- Email: [email protected]
Epidermolysis Bullosa Care in Scandinavia
Epidermolysis Bullosa C a re i n S c a n d i n a v i a Anders Vahlquist, MD, PhDa,*, Kaisa Tasanen, MD, PhDb KEYWORDS EB Gene Mutation Therapy
One of the first papers published on epidermolysis bullosa (EB) in Scandinavia was that of Gillis Herlitz (1902–1982) who, when working as a pediatrician at Uppsala University Hospital in the early 1930s, described a lethal form of the disease now known as junctional EB (JEB) of the Herlitz type. In the beginning of the 1960s, the Norwegian geneticist Tobias Gedde-Dahl (1938–2006) started his pioneering work on EB in Norway, whereby he personally visited and documented virtually all patients with EB, as well as described new forms of the disease, such as epidermolysis bullosa simplex (EBS)–Ogna. Dermatologist Matti Kero,1 in his thesis work, documented during the period between 1971 and 1980 the clinical and ultrastructural features of 121 patients affected by recessively inherited EB living in Finland. Research group of Professor Jouni Uitto, originally from Finland, was the first to discover the genetic linkage between the type VII collagen gene and dystrophic EB (DEB) in a large Finnish pedigree in 4 generations.2–4
EPIDEMIOLOGY The recessive forms of EB are relatively common in Scandinavia, especially in the northern parts of Norway and Sweden where a founder effect for LAMB3 gene mutation (R635X) causing JEBHerlitz has been noted. Table 1 shows very approximate figures for the number of Scandinavian families affected by EB reported during a period of 40 years. It can be seen that the prevalence of JEB and recessive DEB (RDEB) is highest in Norway and Sweden, whereas the other
EB subtypes seem to be more evenly distributed among the Nordic countries. The figures for the mild forms of EBS and dominant DEB are probably grossly underreported in this type of compilation from the literature. In a more recent questionnaire sent to all Swedish dermatologists and pediatricians, 39 patients with EBS, 5 with JEB, and 28 with DEB were identified (Wittbolt and Vahlquist, unpublished data, 2005). Only 6 of the DEB cases were of the recessive type; however a few of these patients died prematurely. The highest death rate is no doubt among patients with JEB-Herlitz of whom practically all babies die within 1 to 2 years, thus heavily reducing the prevalence of this EB subtype. Historically, about 1 child per year with JEB-Herlitz was born in Sweden. However the incidence of this subtype and RDEB is increasing, particularly in Sweden receiving many immigrants from countries where cousin marriage is common. This also introduces new types of mutations.
THE ORGANIZATION OF EB HEALTH SERVICES The care of EB in Scandinavia is organized around the patient via settings at the local hospital or health service. However, the diagnosis of EB and providing correct patient/family information usually require a specialized service, which in Sweden is provided at the Genodermatosis Center in Uppsala. This center mainly operates on an outpatient basis where patients come for 1 to 2 visits, either a couple of months after birth or in the case of older patients, whenever there is a need for improved diagnoses and information about EB. When a child with suspected EB is born in Sweden, there is usually
a
Department of Medical Sciences, Uppsala University, University Hospital, SE-751 85 Uppsala, Sweden Department of Dermatology, Clinical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland * Corresponding author. E-mail address: [email protected]
b
Dermatol Clin 28 (2010) 425–427 doi:10.1016/j.det.2010.02.018 0733-8635/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
derm.theclinics.com
A SHORT HISTORY
426
Vahlquist & Tasanen
Table 1 Estimated number of EB families in the Nordic countries (no data available from Iceland)
Sweden Norway Finland Denmark Total
Population Size (Millions)
(Total)
EBS
JEB
DDEB
RDEB
9 5 5 5 24
(93) (80) (37) (19) (229)
13 30 24 9 76
53 27 3 4 87
9 13 8 3 33
18 10 2 3 33
From Kero M. Occurrence of epidermolysis bullosa in Finland. Acta Derm Venereol 1984;64:57–62; Gedde-Dahl T. Epidermolysis bullosa: a clinical, genetic and epidemiological study. Oslo (Norway): Scandinavian University Books; 1971. p. 180; and Gedde-Dahl T. Epidemiology of epidermolysis bullosa in Scandinavia [abstract]. Acta Derm Venerol 2002;82:238.
