Concordance rate of alopecia areata in identical twins supports both genetic and environmental factors

Abstract

To the Editor: We previously reported that alopecia areata (AA), an autoimmune disease targeting the hair follicle causing hair loss, had a 55% concordance rate in monozygotic twins, suggesting both genetic and environmental triggers.1Jackow C. Puffer N. Hordinsky M. Nelson J. Tarrand J. Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment?.J Am Acad Dermatol. 1998; 38: 418-425Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Recently, we also reported a possible association between Epstein–Barr virus (EBV)-related mononucleosis and onset of AA in 12 young individuals.2Rodriguez T.A. Duvic M. Onset of alopecia areata after Epstein–Barr virus infectious monunucleosis.J Am Acad Dermatol. 2008; 59: 137-139Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar To further study the role of genes versus environment in the pathogenesis of AA, we examined concordance rates for AA and exposure to EBV by IgG serology in a new cohort of twins from the National Alopecia Areata Registry.We identified 58 sets of multiple birth individuals who were willing to answer a questionnaire. AA was concordant in eight of 19 (42%) sets of monozygotic twins, in 10% (3/31) dizygotic twins, in 0% among five sets of triplets and one set of quadruplets, and 0% (0/2) in two unknown sets (Table I). Presentation before age 20 years of age was found in 75% of affected individuals, including 67% of monozygotic twins, 82% of dizygotic twins, and 100% of the triplets and the quadruplet set. Sixty-six percent of the affected monozygotic twins had progressed to alopecia totalis (AT) or alopecia universalis (AU). The high prevalence of AT and AU may be explained by the association between the severity of alopecia and age of onset3Kakourou T. Karachristou K. Chrousos G. A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity.J Eur Acad Dermatol Venereol. 2007; 21: 356-359Crossref PubMed Scopus (64) Google Scholar, 4Gilhar A. Paus R. Kalish R.S. Lymphocytes, neuropeptides, and genes involved in alopecia areata.J Clin Invest. 2007; 117: 2019-2027Crossref PubMed Scopus (223) Google Scholar or a recruitment bias for patients with more extensive alopecia. The median age of onset in the 19 monozygotic twin sets was 13 years (range, 1-48 years). However, six of the eight concordant monozygotic twins were males and two were females (Table II). This agreed with our previous observation that all six concordant monozygotic twin pairs were males.1Jackow C. Puffer N. Hordinsky M. Nelson J. Tarrand J. Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment?.J Am Acad Dermatol. 1998; 38: 418-425Abstract Full Text Full Text PDF PubMed Scopus (114) Google ScholarTable ICondordance rate, alopecia areata phenotype, and age of onset in twinsPhenotype, no. of patientsAge of onset, y (%)Multiple birth typeNo. (sets)ConcordantAAAT/AUN/A≤20>20Monozygotic twins38 (19)8/19 (42.11%)9181118 (67%)9 (33%)Dizygotic twins62 (31)3/31 (9.68%)13212828 (82%)6 (18%)Triplets15 (5)0/5 (0%)23105 (100%)0 (0%)Quadruplets4 (1)0/1 (0%)0131 (100%)0 (0%)Unknown4 (2)0/2 (0%)0221 (50%)1 (50%)Total123 (58)11/58 (18.97%)24455453 (77%)16 (23%)AA, Alopecia areata; AT, alopecia totalis; AU, alopecia universalis; N/A, nonaffected. Open table in a new tab Table IIDemographic and environmental data from monozygotic twins concordant and disconcordant for alopecia areataTwin set no.Twins sexConcordant for AASame household∗Same household refers to whether the twins lived in the same environment when diagnosed with AA.Family history of AA†Family history refers to relatives with AA other than the concordant twin.First affected twin, dx‡Refers to the worst diagnosis of AA experienced by the patient during their lifetime. (age of AA onset, y)Second affected twin, dx‡Refers to the worst diagnosis of AA experienced by the patient during their lifetime. (age of AA onset, y)1MYesYesNoAU (3)AU (3)2FYesYesYesAU (2)AA (7)3MYesYesNoAT (8.5)AT (8.5)4MYesYesNoAT (2)AT (4)5MYesNoNoAU (48)AU (54)6MYesYesNoAA (13)AA (13)7FYesYesNoAA (4)AA (5)8MYesYesNoAU (5)AU (13)9MNoYesNoAU (1)—10FNoNoNoAU (25)—11FNoNoYesAT (46)—12FNoNoYesAA (24)—13FNoNoNoAU (29)—14MNoNoNoAU (21)—15FNoNoNoAU (45)—16FNoNoNoAA (19)—17MNoYesNoAT (6)—18FNoYesNoAA (10)—19FNoNoYesAA (44)—AA, Alopecia areata; AT, alopecia totalis; AU, alopecia universalis; dx, diagnosis; F, female; M, male.∗ Same household refers to whether the twins lived in the same environment when diagnosed with AA.† Family history refers to relatives with AA other than the concordant twin.‡ Refers to the worst diagnosis of AA experienced by the patient during their lifetime. Open table in a new tab With respect to environmental factors, seven of eight sets of all monozygotic concordant twins were living in the same household during the onset of AA (Table II). Six of these eight concordant monozygotic twins living together developed an identical AA phenotype. One concordant monozygotic twin pair living in separate households at onset also developed the same phenotype. The average time interval between first onset of AA in one twin and onset in the second was 4.85 years (median, 2 years; range, 2.5 months to 27 years). In the concordant dizygotic twin set, one female developed AA in childhood, and the other at 39 years of age.Lymphocytes are able to transfer AA in a mouse model, but the experiment cannot be performed in human.3Kakourou T. Karachristou K. Chrousos G. A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity.J Eur Acad Dermatol Venereol. 