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Familial dermatitis herpetiformis
Familial Dermatitis Herpetiformis TIM0 L. REUNALA, MD, SAIA KOSKIMIES,MD
_
he possibility that dermatitis herpetiformis (DH) might have a genetic background had been set forth during the past 20 years. Before that only a few familial cases were reported (l4), and several surveys of DH patients do not mention or did not find affected relatives (5-7). When DH was linked in 1966 to celiac disease (8), a known familial disease with 10 to 20% of affected first-degree relatives (9,10), it seemed natural to carry out similar surveys on relatives of patients with DH. Marks et al (11) performed jejunal biopsies on 18 relatives and showed that 7 (40%) had findings consistent with gluten-sensitive enteropathy. Reunala et al (12) investigated the families of six DH patients and found in their relatives a similar high frequency of jejunal villous atrophy. The enteropathy was often subclinical and this seems to be one reason why celiac disease has previously escaped the diagnosis in the relatives of DH patients. At present it is well documented that both in adults and in children the clinical spectrum of celiac disease can vary from the overt gastrointestinal disease with severe malabsorption to totally asymptomatic disease (13,14). Despite the increasing knowledge among dermatologists that DH has an immunogenetic background similar to that of celiac disease (CD), it is curious that only a few reports exist on familial DH.
T
Dermatitis Herpetiformis in Twins Marks et al (15) reported monozygotic male twins who both had DH. In this study the diagnosis of DH was not based on the demonstration of immunoglobulin A (IgA) deposits in the skin. Thereafter, four studies of monozyFrom the Department ofDermatology, Universify Hospital and University of Helsinki, and the Finnish Red Cross Blood Transfusion Service, Helsinki, Finland. Address correspondence to: Timo L Reunala, MD, Associate Professor in Dermatology, Department of Dermatology and Clinical Sciences, University of Tumpere, SF-33520 Tampere, Finland.
0 2992 by Elsevier Science Publishing Co., Inc.
l
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gotic twins with skin immunofluorescence examinations were published (16- 19). In these, two twin pairs have been concordant for DH, whereas in the other two pairs, one twin had DH and the other twin had celiac disease. In addition to these cases, we found one monozygotic DH DH and two monozygotic DH- CD twin pairs in our Finnish series of patients with DH (20). The existence of monozygotic DH-DH or DH-CD twins obviously indicates that a genetic component is involved in the pathogenesis. That the penetration in monozygotic twins is not always 100% is suggested by the report of Ermacora et al (21). They reported on one monozygotic twin who had DH and its twin who did not have DH, but did not comment on the intestinal status of the latter twin. In celiac disease, the concordance rate among monozygotic twins is virtually lOO%, whereas in dizygotic twins, it is only about 30 to 40% (22). In DH no data are available on the concordance rate in dizygotic twins but a frequency similar to that reported in celiac disease could be expected.
Familial Incidence of Dermatitis Herpetiformis Familial incidence of DH has been regarded low but several recent surveys (23 - 26), especially that of Meyer and Zone (27), have provided strong evidence that familial DH is not uncommon. In previous DH series familial DH cases were encountered at frequencies ranging from 0 to 3.4% (Table 1). Meyer and Zone (27) examined 92 propositi with DH, and found that 6 (6.5%) had affected firstdegree relatives. All of these were females with DH, including three daughters, two sisters, and one mother of the DH propositus. Meyer and Zone (27) did not have any data on the prevalence of DH in Utah but, using prevalence data from other sources, they showed that the familial incidence was significantly (P < .OOOl) increased from the expected. In Finland we have collected DH cases from 1969, and at the end of 1984 the series comprised 530 DH patients. Most of these patients have been regularly followed up in special outpatient clinics. In this series were
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336
REUNALA
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AND KOSKIMIES
1992;9:335-339 Table 2. Occurrence of Familial Cases in Dermatitis Herpetiformis
Series Patients with Affected First-Degree Relatives
Series Adult patients with DH Marks et al, 1970 (11) Reunala et al, 1976 (12) Leonard et al, 1982 (23) Buckley et al, 1983 (24) Moi, 1984 (25) Reunala et al, 1987 (26) Meyer and Zone, 1987 (27) Children with DH Ermacora et al, 1986 (21) Karpati et al, 1986 (29) l
Country
Number of Patients
Relatives With DH
Relatives With Celiac Disease
29 184 109 119 123 530 92
1 (3.4%) 0 1 (0.9%) nk 2 (1.6%) 24 (4.5%) 6 (6.5%)
nk’ 4 (2.5%) nk nk nk 29 (5.5%) nk
8 (?7%) nk 53 (10%) nk
76 45
0 2 (4.4%)
nk 3 (6.7%)
5 (I:%)
England Finland England Ireland Sweden Finland United States Italy Hungary, Finland
Total nk 4 (2.5%)
Not known.