a telephone call or an e-mail contact within days after the delivery, whereby a preliminary diagnosis is discussed over digital pictures. Concurrently, a specially trained nurse is alerted to assist the hospital staff and the family by visiting the birthplace. A skin biopsy is taken and send to the laboratory of Professor Leena Bruckner-Tuderman’s department in Freiburg, Germany (http://www.netzwerk-eb. de/index_eng.html) for immunofluorescence (IF)analysis of candidate proteins. In case of suspected JEB, a blood sample is send for screening of the LAMB3 hotspot mutation, whereas in suspected EBS, a screening of keratin mutation is made usually in collaboration with a research laboratory. Only rarely do we take biopsies for electron microscopy analysis. In Finland, the diagnostics and follow-up of patients with EB is focused in the dermatology clinics of 5 university hospitals where there is at least 1 dermatologist specialized in inherited skin diseases, especially Tampere University Hospital has long traditions in this field. After the birth, babies with severe EB are usually transferred to the pediatric intensive care units of the university hospitals, and dermatologists visit the newborns within 1 or 2 days after birth. Similar to Sweden, the diagnosis of EB in Finland is also based on IF-analysis of skin biopsies that is performed in Freiburg. The mutation analysis of patients with EB is made in collaboration with geneticists, and most of the samples are analyzed in Freiburg. Similar approaches are used in Denmark and in Norway where Rikshospitalet (in Oslo) is the leading center.
dental problems there are 2 specialized centers in Sweden (Jo¨nko¨ping and Gothenburg) to which patients are referred. Similar services are available in Norway at Rikshospitalet in Oslo together with the TAKO-center. Psychological support and lengthy discussions (sometimes via interpreter) about the disease and its consequences are essential and should be provided as soon as feasible. Wound management is taught to parents, adult patients, and in some cases also to accompanying hospital staff. When desirable, contacts are made between the family and the appropriate patient organization (eg, DebRA-Sweden, DebRA-Norway, DebRA-Finland). A special service for young patients that is very much appreciated by the families is provided by the A˚grenska and Frambue rehabilitation centers in Sweden and Norway, respectively. EB families are invited to stay for 1 week at these centers where they will meet specialists of all kinds teaching them about the disease and how to cope and deal with EB. The program also includes lectures and group discussions about the biology of skin and various inheritance patterns. General principles for wound care and future prospects for novel therapies are discussed. In Finland, there are no rehabilitation centers for patients with EB or other rare skin diseases; instead, the Finnish Central Organization for Skin Patients (Iholiitto ry) is organizing regularly rehabilitation courses for adult and young patients with EB and their families.
OTHER COLLABORATORS AND PATIENT EDUCATION
Every 3 years the Nordic EB Association arranges a 2-day symposium to which doctors, nurses, dentists and social workers dealing with patients with EB are invited. These meetings are rotated among the 4 Nordic countries, and the faculty
Pediatricians, physical therapists, geneticists, and dieticians are contacted whenever needed. For
EDUCATION OF HOSPITAL STAFF
Epidermolysis Bullosa Care in Scandinavia involves leading experts on EB from Scandinavia and abroad. This activity is also supported by the Nordic EB forum, which is a Web site where questions about EB can be asked and new information is distributed to professionals.
RESEARCH AND NEW IDEAS ABOUT THERAPY Norway has a long tradition of EB research (see the section ‘‘A short history’’) and more recent activities.5,6 In Finland, the current topics of the EB research include the molecular mechanisms of EB mutations and EB-associated squamous cell carcinomas.7,8 In Denmark and Sweden, there is a special interest in keratin mutations causing EBS.9,10 A new therapeutic concept was developed in Sweden to reduce hidrosis-induced precipitation of foot blisters in EBS. The idea to use plantar injections of botulinum toxin to prevent hyperhidrosis was originally described in patients with pachyonychia congenita,11 but this therapy has also proved beneficial in cases of EBS with ‘‘summer blisters.’’ A double-blind placebo controlled study of botulinum toxin in EBS is underway.
SUMMARY Specialized EB care in Scandinavia is mainly provided by dermatologists, pediatricians, and dentists working together in a team. This type of health service is facilitated in Sweden by the establishment of a national center for genodermatoses in Uppsala 10 years ago and by working in a network with many international collaborators (the European GENESKIN project). The increasing number of EB families with foreign ethnic backgrounds and language problems is a challenge to the health service, especially in Sweden, and demands increased facilities. Also, the high expectations by parents of children with JEB and RDEB about new, revolutionizing therapies (stem cell therapy, bone marrow transplantation, gene therapy) are challenges that can only be met by international collaboration and more research in specialized centers for EB. A close collaboration with patient organizations and various charity organizations will be very helpful in this respect.
ACKNOWLEDGMENTS The valuable discussions with Dr Anette Bygum Odense, Denmark and Dr Dorte Koss-Harness, Oslo, Norway are gratefully acknowledged.