2007; 21: 356-359Crossref PubMed Scopus (64) Google Scholar However, one set of monozygotic twins, who were born prematurely, each received a blood transfusion from different donor. One developed alopecia universalis before 1 year of age, and the other has remained unaffected through 7 years of age. We previously reported the onset of AA in a brother after he received an allogeneic transplant from his AA-affected brother.5Barahmani N. Whaley K. Duvic M. Alopecia areata after allogenic bone marrow transplantation from an affected, human leukocyte antigen-matched sibling.J Am Acad Dermatol. 2003; 49: 1192PubMed Google Scholar These cases, although anecdotal and circumstantial, suggest that the transmissabilty of AA many occur in humans.To examine whether exposure to EBV, as manifested by seropositivity, is associated with onset of alopecia, we tested sera from 10 sets of monozygotic twins and four sets of dizygotic twins for EBV IgG serology (Table III). There were four sets of concordant monozygotic twins who were tested for EBV. In one male set, the twin with onset at 2 years of age had no titers, but his twin with onset at 4 years of age had titers of 1:320. In two female sets, both twins had negative EBV titers. The remaining male set, with onset at 48 and 54 years of age, had titers of 1:640 and 1:320, respectively. In the six disconcordant monozygotic twin sets tested, all were serologically positive for EBV, regardless of AA. In our only concordant set of dizygotic female twins, both developed alopecia within a month of each other at 4 years of age, and both had high EBV titers when tested at 7 years of age.Table IIIEpstein–Barr virus IgG serology testing in twin setsTwin set no.Twin typeConcordant?Age of AA onset, yAge at sera donation, ySexEBV-IgG antibody titer1MZYes212M<1:10 undetectedMZYes412M1:3202MZYes5472M1:320MZYes4872M1:6403MZYes46F<1:10 undetectedMZYes56F<1:10 undetected4MZYes210F<1:10 undetectedMZYes710F<1:10 undetected5MZNo2557F1:80MZNoN/A57F1:3206MZNo4650F1:320MZNoN/A50F1:6407MZNo4546F1:640MZNoN/A46F1:1608MZNo2471F1:320MZNoN/A71F1:1609MZNo2933F1:320MZNoN/A33F1:32010MZNo1054F1:320MZNoN/A54F1:32011DZYes47F1:640DZYes47F1:128012DZNo2.59M<1:10 undetectedDZNoN/A9F<1:10 undetected13DZNo2447F1:5120DZNoN/A48F1:128014DZNo79M<1:10 undetectedDZNoN/A9M<1:10 undetectedAA, Alopecia areata; DZ, dizygote; EBV, Epstein-Barr virus; F, female; M, male; MZ, monozygote; N/A, nonaffected. Open table in a new tab We report a 42% concordance rate of AA in identical twins and 10% in dizygotic twins in a new cohort, and find it similar to the 55% and 0% rate previously reported by our group.1Jackow C. Puffer N. Hordinsky M. Nelson J. Tarrand J. Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment?.J Am Acad Dermatol. 1998; 38: 418-425Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Our data suggest that AA is not purely a genetic trait, because the expected concordance rate would be 100% in identical twins. Because virus infections are potential environmental triggers, we examined the association between cytomegalovirus1Jackow C. Puffer N. Hordinsky M. Nelson J. Tarrand J. Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment?.J Am Acad Dermatol. 1998; 38: 418-425Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar or EBV serologies and onset of AA, but failed to see a correlation. However, observations that identical twins concordant for AA often share the same household and that AA can follow transfusions or bone marrow transplant suggest that environmental factors may be important. To the Editor: We previously reported that alopecia areata (AA), an autoimmune disease targeting the hair follicle causing hair loss, had a 55% concordance rate in monozygotic twins, suggesting both genetic and environmental triggers.1Jackow C. Puffer N. Hordinsky M. Nelson J. Tarrand J. Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment?.J Am Acad Dermatol. 1998; 38: 418-425Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Recently, we also reported a possible association between Epstein–Barr virus (EBV)-related mononucleosis and onset of AA in 12 young individuals.2Rodriguez T.A. Duvic M. Onset of alopecia areata after Epstein–Barr virus infectious monunucleosis.J Am Acad Dermatol. 2008; 59: 137-139Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar To further study the role of genes versus environment in the pathogenesis of AA, we examined concordance rates for AA and exposure to EBV by IgG serology in a new cohort of twins from the National Alopecia Areata Registry. We identified 58 sets of multiple birth individuals who were willing to answer a questionnaire. AA was concordant in eight of 19 (42%) sets of monozygotic twins, in 10% (3/31) dizygotic twins, in 0% among five sets of triplets and one set of quadruplets, and 0% (0/2) in two unknown sets (Table I). Presentation before age 20 years of age was found in 75% of affected individuals, including 67% of monozygotic twins, 82% of dizygotic twins, and 100% of the triplets and the quadruplet set. Sixty-six percent of the affected monozygotic twins had progressed to alopecia totalis (AT) or alopecia universalis (AU). The high prevalence of AT and AU may be explained by the association between the severity of alopecia and age of onset3Kakourou T. Karachristou K. Chrousos G. A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity.J Eur Acad Dermatol Venereol. 