Uitto, Jouni

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Thomas Jefferson UniversityJefferson Digital CommonsDepartment of Dermatology and CutaneousBiology Faculty PapersDepartment of Dermatology and CutaneousBiology2-28-2019Genetic Susceptibility to Alopecia.Jouni UittoThomas Jefferson University, jouni.uitto@jefferson.eduLet us know how access to this document benefits youFollow this and additional works at: https://jdc.jefferson.edu/dcbfpPart of the Dermatology CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inDepartment of Dermatology and Cutaneous Biology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For moreinformation, please contact: JeffersonDigitalCommons@jefferson.edu.Recommended CitationUitto, Jouni, "Genetic Susceptibility to Alopecia." (2019). Department of Dermatology and CutaneousBiology Faculty Papers. Paper 111.https://jdc.jefferson.edu/dcbfp/111Editorialsn engl j med 380;9 nejm.org February 28, 2019 873tomy for advanced ovarian cancer — therapeutic advance or sur-gical folly? Gynecol Oncol 1995; 56: 325-7.3. Aletti GD, Dowdy S, Podratz KC, Cliby WA. Role of lymphad-enectomy in the management of grossly apparent advanced stage epithelial ovarian cancer. Am J Obstet Gynecol 2006; 195: 1862-8.4. Chan JK, Urban R, Hu JM, et al. The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13918 patients. Br J Cancer 2007; 96: 1817-22.5. du Bois A, Reuss A, Harter P, Pujade-Lauraine E, Ray-Co-quard I, Pfisterer J. Potential role of lymphadenectomy in ad-vanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials. J Clin Oncol 2010; 28: 1733-9.6. Rungruang BJ, Miller A, Krivak TC, et al. What is the role of retroperitoneal exploration in optimally debulked stage IIIC epithelial ovarian cancer? An NRG Oncology/Gynecologic On-cology Group ancillary data study. Cancer 2017; 123: 985-93.7. Panici PB, Maggioni A, Hacker N, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst 2005; 97: 560-6.8. Harter P, Sehouli J, Lorusso D, et al. A randomized trial of lymphadenectomy in patients with advanced ovarian neoplasms. N Engl J Med 2019; 380: 822-32.DOI: 10.1056/NEJMe1900044Copyright © 2019 Massachusetts Medical Society.Genetic Susceptibility to AlopeciaJouni Uitto, M.D., Ph.D.The hair unit is composed of specialized com-partments that are coordinately responsible for synthesis of the hair fiber. The principal signaling center of the hair follicle resides in the dermal papilla, which consists of a specialized fibro-blast population that is responsible for regenera-tion and cycling of the follicle. The dermal pa-pilla interacts with the overlying epithelial cells, known as the hair matrix, to generate the hair shaft.1 The size of the dermal papilla niche is dynamic and actively regulated, and a reduction in the number of cells that make up the dermal papilla is believed to contribute to the loss or thinning of hair. The hair shaft itself contains a complex configuration of structural proteins, in-cluding many different hair keratins with asso-ciated proteins, which are responsible for the proper formation and growth of the hair shaft.Distinct differences have been documented in the hair morphology in human populations of different ancestries, which are believed to be genetically determined.2 The hair of persons of African ancestry has a flattened cross-sectional appearance, and the hair is usually coiled. The hair of persons of European ancestry has an oval cross section, and the hair of persons of Asian ancestry has a rounder, more circular perimeter, resulting in straighter hair.Considering the complexity of hair biology, it is perhaps not unexpected that hair growth is affected in several disorders, ranging from ex-tremely rare (usually single-gene disorders) to very common (mainly polygenic). The more com-mon, polygenic conditions have been attributed to a number of distinct pathomechanisms. Age-associated thinning and loss of hair can be explained in part by hormonally influenced miniaturization of the follicle, which is often associated with androgenetic alopecia or pattern hair loss. Immune factors, such as lymphocyte-mediated destruction of the lower part of the follicle, are a hallmark feature of autoimmune forms of hair loss, such as alopecia areata (patchy hair loss). Genetic factors also play a role, as is the case in rare, mendelian forms of hair loss and hair fragility syndromes. For exam-ple, hair-shaft abnormalities, known as trichor-rhexis invaginata (also called bamboo hair), are associated with a keratinization phenotype of dry and scaly skin in the Netherton syndrome, caused by mutations in the gene SPINK5, which encodes a serine protease inhibitor.Finally, there are other forms of alopecia for which the cause has not yet been described. These include the group of primary cicatricial alopecias, including lichen