24 (4.5%) DH patients who had affected first-degree relatives with DH (26). In contrast to the rather high familial incidence observed in DH series in Utah and Finland, a patient series from London followed up since 1969 reports clearly lower (0.9%) familial incidence (23). In our Finnish series about half of the affected relatives were encountered at the time of diagnosis of the propositi; the other familial cases were diagnosed during follow-up of the DH patients. We have not actively searched for the familial cases other than asking DH patients at follow-up visits to inform us about possible cases of DH or CD in their relatives. Therefore, the sampling error does not seem to explain the high incidences of familial DH in the Utah and Finnish DH series. In the Utah series, one reason may be demography, as the average number of firstdegree relatives was as high as 8. In addition to large family size, the Utah population is also characterized by its geographic stability, and the same is true for the Finnish people (27,28). Family size is much smaller in Finnish DH patients but, interestingly, the Utah population’s ethnic origins can be traced to European countries known to have a high prevalence of DH and CD. This genetic link could be one reason for the observed high familial tendency of DH in Utah, Finland, and Ireland (24). Environmental factors such as a more pronounced gluten consumption might also have influenced the occurrence of familial disease in these populations. It is also of interest that children with DH can have affected relatives. We found 2 (4.4%) DH children in a series of 45 patients who had affected first-degree relatives (29). In contrast, Ermacora et al (21) did not observe such cases in an Italian DH series. The monozygotic twins reported by Kosnai et al (17) contracted the disease at the age of 5 years. The reports in children and adults with DH show that a patient can have familial cases at any age. In addition to familial DH, celiac disease has been
noted in the relatives of patients with DH by several dermatologists. Alexander (30) has noted isolated instances of celiac disease in relatives of patients with DH. Meyer and Zone (27) found many family histories suggestive of celiac disease, but documentation of this condition with jejunal biopsy was not regularly performed. In the Finnish series, 29 (5.5%) DH patients had first-degree relatives with celiac disease, a percentage somewhat higher that that of familial DH (26,Table 1). As with DH, no active search for celiac disease was performed in the Finnish series, and all affected relatives had been examined because of clinical symptoms or signs of celiac disease in other hospitals and diagnosed there by jejunal biopsy. In the Finnish DH series the total percentage of familial DH or CD was as high as 10%. Buckley et al (24) reported an overall frequency of 6.7% familial cases in their series of 119 DH patients in Northern Ireland, but they did not know if the affected relatives had DH or CD. The 6.7% incidence is not far from the overall 10% familial incidence observed in the Finnish DH series. These two percentages correspond rather well to those found in the relatives of patients with celiac disease when no systematic search with jejunal biopsies was performed (10). In 1981 Love (31) reported very interesting familial data from Scotland. He compared the occurrence of familial cases in the relatives of patients with DH to that in the relatives of patients with CD. First-degree relatives of 60 patients with DH and 60 patients with CD diagnosed between 1975 and 1978 were surveyed for familial disease. The exact number of DH patients with affected relatives was not given, but among the 446 relatives were 11 (2.4%) with DH and 3 (0.6%) with CD. Sixty propositi with celiac disease had 435 first-degree relatives, of whom 5 (1%) had DH and 24 (5.5%) had CD. This shows that the first-degree relatives of patients with CD can have DH, but the incidence of DH in relatives seems to be
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FAMILIAL DERMATITIS HERPETIFORMIS
Table 2. Distribution of Dermatitis Herpetiformis and Celiac Disease Among the First-Degree Relatives in 53 Finnish Multiple-Case Families* Relative
Number Alive
With DH
Parents Siblings Children All
53 189 67 309
6 (11%) 18 (10%) 7 (10%) 31 (10%)
With Celiac Disease 4 24 9 37
(8%) (13%) (13%) (12%)
Total 10 (19%) 42 (22%) 16 (24%) 68 (22%)
Note. The propositus had DH and the affected relatioes had either DH or CD, which they contracted either before or after the DH was diagnosed in the propositi. l Forty-three families had one, five families had two, and five families had three ujfected first-degree relatives.
