Thomas Jefferson University Jefferson Digital Commons Department of Dermatology and Cutaneous Department of Dermatology and Cutaneous Biology Faculty Papers Biology 2-28-2019 Genetic Susceptibility to Alopecia. Jouni Uitto Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/dcbfp Part of the Dermatology Commons Let us know how access to this document benefits ouy Recommended Citation Uitto, Jouni, "Genetic Susceptibility to Alopecia." (2019). Department of Dermatology and Cutaneous Biology Faculty Papers. Paper 111. https://jdc.jefferson.edu/dcbfp/111 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Dermatology and Cutaneous Biology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Editorials tomy for advanced ovarian cancer — therapeutic advance or sur- 6. Rungruang BJ, Miller A, Krivak TC, et al. What is the role of gical folly? Gynecol Oncol 1995; 56: 325-7. retroperitoneal exploration in optimally debulked stage IIIC 3. Aletti GD, Dowdy S, Podratz KC, Cliby WA. Role of lymphad- epithelial ovarian cancer? An NRG Oncology/Gynecologic On- enectomy in the management of grossly apparent advanced cology Group ancillary data study. Cancer 2017; 123: 985-93. stage epithelial ovarian cancer. Am J Obstet Gynecol 2006; 195: 7. Panici PB, Maggioni A, Hacker N, et al. Systematic aortic and 1862-8. pelvic lymphadenectomy versus resection of bulky nodes only in 4. Chan JK, Urban R, Hu JM, et al. The potential therapeutic optimally debulked advanced ovarian cancer: a randomized role of lymph node resection in epithelial ovarian cancer: a study clinical trial. J Natl Cancer Inst 2005; 97: 560-6. of 13918 patients. Br J Cancer 2007; 96: 1817-22. 8. Harter P, Sehouli J, Lorusso D, et al. A randomized trial of 5. du Bois A, Reuss A, Harter P, Pujade-Lauraine E, Ray-Co- lymphadenectomy in patients with advanced ovarian neoplasms. quard I, Pfisterer J. Potential role of lymphadenectomy in ad- N Engl J Med 2019; 380: 822-32. vanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials. J Clin DOI: 10.1056/NEJMe1900044 Oncol 2010; 28: 1733-9. Copyright © 2019 Massachusetts Medical Society. Genetic Susceptibility to Alopecia Jouni Uitto, M.D., Ph.D. The hair unit is composed of specialized com- very common (mainly polygenic). The more com- partments that are coordinately responsible for mon, polygenic conditions have been attributed synthesis of the hair fiber. The principal signaling to a number of distinct pathomechanisms. Age- center of the hair follicle resides in the dermal associated thinning and loss of hair can be papilla, which consists of a specialized fibro- explained in part by hormonally influenced blast population that is responsible for regenera- miniaturization of the follicle, which is often tion and cycling of the follicle. The dermal pa- associated with androgenetic alopecia or pattern pilla interacts with the overlying epithelial cells, hair loss. Immune factors, such as lymphocyte- known as the hair matrix, to generate the hair mediated destruction of the lower part of the shaft.1 The size of the dermal papilla niche is follicle, are a hallmark feature of autoimmune dynamic and actively regulated, and a reduction forms of hair loss, such as alopecia areata in the number of cells that make up the dermal (patchy hair loss). Genetic factors also play a papilla is believed to contribute to the loss or role, as is the case in rare, mendelian forms of thinning of hair. The hair shaft itself contains a hair loss and hair fragility syndromes. For exam- complex configuration of structural proteins, in- ple, hair-shaft abnormalities, known as trichor- cluding many different hair keratins with asso- rhexis invaginata (also called bamboo hair), are ciated proteins, which are responsible for the associated with a keratinization phenotype of proper formation and growth of the hair shaft. dry and scaly skin in the Netherton syndrome, Distinct differences have been documented in caused by mutations in the gene SPINK5, which the hair morphology in human populations of encodes a serine protease inhibitor. different ancestries, which are believed to be Finally, there are other forms of alopecia for genetically determined.2 The hair of persons of which the cause has not yet been described. African ancestry has a flattened cross-sectional These include the group of primary cicatricial appearance, and the hair is usually coiled. The alopecias, including lichen planopilaris, frontal hair of persons of European ancestry has an oval fibrosing alopecia, and until now, central centrif- cross section, and the hair of persons of Asian ugal cicatricial alopecia (CCCA). In these disor- ancestry has a rounder, more circular