planopilaris, frontal fibrosing alopecia, and until now, central centrif-ugal cicatricial alopecia (CCCA). In these disor-ders, hair loss is associated with rapid, progres-sive, and permanent destruction of follicles, followed by replacement with fibrotic connective tissue, which leads to irreversible hair loss.3CCCA is a common and progressive form of scarring alopecia, in which histopathological 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. T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 380;9 nejm.org February 28, 2019874examination of the skin reveals the presence of lymphocytes early on in the proximity of hair follicles, eventually resulting in the destruction of the follicle and deposition of extracellular matrix.4 CCCA is seen predominantly in women of African ancestry, with a reported prevalence of 2.7% among women in South Africa and 5.6% among women of African descent in North America.5 This condition, which is also some-times described as hot comb alopecia because it is often associated with traction-inducing hair-styling practices and use of hair chemicals, has a late onset, usually in the fourth decade of life.6 The disorder sometimes runs in families in a perceived autosomal dominant pattern, although styling preferences within households may also contribute to the clustering of cases within families. The majority of cases of CCCA appear to be sporadic.Malki et al., an international group of inves-tigators, now report in the Journal 7 the results of a study of the genetics of CCCA, including mo-lecular analyses of a series of 58 patients with CCCA. First, the exomes of a discovery set com-prising 16 women with CCCA who were of Afri-can ancestry and living in the United States and South Africa, were sequenced; analyses of the sequence data yielded four mutations in PADI3 in 5 women (each woman was heterozygous for the mutation). Characterization of mutant proteins led the authors to conclude that some of these mutations cause the encoded protein, peptidyl arginine deiminase 3 (PADI3), to misfold and form intracellular aggregates. PADI3 catalyzes the post-translational modification of proteins by converting arginine into citrulline — a modifi-cation that changes the charge of PADI3 and therefore results in physicochemical differences in the substrate proteins, such as trichohyalin, that can be modified by PADI3 (Fig. 1). Tricho-hyalin is critical to the formation and shaping of the hair shaft.Further analyses showed that genes that are critical to hair formation (and that have been previously shown, when variant, to be associated with hair loss) are expressed at different levels in the scalp skin of women with CCCA than in unaf-fected women. This pattern of dysregulation may also mark a point in the progression of the dis-ease — a point emphasized by recent findings that fibroproliferative genes, such as those for collagen types I and III, and various matrix metalloproteinases, are overexpressed in the fi-brotic stage of the disease.9In the second phase of their work, the authors provided replication of the findings in a cohort of 42 patients with CCCA and identified muta-tions (including two novel mutations) in PADI3 in 9 of them. In total, six distinct mutations were found in 14 of 58 patients (24%) with CCCA. It is unclear whether the remaining three quarters of the patients have a type of CCCA that is phenotypically indistinguishable from those with PADI3. Given the complex physiology of CCCA and the results reported by Malki et al., it is unlikely that PADI3 variants are solely respon-sible for the disease. Variants in other genes probably contribute to pathogenesis.It is interesting to note that another hair dis-order, uncombable hair syndrome, has also been shown in some cases to involve mutations in PADI3, whereas in others the gene TCHH, which encodes trichohyalin, is mutated.8 The uncomb-able hair syndrome is a rare disorder involving hair-shaft abnormality, which is characterized by a frizzy appearance of difficult-to-manage hair (Fig. 1).10 The manifestation of this disorder dif-fers entirely from that of CCCA and is not as-sociated with alopecia or scarring. The uncomb-able hair syndrome occurs in children, usually resolves with age, and shows no association with ancestral origin. Mutations in PADI3 in chil-dren with the uncombable hair syndrome occur in either a homozygous or a compound heterozy-gous pattern, which suggests an autosomal re-cessive inheritance pattern,8 in contrast to CCCA, in which the mutations were heterozygous. The mutations in PADI3 in these two conditions are distinct, which suggests different pathogenic consequences of specific PADI3 variants on hair development. The observation that the heterozy-gous parents of children with uncombable hair syndrome are apparently unaffected supports