somewhat lower than that of CD. In Love’s series (31) the actual incidence of celiac disease in relatives may be even higher because intestinal biopsy was performed only in clinical suspicious circumstances; therefore, several asymptomatic cases may have escaped diagnosis. The finding of DH in relatives is not as difficult because the skin symptoms are rather suggestive of this disease and the demonstration of granular IgA deposits easily confirms the diagnosis. The use of skin biopsies to demonstrate IgA in relatives with no skin symptoms seems, however, useless because in two family studies the immunofluorescence examination yielded no new diagnoses of DH in the relatives of patients with celiac disease (12,23).
linked genetic component is very important in the pathogenesis of familial DH; however, the penetrance of DH or CD in relatives of DH patients seems to be rather low, and the important practical point is that a majority of DH patients do not show familial cases even if they are followed up for the rest of their lives. The Finnish multiple-case families with more than two affected relatives had either DH, CD, or a combination of these diseases. We have also reported one couple with DH whose child contracted CD but not DH (12). Afterward we detected a similar DH couple who had a child with CD and a third family in which the father had DH, and the mother and child, CD (Table 3). Interestingly, in the first family both DH parents had no evidence of gluten-sensitive enteropathy, whereas in the second and third families the affected DH father showed subtotal villous atrophy in jejunal biopsy. The evidence from these three families where the child contracted CD strongly suggests that primarily gluten-sensitive enteropathy, that is, celiac disease, is inherited, and that development of the skin disease, DH, seems to be a secondary phenomenon. A long-lasting but clinically inapparent, gluten-sensitive small intestinal disease might well be a prerequisite for the development of a rash with IgA deposits, the disease we call DH. Favoring this hypothesis, several adult Finnish DH patients and those reported by Buckley et al (24) had, in childhood, symptoms suggestive of celiac disease. Also when adult patients with celiac disease are carefully examined several of them give histories suggesting that the disease started in childhood (13).
Segregation of Dermatitis Herpetiformis in Multiple-Case Families We have analyzed the segregation of the disease in 53 families with multiple cases. The propositus had DH and the first-degree relative either DH or CD. A single firstdegree relative was affected in 43 families, two relatives were affected in 5 other families, and three relatives were affected in the remaining 5 families. The disease frequencies encountered among parents, siblings, and children are shown in Table 2. In these multiple-case families 19% of the parents, 22% of the siblings and 24% of the children were affected. These percentages fit well with the segregation pattern of a dominant disease. In these multiple-case families the overall frequency of DH was 10% among first-degree relatives; the frequency of CD was 13%. This shows that DH and CD seem to segregate in a similar frequency in relatives of DH patients. Substantiating this, the affected 28 sibpairs among these multiple-case families comprise 14 DH-DH pairs and 14 DHCD pairs (26). Of these 28 sibpairs 17 shared both HLA haplotypes, 10 shared one haplotype, and only one sibpair was HLA discordant. This clearly shows that a HLA-
Conclusions The reported monozygotic twins with DH-DH or DH-CD and several DH series with patients having affected firstdegree relatives indicate that DH is a genetic disease. The affected relatives of patients with DH may contract either DH or CD, and the incidences of these diseases seem to be rather similar in relatives. Recent studies reporting familial incidences of DH as high as 7 to 10% suggest that at least in certain populations, DH patients may have affected relatives in almost the same frequency as patients with CD. The reason for detecting none or only a small number of familial cases in some DH series may be due to the short follow-up, patients’ poor knowledge of the disease histories of their relatives, and environmental factors such as differences in gluten consumption and viral exposure. To further understand the genetic basis of DH and its very close relationship to CD more research is needed to explain the mode of inheritance of DH (26,32) and the associated HLA genes and gene products (20,33,34).