2007; 21: 356-359Crossref PubMed Scopus (64) Google Scholar, 4Gilhar A. Paus R. Kalish R.S. Lymphocytes, neuropeptides, and genes involved in alopecia areata.J Clin Invest. 2007; 117: 2019-2027Crossref PubMed Scopus (223) Google Scholar or a recruitment bias for patients with more extensive alopecia. The median age of onset in the 19 monozygotic twin sets was 13 years (range, 1-48 years). However, six of the eight concordant monozygotic twins were males and two were females (Table II). This agreed with our previous observation that all six concordant monozygotic twin pairs were males.1Jackow C. Puffer N. Hordinsky M. Nelson J. Tarrand J. Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment?.J Am Acad Dermatol. 1998; 38: 418-425Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar AA, Alopecia areata; AT, alopecia totalis; AU, alopecia universalis; N/A, nonaffected. AA, Alopecia areata; AT, alopecia totalis; AU, alopecia universalis; dx, diagnosis; F, female; M, male. With respect to environmental factors, seven of eight sets of all monozygotic concordant twins were living in the same household during the onset of AA (Table II). Six of these eight concordant monozygotic twins living together developed an identical AA phenotype. One concordant monozygotic twin pair living in separate households at onset also developed the same phenotype. The average time interval between first onset of AA in one twin and onset in the second was 4.85 years (median, 2 years; range, 2.5 months to 27 years). In the concordant dizygotic twin set, one female developed AA in childhood, and the other at 39 years of age. Lymphocytes are able to transfer AA in a mouse model, but the experiment cannot be performed in human.3Kakourou T. Karachristou K. Chrousos G. A case series of alopecia areata in children: impact of personal and family history of stress and autoimmunity.J Eur Acad Dermatol Venereol. 2007; 21: 356-359Crossref PubMed Scopus (64) Google Scholar However, one set of monozygotic twins, who were born prematurely, each received a blood transfusion from different donor. One developed alopecia universalis before 1 year of age, and the other has remained unaffected through 7 years of age. We previously reported the onset of AA in a brother after he received an allogeneic transplant from his AA-affected brother.5Barahmani N. Whaley K. Duvic M. Alopecia areata after allogenic bone marrow transplantation from an affected, human leukocyte antigen-matched sibling.J Am Acad Dermatol. 2003; 49: 1192PubMed Google Scholar These cases, although anecdotal and circumstantial, suggest that the transmissabilty of AA many occur in humans. To examine whether exposure to EBV, as manifested by seropositivity, is associated with onset of alopecia, we tested sera from 10 sets of monozygotic twins and four sets of dizygotic twins for EBV IgG serology (Table III). There were four sets of concordant monozygotic twins who were tested for EBV. In one male set, the twin with onset at 2 years of age had no titers, but his twin with onset at 4 years of age had titers of 1:320. In two female sets, both twins had negative EBV titers. The remaining male set, with onset at 48 and 54 years of age, had titers of 1:640 and 1:320, respectively. In the six disconcordant monozygotic twin sets tested, all were serologically positive for EBV, regardless of AA. In our only concordant set of dizygotic female twins, both developed alopecia within a month of each other at 4 years of age, and both had high EBV titers when tested at 7 years of age. AA, Alopecia areata; DZ, dizygote; EBV, Epstein-Barr virus; F, female; M, male; MZ, monozygote; N/A, nonaffected. We report a 42% concordance rate of AA in identical twins and 10% in dizygotic twins in a new cohort, and find it similar to the 55% and 0% rate previously reported by our group.1Jackow C. Puffer N. Hordinsky M. Nelson J. Tarrand J. Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment?.J Am Acad Dermatol. 1998; 38: 418-425Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Our data suggest that AA is not purely a genetic trait, because the expected concordance rate would be 100% in identical twins. Because virus infections are potential environmental triggers, we examined the association between cytomegalovirus1Jackow C. Puffer N. Hordinsky M. Nelson J. Tarrand J. Duvic M. Alopecia areata and cytomegalovirus infection in twins: genes versus environment?.J Am Acad Dermatol. 1998; 38: 418-425Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar or EBV serologies and onset of AA, but failed to see a correlation. However, observations that identical twins concordant for AA often share the same household and that AA can follow transfusions or bone marrow transplant suggest that environmental factors may be important.