perimeter, ders, hair loss is associated with rapid, progres- resulting in straighter hair. sive, and permanent destruction of follicles, Considering the complexity of hair biology, followed by replacement with fibrotic connective it is perhaps not unexpected that hair growth is tissue, which leads to irreversible hair loss.3 affected in several disorders, ranging from ex- CCCA is a common and progressive form of tremely rare (usually single-gene disorders) to scarring alopecia, in which histopathological n engl j med 380;9 nejm.org February 28, 2019 873 The New England Journal of Medicine Downloaded from nejm.org at THOMAS JEFFERSON UNIVERSITY on March 20, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. The new england journal of medicine examination of the skin reveals the presence of collagen types I and III, and various matrix lymphocytes early on in the proximity of hair metalloproteinases, are overexpressed in the fi- follicles, eventually resulting in the destruction brotic stage of the disease.9 of the follicle and deposition of extracellular In the second phase of their work, the authors matrix.4 CCCA is seen predominantly in women provided replication of the findings in a cohort of African ancestry, with a reported prevalence of 42 patients with CCCA and identified muta- of 2.7% among women in South Africa and 5.6% tions (including two novel mutations) in PADI3 among women of African descent in North in 9 of them. In total, six distinct mutations America.5 This condition, which is also some- were found in 14 of 58 patients (24%) with times described as hot comb alopecia because it CCCA. It is unclear whether the remaining three is often associated with traction-inducing hair- quarters of the patients have a type of CCCA that styling practices and use of hair chemicals, has is phenotypically indistinguishable from those a late onset, usually in the fourth decade of life.6 with PADI3. Given the complex physiology of The disorder sometimes runs in families in a CCCA and the results reported by Malki et al., perceived autosomal dominant pattern, although it is unlikely that PADI3 variants are solely respon- styling preferences within households may also sible for the disease. Variants in other genes contribute to the clustering of cases within probably contribute to pathogenesis. families. The majority of cases of CCCA appear It is interesting to note that another hair dis- to be sporadic. order, uncombable hair syndrome, has also been Malki et al., an international group of inves- shown in some cases to involve mutations in tigators, now report in the Journal 7 the results of PADI3, whereas in others the gene TCHH, which a study of the genetics of CCCA, including mo- encodes trichohyalin, is mutated.8 The uncomb- lecular analyses of a series of 58 patients with able hair syndrome is a rare disorder involving CCCA. First, the exomes of a discovery set com- hair-shaft abnormality, which is characterized by prising 16 women with CCCA who were of Afri- a frizzy appearance of difficult-to-manage hair can ancestry and living in the United States and (Fig. 1).10 The manifestation of this disorder dif- South Africa, were sequenced; analyses of the fers entirely from that of CCCA and is not as- sequence data yielded four mutations in PADI3 in sociated with alopecia or scarring. The uncomb- 5 women (each woman was heterozygous for the able hair syndrome occurs in children, usually mutation). Characterization of mutant proteins resolves with age, and shows no association led the authors to conclude that some of these with ancestral origin. Mutations in PADI3 in chil- mutations cause the encoded protein, peptidyl dren with the uncombable hair syndrome occur arginine deiminase 3 (PADI3), to misfold and in either a homozygous or a compound heterozy- form intracellular aggregates. PADI3 catalyzes the gous pattern, which suggests an autosomal re- post-translational modification of proteins by cessive inheritance pattern,8 in contrast to CCCA, converting arginine into citrulline — a modifi- in which the mutations were heterozygous. The cation that changes the charge of PADI3 and mutations in PADI3 in these two conditions are therefore results in physicochemical differences distinct, which suggests different pathogenic in the substrate proteins, such as trichohyalin, consequences of specific PADI3 variants on hair that can be modified by PADI3 (Fig. 1). Tricho- development. The observation that the heterozy- hyalin is critical to the formation and shaping of gous parents of children with uncombable hair the hair shaft. syndrome are apparently unaffected supports Further analyses showed that genes that are this hypothesis.