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Clinics in Dermatology 1992:9:335-339
Table 3. Disease Inheritance in Three Dermatitis Herpetiformis Were Affected with Either DH or Celiac Disease Father
@H) Families Where Both Parents
Mother Jejunal Biopsy
Disease/Age at Diagnosis
Affected Child
Family
Disease/Age at Diagnosis
]ejunal Biopsy
Disease/Sex/Age at Diagnosis
1
DH/52
Normal
DH/57
Normal
CD/F/31*
2
DH/42
Subtotal villous atrophy
DH/37
Normal
CD/F/22
3
DH/60
Subtotal villous atrophy
CD/67
Subtotal villous atrophy
CD/M/35
Healthy Children Jejunal Biopsy
Subtotal villous atrophy Subtotal villous atrophy Subtotal villous atrophy
Males/ Females
Jejunal Biopsy
3M/lF
ndt/md
lM/IF
2M/lF
Normal Partial villous atrophy nd/md nd
l CD, celiac disease;M, man; F, woman. t Nof done.
References 1. Ferguson Smith J. Dermatitis herpetiformis in brother and sister. Br J Dermatol Syphiligr 1928;40:19. 2. Bock HD. Gleichzeitiges Auftreten von Dermatitis Herpetiformis Duhring bei Vater und Sohn. Hautartz 1954;5:41. 3. Kinmont PDC. Familial dermatitis herpetiformis. matol 1955;67:410.
Br J Der-
4. Deeken JH, Bamshad J. Dermatitis herpetiformis in siblings. Cutis 1970;6:73-6. 5. Eyster WH, Kierland RR. Prognosis of dermatitis herpetiformis, treated and untreated. Arch Dermatol Syphiligr 1951;64:1-9. 6. Bjomberg A, Hellgren L. Dermatitis herpetiformis. Dermatologica 1962;125:205-25. 7. Smith EL. The diagnosis of dermatitis herpetiformis. Trans St John’s Hosp Dermatol Sot [Lond] 1966;52:176-96. 8. Marks J, Shuster S, Watson AJ. Small bowel changes in dermatitis herpetiformis. Lancet 1966;2:1280-2. 9. Stokes PL, Ferguson R, Holmes GKT, et al. Familial aspects of coeliac disease. Q J Med 1976;45:567-82. 10. Cooke WT, Holmes GKT. CoeIiac disease. Churchill Livingstone, 1984: 17-9.
Edinburgh:
11. Marks J, Birkett D, Shuster S, et al. Small intestinal mucosal abnormalities in relatives of patients with dermatitis herpetiformis. Gut 1970;11:493-7.
16. Jepsen LV, Ullman S. Dermatitis herpetiformis and glutensensitive enteropathy in monozygotic twins. Acta Dermatovenereol (Stockh) 1980;60:353-5. 17. Kosnai I, Karpati S, T&ok E, et al. Dermatitis herpetiformis in monozygotic twins: Discordance for dermatitis herpetiformis and concordance for gluten-sensitive enteropathy. Eur J Pediatr 1985;144:404-5. 18. Amstey A, Wilkinson JD, Walshe MM. Dermatitis herpetiformis in monozygous twins-Concordance for dermatitis herpetiformis and gluten-sensitive enteropathy. Clin Exp Dermatol 1991;16:51-2. 19. Green ST, Natarjan S, Connor JM, et al. Monozygotic twins concordant for duodenojejunal villous atrophy and dermatitis herpetiformis. Gut 1986;27:970-1. 20. Reunala T, Koskimies S, Ilonen J. Dermatitis herpetiformis in identical twins [abstract]. J Invest Dermatol 1991; 96:1023. 21. Ermacora E, PrampoIini L, Tribbia G, et al. Long-term follow-up of dermatitis herpetiformis in children. J Am Acad Dermatol 1986;15:24-30. 22. Greenberg DA, Hodge SE, Rother JI. Evidence for recessive and against dominant inheritance at the HLA “linked’ locus in coeliac disease. Am J Hum Genet 1982;34:263- 77. 23. Leonard JN, Haffenden GP, Tucker WFG, et al. Skin biopsies in relatives of patients with dermatitis herpetiformis. Acta Dermatovenereol (Stockh) 1982;63:252-4.