this hypothesis.What are the implications of these findings for clinical management? The observations by Malki et al. suggest that PADI3 mutations predis-pose persons to CCCA, which is then clinically manifested when hairstyling practices damage the hair. Thus, in the familial setting, such prac-tices should be discouraged in both symptomatic and asymptomatic family members. Although 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. Editorialsn engl j med 380;9 nejm.org February 28, 2019 875PADI3 mutations would appear to predispose women to CCCA, the screening of asymptomatic women for pathogenic mutations in PADI3 would be premature. Perhaps, once the association is tested in larger groups of women and the effect on risk is better understood7 and there is a com-prehensive genomic landscape of CCCA (i.e., other risk variants and genes are identified and their effect on risk delineated), genotyping of asymptomatic women would be warranted. The presence of variants in PADI3 in both CCCA and uncombable hair syndrome suggests that this Figure 1. Central Centrifugal Cicatricial Alopecia (CCCA) and Uncombable Hair Syndrome.The integrity of the gene PADI3, which encodes peptidyl arginine deiminase (PADI3), permits normal hair-follicle function (Panel A). The study by Malki et al.7 implicates variants in PADI3 regarding susceptibility to CCCA (Panel B), which has been reported to be associated with hot comb treatment. Previous work has shown that homozygous variants in PADI3 cause uncombable hair syndrome (Panel C).8 Photos courtesy of Amy McMichael, M.D., Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.A UnaffectedpersonPerson with central centrifugalcicatricial alopecia (CCCA)Person with uncombable hairsyndromeB CEnvironmentalstress such ashot combNonmutated PADI3 Heterozygous mutationsin PADI3Reduced expressionof genes regulating hairformation and structureLate-onset fibrosis,scarring, and hair loss Early-onset frizzy hairthat stands out from scalpHomozygous mutationsin PADI3LongitudinalgroovingNormalexpressionof PADI3↓PADI3expressionHAIRFOLLICLEAltered post-translationalmodification of trichohyalin↓PADI3expressionThe 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. Editorialsn engl j med 380;9 nejm.org February 28, 2019876gene has a pleiotropic effect on the determina-tion of hair texture, and the finding holds impli-cations for future development of therapy, such as the restoration of PADI3 activity.Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.From the Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Philadelphia. This editorial was published on February 13, 2019, at NEJM.org.1. Morgan BA. The dermal papilla: an instructive niche for epithelial stem and progenitor cells in development and regen-eration of the hair follicle. Cold Spring Harb Perspect Med 2014; 4(7): a015180.2. Lawson CN, Hollinger J, Sethi S, et al. Updates in the under-standing and treatments of skin & hair disorders in women of color. Int J Womens Dermatol 2015; 1: 59-75.3. Sundberg JP, Hordinsky MK, Bergfeld W, et al. Cicatricial Alopecia Research Foundation meeting, May 2016: progress to-wards the diagnosis, treatment and cure of primary cicatricial alopecias. Exp Dermatol 2018; 27: 302-10.4. Subash J, Alexander T, Beamer V, McMichael A. A proposed mechanism for central centrifugal cicatricial alopecia. Exp Der-matol 2018 April 16 (Epub ahead of print).5. Dlova NC, Salkey KS, Callender VD, McMichael AJ. Central centrifugal cicatricial alopecia: new insights and a call for ac-tion. J Investig Dermatol Symp Proc 2017; 18: S54-S56.6. Lindsey SF, Tosti A. Ethnic hair disorders. Curr Probl Der-matol 2015; 47: 139-49.7. Malki L, Sarig O, Romano M-T, et al. Variant PADI3 in central centrifugal cicatricial alopecia. N Engl J Med 2019; 380: 833-41.8. Ü Basmanav FB, Cau L, Tafazzoli A, et al. Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome. Am J Hum Genet 2016; 99: 1292-304.9. Aguh C, Dina Y, Talbot CC Jr, Garza L. Fibroproliferative genes are preferentially expressed in central centrifugal cicatri-cial alopecia. J Am Acad Dermatol 2018; 79(5): 904.e1-912.e1.10. Calderon P, Otberg N, Shapiro J. Uncombable hair syn-drome. J Am Acad Dermatol 2009; 61: 512-5.DOI: 10.1056/NEJMe1900042Copyright © 2019 Massachusetts Medical Society.early job alert service available at the nejm careercenterRegister to receive weekly email messages with the latest job openings  that match your specialty, as well as preferred geographic region,  practice setting, call schedule, and more. Visit the NEJM CareerCenter  at nejmjobs.org for more information.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. 

Genetic Susceptibility to Alopecia.

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Genetic Susceptibility to Alopecia.

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