culminate in lethal cardiomyopathy. Clin Exp Dermatol. 2014;39:506-8. doi:10.1111/ced.12329.

11. Sen-Chowdhry S, Syrris P, Prasad SK, et al. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol. 2008;52:2175-87. doi:10.1016/j.jacc.2008.09.019.

12. Smith FJ, Wilson NJ, Moss C, et al. Compound heterozygous mutations in desmoplakin cause skin fragility and woolly hair. Br J Dermatol. 2012;166:894-96. doi:10.1111/jdv.14834.

13. Nitoiu D, Etheridge SL, Kelsell DP. Insights into desmosome biology from inherited human skin disease and cardiocutaneous syndromes. Cell Commun Adhes. 2014;21:129-40. doi:10.3109/15419061.2014.908854.

14. Patel DM, Green KJ. Desmosomes in the heart: a review of clinical and mechanistic analyses. Cell Commun Adhes. 2014;21:109-28. doi:10.3109/15419061.2014.906533.

15. Molho-Pessach V, Sheffer S, Siam R, et al. Two novel homozygous desmoplakin mutations in Carvajal syndrome. Pediatr. Dermatol. 2015;32:641-46. doi:10.1111/pde.12541.

16. Antonov NK, Kingsbery MY, Rohena LO, et al. Early-onset heart failure, alopecia, and cutaneous abnormalities associated with a novel compound heterozygous mutation in desmoplakin. Pediatr. Dermatol. 2015;32:102-8. doi:10.1111/pde.12484.

17. Madhu KJ, Vijyalakshmi IB, Narsimhan C, et al. Carvajal Syndrome: A Rare Variant of Naxos Disease. Cardiovasc Ther. 2016;1:103.

18. Mohammadpour Ahranjani B, Moradi P, Nazari S, et al. A Nine-Year-Old Girl With Left Ventricle Non-Compaction and Skin Lesions (Carvajal Syndrome). Iran J Pediatr. 2015;25(4):e370. doi:10.5812/ijp.370.

19. Barber S, Day P, Judge M, et al. Variant Carvajal syndrome with additional dental anomalies. Int J Paediatr Dent. 2012;22(5):390-6. doi:10.1111/j.1365-263X.2012.01230.x.

20. Mahoney MG, Sadowski S, Brennan D, et al. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. J Invest. Dermatol. 2010;130(4):968-78. doi:10.1038/jid.2009.357.

21. Norgett EE, Lucke TW, Bowers B, et al. Early death from cardiomyopathy in a family with autosomal dominant striate palmoplantar keratoderma and woolly hair associated with a novel insertion mutation in desmoplakin. J Invest Dermatol. 2006;126(7):1651-4. doi:10.1038/sj.jid.5700291.

22. Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet. 2000;9:2761-6.

23. Drezner JA, Fudge J, Harmon KG, et al. Warning symptoms and family history in children and young adults with sudden cardiac arrest. J Am Board Fam Med. 2012;25(4):408-15. doi:10.3122/jabfm.2012.04.110225.

24. Williams T, Machann W, Kuhler L, et al. Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma.Clin Res Cardiol. 2011;100(12):1087-93. doi:10.1007/s00392-011-0345-9.

25. Stollberger C, Blazek G, Gessner M, et al. Age-dependency of cardiac and neuromuscular findings in adults with left ventricular hypertrabeculation/noncompaction. Am J Cardiol. 2015;115(9):1287-92. doi:10.1016/j.amjcard.2015.02.014.

26. Bharucha T, Lee KJ, Daubeney PE, et al. Sudden death in childhood cardiomyopathy: results from a long-term national population-based study. J Am Coll Cardiol. 2015;65(21):2302- 10. doi:10.1016/j.jacc.2015.03.552.

27. Maleic I, Buljevic B. Arrhythmogenic right ventricular cardiomyopathy, Naxos island disease and Carvajal syndrome. Central European Journal of Paediatrics. 2017;13(2):93- 106. doi:10.5457/p2005-114.177.

28. Baykan A, Olgar S, Argun M, et al. Different clinical presentations of Naxos disease and Carvajal syndrome: Case series from a single tertiary center and review of the literature. Anatol J Cardiol. 2015;15(5):404-8. doi:10.5152/akd.2014.5413.

29. Rasmussen TB, Hansen J, Nissen PH, et al. Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms. Clin Genet. 2013;84(1):20-30. doi:10.1111/cge.12056.

30. Alcalai R, Metzger S, Rosenheck S, et al. A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J. Am. Coll. Cardiol. 2003;42:319-27. doi:10.1016/S0735-1097(03)00628-4.

31. Arbustini E, Narula N, Dec WG, et al. The MOGE(S) Classification for a phenotype- genotype nomenclature of cardiomyopathy endorsed by the World Heart Federation. J Am Coll Cardiol. 2013;62(22):2046-72. doi:10.1016/j.jacc.2013.08.1644.

32. Herbert Pratt C, Potter CS, Fairfield H, et al. DSP rul: a spontaneous mouse mutation in desmoplakin as a model of Carvajal-Huerta syndrome. Exp Mol Pathol. 2015;98(2):164- 72. doi:10.1016/j.yexmp.2015.01.015.

33. Armstrong DK, McKenna KE, Purkis PE, et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum. Molec. Genet. 1999;8:143-48.

34. Uzumcu A, Norgett EE, Dindar A, et al. Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome. J Med. Genet. 2006;43(2):e5. doi:10.1136/jmg.2005.032904.

35. Pigors M, Schwieger-Briel A, Cosgarea R, et al. Desmoplakin mutations with palmoplantar keratoderma, woolly hair and cardiomyopathy. Acta Derm. Venereol. 2015;95:337-40. doi:10.2340/00015555-1974.

36. Kang H, Weiss TM, Bang I, et al. Structure of the Intermediate Filament-Binding Region of Desmoplakin. PLoS ONE 2016;11:e0147641. doi:10.1371/journal.pone.0147641.