12. Reunala T, Salo OF’, Tiilikainen A, et al. Family studies in dermatitis herpetiformis. Ann Clin Res 1976;8:254 - 61.
24. Buckley DB, English J, Molloy W, et al. Dermatitis herpetiformis: Review of 119 cases. Clin Exp Dermatol 1983;8:477-87.
13. Logan RFA, Rifkind EA, Busuttil A, et al. Prevalence and incidence of celiac disease in Edinburg and the Lothian region of Scotland. Gastroenterology 1986;90:334-42.
25. Moi H. Incidence and prevalence of dermatitis herpetiformis in a county in central Sweden. Acta Dermatovenereol (Stockh) 1984;64:144-50.
14. Auricchio S, Mazzacca G, Tosi R, et al. Coeliac disease as a familial condition: Identification of asymptomatic coeliac patients within family groups. Gastroenterol Int 1988; 1:25-31.
26. Reunala T, Karvonen J, Koskimies S. Dominant inheritance of dermatitis herpetiformis. 17th World Congress of Dermatology; Berlin; May 25-29, 1987. Abstract II, p 289.
15. Marks J, May SB, Roberts DF. Dermatitis herpetiformis occurring in monozygotic twins. Br J Dermatol 1971;84: 417-9.
27. Meyer LJ, Zone JJ. Familial incidence of dermatitis herpetiformis. J Am Acad Dermatol 1987;17:643-7. 28. Reunala T, Lokki J. Dermatitis herpetiformis in Finland. Acta Derm Venereol (Stockh) 1978;58:505 - 10.
Clinics in Dermatology 1992;9:335-339 29. Karpati S, Kosnai I, Verkasalo M, et al. HLA antigens, jejunal morphology and associated diseases in children with dermatitis herpetiformis. Acta Paediatr Stand 1986;75: 297-301. 30. Alexander J O’D. Genetic aspects of dermatitis herpetiformis. In: Major problems in dermatology. London: WB Saunders 1975;4:281-4. 3 1. Love AHG. Epidemiological and genetic aspects of the coeliac syndrome in relation to dermatitis herpetiformis. In: McConnel RB, editor. The genetics of coeliac disease. Lancaster: MTP Press, 1981: 95-9.
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32. Karvonen J, Reunala T, Lokki J, et al. Theoretical considerations on HLA-associated illness-susceptibility genes in dermatitis herpetiformis and psoriasis. Tissue Antigens 1979;14:331-5. 33. Sachs JA, Awad J, McCloskey D, et al. Different HLA associated gene combinations contribute to susceptibility for coeliac disease and dermatitis herpetiformis. Gut 1986; 27:515-20. 34. Hall RF’, Sanders ME, Duquesnoy RJ, et al. Alterations in HLA-DP and HLA-DQ antigen frequency in patients with dermatitis herpetiformis. J Invest Dermatol1989;93:501-5.
_
he possibility that dermatitis herpetiformis (DH) might have a genetic background had been set forth during the past 20 years. Before that only a few familial cases were reported (l4), and several surveys of DH patients do not mention or did not find affected relatives (5-7). When DH was linked in 1966 to celiac disease (8), a known familial disease with 10 to 20% of affected first-degree relatives (9,10), it seemed natural to carry out similar surveys on relatives of patients with DH. Marks et al (11) performed jejunal biopsies on 18 relatives and showed that 7 (40%) had findings consistent with gluten-sensitive enteropathy. Reunala et al (12) investigated the families of six DH patients and found in their relatives a similar high frequency of jejunal villous atrophy. The enteropathy was often subclinical and this seems to be one reason why celiac disease has previously escaped the diagnosis in the relatives of DH patients. At present it is well documented that both in adults and in children the clinical spectrum of celiac disease can vary from the overt gastrointestinal disease with severe malabsorption to totally asymptomatic disease (13,14). Despite the increasing knowledge among dermatologists that DH has an immunogenetic background similar to that of celiac disease (CD), it is curious that only a few reports exist on familial DH.
T
Dermatitis Herpetiformis in Twins Marks et al (15) reported monozygotic male twins who both had DH. In this study the diagnosis of DH was not based on the demonstration of immunoglobulin A (IgA) deposits in the skin. Thereafter, four studies of monozyFrom the Department ofDermatology, Universify Hospital and University of Helsinki, and the Finnish Red Cross Blood Transfusion Service, Helsinki, Finland. Address correspondence to: Timo L Reunala, MD, Associate Professor in Dermatology, Department of Dermatology and Clinical Sciences, University of Tumpere, SF-33520 Tampere, Finland.
0 2992 by Elsevier Science Publishing Co., Inc.
l
0738-081x/92/$5.00
gotic twins with skin immunofluorescence examinations were published (16- 19). In these, two twin pairs have been concordant for DH, whereas in the other two pairs, one twin had DH and the other twin had celiac disease. In addition to these cases, we found one monozygotic DH DH and two monozygotic DH- CD twin pairs in our Finnish series of patients with DH (20). The existence of monozygotic DH-DH or DH-CD twins obviously indicates that a genetic component is involved in the pathogenesis. That the penetration in monozygotic twins is not always 100% is suggested by the report of Ermacora et al (21). They reported on one monozygotic twin who had DH and its twin who did not have DH, but did not comment on the intestinal status of the latter twin. In celiac disease, the concordance rate among monozygotic twins is virtually lOO%, whereas in dizygotic twins, it is only about 30 to 40% (22). In DH no data are available on the concordance rate in dizygotic twins but a frequency similar to that reported in celiac disease could be expected.
Familial Incidence of Dermatitis Herpetiformis Familial incidence of DH has been regarded low but several recent surveys (23 - 26), especially that of Meyer and Zone (27), have provided strong evidence that familial DH is not uncommon. In previous DH series familial DH cases were encountered at frequencies ranging from 0 to 3.4% (Table 1). Meyer and Zone (27) examined 92 propositi with DH, and found that 6 (6.5%) had affected firstdegree relatives. All of these were females with DH, including three daughters, two sisters, and one mother of the DH propositus. Meyer and Zone (27) did not have any data on the prevalence of DH in Utah but, using prevalence data from other sources, they showed that the familial incidence was significantly (P < .OOOl) increased from the expected. In Finland we have collected DH cases from 1969, and at the end of 1984 the series comprised 530 DH patients. Most of these patients have been regularly followed up in special outpatient clinics. In this series were
335
336
REUNALA
Clinics in Dermatology
AND KOSKIMIES
1992;9:335-339 Table 2. Occurrence of Familial Cases in Dermatitis Herpetiformis
Series Patients with Affected First-Degree Relatives
Series Adult patients with DH Marks et al, 1970 (11) Reunala et al, 1976 (12) Leonard et al, 1982 (23) Buckley et al, 1983 (24) Moi, 1984 (25) Reunala et al, 1987 (26) Meyer and Zone, 1987 (27) Children with DH Ermacora et al, 1986 (21) Karpati et al, 1986 (29) l
Country
Number of Patients
Relatives With DH
Relatives With Celiac Disease
29 184 109 119 123 530 92
1 (3.4%) 0 1 (0.9%) nk 2 (1.6%) 24 (4.5%) 6 (6.5%)
nk’ 4 (2.5%) nk nk nk 29 (5.5%) nk
8 (?7%) nk 53 (10%) nk
76 45
0 2 (4.4%)
nk 3 (6.7%)
5 (I:%)
England Finland England Ireland Sweden Finland United States Italy Hungary, Finland
Total nk 4 (2.5%)
Not known.
24 (4.5%) DH patients who had affected first-degree relatives with DH (26). In contrast to the rather high familial incidence observed in DH series in Utah and Finland, a patient series from London followed up since 1969 reports clearly lower (0.9%) familial incidence (23). In our Finnish series about half of the affected relatives were encountered at the time of diagnosis of the propositi; the other familial cases were diagnosed during follow-up of the DH patients. We have not actively searched for the familial cases other than asking DH patients at follow-up visits to inform us about possible cases of DH or CD in their relatives. Therefore, the sampling error does not seem to explain the high incidences of familial DH in the Utah and Finnish DH series. In the Utah series, one reason may be demography, as the average number of firstdegree relatives was as high as 8. In addition to large family size, the Utah population is also characterized by its geographic stability, and the same is true for the Finnish people (27,28). Family size is much smaller in Finnish DH patients but, interestingly, the Utah population’s ethnic origins can be traced to European countries known to have a high prevalence of DH and CD. This genetic link could be one reason for the observed high familial tendency of DH in Utah, Finland, and Ireland (24). Environmental factors such as a more pronounced gluten consumption might also have influenced the occurrence of familial disease in these populations. It is also of interest that children with DH can have affected relatives. We found 2 (4.4%) DH children in a series of 45 patients who had affected first-degree relatives (29). In contrast, Ermacora et al (21) did not observe such cases in an Italian DH series. The monozygotic twins reported by Kosnai et al (17) contracted the disease at the age of 5 years. The reports in children and adults with DH show that a patient can have familial cases at any age. In addition to familial DH, celiac disease has been
noted in the relatives of patients with DH by several dermatologists. Alexander (30) has noted isolated instances of celiac disease in relatives of patients with DH. Meyer and Zone (27) found many family histories suggestive of celiac disease, but documentation of this condition with jejunal biopsy was not regularly performed. In the Finnish series, 29 (5.5%) DH patients had first-degree relatives with celiac disease, a percentage somewhat higher that that of familial DH (26,Table 1). As with DH, no active search for celiac disease was performed in the Finnish series, and all affected relatives had been examined because of clinical symptoms or signs of celiac disease in other hospitals and diagnosed there by jejunal biopsy. In the Finnish DH series the total percentage of familial DH or CD was as high as 10%. Buckley et al (24) reported an overall frequency of 6.7% familial cases in their series of 119 DH patients in Northern Ireland, but they did not know if the affected relatives had DH or CD. The 6.7% incidence is not far from the overall 10% familial incidence observed in the Finnish DH series. These two percentages correspond rather well to those found in the relatives of patients with celiac disease when no systematic search with jejunal biopsies was performed (10). In 1981 Love (31) reported very interesting familial data from Scotland. He compared the occurrence of familial cases in the relatives of patients with DH to that in the relatives of patients with CD. First-degree relatives of 60 patients with DH and 60 patients with CD diagnosed between 1975 and 1978 were surveyed for familial disease. The exact number of DH patients with affected relatives was not given, but among the 446 relatives were 11 (2.4%) with DH and 3 (0.6%) with CD. Sixty propositi with celiac disease had 435 first-degree relatives, of whom 5 (1%) had DH and 24 (5.5%) had CD. This shows that the first-degree relatives of patients with CD can have DH, but the incidence of DH in relatives seems to be
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FAMILIAL DERMATITIS HERPETIFORMIS
Table 2. Distribution of Dermatitis Herpetiformis and Celiac Disease Among the First-Degree Relatives in 53 Finnish Multiple-Case Families* Relative
Number Alive
With DH
Parents Siblings Children All
53 189 67 309
6 (11%) 18 (10%) 7 (10%) 31 (10%)
With Celiac Disease 4 24 9 37
(8%) (13%) (13%) (12%)
Total 10 (19%) 42 (22%) 16 (24%) 68 (22%)
Note. The propositus had DH and the affected relatioes had either DH or CD, which they contracted either before or after the DH was diagnosed in the propositi. l Forty-three families had one, five families had two, and five families had three ujfected first-degree relatives.
somewhat lower than that of CD. In Love’s series (31) the actual incidence of celiac disease in relatives may be even higher because intestinal biopsy was performed only in clinical suspicious circumstances; therefore, several asymptomatic cases may have escaped diagnosis. The finding of DH in relatives is not as difficult because the skin symptoms are rather suggestive of this disease and the demonstration of granular IgA deposits easily confirms the diagnosis. The use of skin biopsies to demonstrate IgA in relatives with no skin symptoms seems, however, useless because in two family studies the immunofluorescence examination yielded no new diagnoses of DH in the relatives of patients with celiac disease (12,23).
linked genetic component is very important in the pathogenesis of familial DH; however, the penetrance of DH or CD in relatives of DH patients seems to be rather low, and the important practical point is that a majority of DH patients do not show familial cases even if they are followed up for the rest of their lives. The Finnish multiple-case families with more than two affected relatives had either DH, CD, or a combination of these diseases. We have also reported one couple with DH whose child contracted CD but not DH (12). Afterward we detected a similar DH couple who had a child with CD and a third family in which the father had DH, and the mother and child, CD (Table 3). Interestingly, in the first family both DH parents had no evidence of gluten-sensitive enteropathy, whereas in the second and third families the affected DH father showed subtotal villous atrophy in jejunal biopsy. The evidence from these three families where the child contracted CD strongly suggests that primarily gluten-sensitive enteropathy, that is, celiac disease, is inherited, and that development of the skin disease, DH, seems to be a secondary phenomenon. A long-lasting but clinically inapparent, gluten-sensitive small intestinal disease might well be a prerequisite for the development of a rash with IgA deposits, the disease we call DH. Favoring this hypothesis, several adult Finnish DH patients and those reported by Buckley et al (24) had, in childhood, symptoms suggestive of celiac disease. Also when adult patients with celiac disease are carefully examined several of them give histories suggesting that the disease started in childhood (13).
Segregation of Dermatitis Herpetiformis in Multiple-Case Families We have analyzed the segregation of the disease in 53 families with multiple cases. The propositus had DH and the first-degree relative either DH or CD. A single firstdegree relative was affected in 43 families, two relatives were affected in 5 other families, and three relatives were affected in the remaining 5 families. The disease frequencies encountered among parents, siblings, and children are shown in Table 2. In these multiple-case families 19% of the parents, 22% of the siblings and 24% of the children were affected. These percentages fit well with the segregation pattern of a dominant disease. In these multiple-case families the overall frequency of DH was 10% among first-degree relatives; the frequency of CD was 13%. This shows that DH and CD seem to segregate in a similar frequency in relatives of DH patients. Substantiating this, the affected 28 sibpairs among these multiple-case families comprise 14 DH-DH pairs and 14 DHCD pairs (26). Of these 28 sibpairs 17 shared both HLA haplotypes, 10 shared one haplotype, and only one sibpair was HLA discordant. This clearly shows that a HLA-
Conclusions The reported monozygotic twins with DH-DH or DH-CD and several DH series with patients having affected firstdegree relatives indicate that DH is a genetic disease. The affected relatives of patients with DH may contract either DH or CD, and the incidences of these diseases seem to be rather similar in relatives. Recent studies reporting familial incidences of DH as high as 7 to 10% suggest that at least in certain populations, DH patients may have affected relatives in almost the same frequency as patients with CD. The reason for detecting none or only a small number of familial cases in some DH series may be due to the short follow-up, patients’ poor knowledge of the disease histories of their relatives, and environmental factors such as differences in gluten consumption and viral exposure. To further understand the genetic basis of DH and its very close relationship to CD more research is needed to explain the mode of inheritance of DH (26,32) and the associated HLA genes and gene products (20,33,34).
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Table 3. Disease Inheritance in Three Dermatitis Herpetiformis Were Affected with Either DH or Celiac Disease Father
@H) Families Where Both Parents
Mother Jejunal Biopsy
Disease/Age at Diagnosis
Affected Child
Family
Disease/Age at Diagnosis
]ejunal Biopsy
Disease/Sex/Age at Diagnosis
1
DH/52
Normal
DH/57
Normal
CD/F/31*
2
DH/42
Subtotal villous atrophy
DH/37
Normal
CD/F/22
3
DH/60
Subtotal villous atrophy
CD/67
Subtotal villous atrophy
CD/M/35
Healthy Children Jejunal Biopsy
Subtotal villous atrophy Subtotal villous atrophy Subtotal villous atrophy
Males/ Females
Jejunal Biopsy
3M/lF
ndt/md
lM/IF
2M/lF
Normal Partial villous atrophy nd/md nd
l CD, celiac disease;M, man; F, woman. t Nof done.
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