REFERENCES 1. Kero M. Occurrence of epidermolysis bullosa in Finland. Acta Derm Venereol 1984;64:57–62. 2. Ryyna¨nen M, Knowlton RG, Parente G, et al. Human type VII collagen: genetic linkage of the gene (COL7A1) on chromosome 3 to dominant dystrophic epidermolysis bullosa. Am J Hum Genet 1991;49: 797–803. 3. Lai-Cheong JE, Liu L, Sethuraman G, et al. Five new homozygous mutations in the KIND1 gene in Kindler syndrome. J Invest Dermatol 2007;127(9): 2268–70. 4. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 2008; 58(6):931–50. 5. Koss-Harnes D, Høyheim B, Jonkman MF, et al. Lifelong course and molecular characterization of the original Dutch family with epidermolysis bullosa simplex with muscular dystrophy due to a homozygous novel plectin point mutation. Acta Derm Venereol 2004;84(2):124–31. 6. Koss-Harnes D, Høyheim B, Anton-Lamprecht I, et al. A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol 2002; 118(1):87–93. 7. Huilaja L, Hurskainen T, Autio-Harmainen H, et al. Glycine substitution mutations cause intracellular accumulation of collagen XVII and its affect posttranslational modifications. J Invest Dermatol 2009; 129:2302–6. 8. Kivisaari AM, Kallajoki M, Mirtti T, et al. Transformation-specific matric metalloproteinase (MMP)-7 nad MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas. Br J Dermatol 2008;158:778–85. 9. Chamcheu JC, Pavez-Lorie` E, Akgul B, et al. Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress conditions. J Dermatol Sci 2009; 53:198–206. 10. Sørensen CB, Andresen BS, Jensen UB, et al. Functional testing of keratin 14 mutant proteins associated with the three major subtypes of epidermolysis bullosa simplex. Exp Dermatol 2003;12(4): 472–9. 11. Swartling C, Vahlquist A. Treatment of pachyonychia congenita with plantar injections of botulinum toxin. Br J Dermatol 2006;154:763–5.
427
One of the first papers published on epidermolysis bullosa (EB) in Scandinavia was that of Gillis Herlitz (1902–1982) who, when working as a pediatrician at Uppsala University Hospital in the early 1930s, described a lethal form of the disease now known as junctional EB (JEB) of the Herlitz type. In the beginning of the 1960s, the Norwegian geneticist Tobias Gedde-Dahl (1938–2006) started his pioneering work on EB in Norway, whereby he personally visited and documented virtually all patients with EB, as well as described new forms of the disease, such as epidermolysis bullosa simplex (EBS)–Ogna. Dermatologist Matti Kero,1 in his thesis work, documented during the period between 1971 and 1980 the clinical and ultrastructural features of 121 patients affected by recessively inherited EB living in Finland. Research group of Professor Jouni Uitto, originally from Finland, was the first to discover the genetic linkage between the type VII collagen gene and dystrophic EB (DEB) in a large Finnish pedigree in 4 generations.2–4
EPIDEMIOLOGY The recessive forms of EB are relatively common in Scandinavia, especially in the northern parts of Norway and Sweden where a founder effect for LAMB3 gene mutation (R635X) causing JEBHerlitz has been noted. Table 1 shows very approximate figures for the number of Scandinavian families affected by EB reported during a period of 40 years. It can be seen that the prevalence of JEB and recessive DEB (RDEB) is highest in Norway and Sweden, whereas the other
EB subtypes seem to be more evenly distributed among the Nordic countries. The figures for the mild forms of EBS and dominant DEB are probably grossly underreported in this type of compilation from the literature. In a more recent questionnaire sent to all Swedish dermatologists and pediatricians, 39 patients with EBS, 5 with JEB, and 28 with DEB were identified (Wittbolt and Vahlquist, unpublished data, 2005). Only 6 of the DEB cases were of the recessive type; however a few of these patients died prematurely. The highest death rate is no doubt among patients with JEB-Herlitz of whom practically all babies die within 1 to 2 years, thus heavily reducing the prevalence of this EB subtype. Historically, about 1 child per year with JEB-Herlitz was born in Sweden. However the incidence of this subtype and RDEB is increasing, particularly in Sweden receiving many immigrants from countries where cousin marriage is common. This also introduces new types of mutations.
THE ORGANIZATION OF EB HEALTH SERVICES The care of EB in Scandinavia is organized around the patient via settings at the local hospital or health service. However, the diagnosis of EB and providing correct patient/family information usually require a specialized service, which in Sweden is provided at the Genodermatosis Center in Uppsala. This center mainly operates on an outpatient basis where patients come for 1 to 2 visits, either a couple of months after birth or in the case of older patients, whenever there is a need for improved diagnoses and information about EB. When a child with suspected EB is born in Sweden, there is usually
a
Department of Medical Sciences, Uppsala University, University Hospital, SE-751 85 Uppsala, Sweden Department of Dermatology, Clinical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland * Corresponding author. E-mail address: [email protected]
b
Dermatol Clin 28 (2010) 425–427 doi:10.1016/j.det.2010.02.018 0733-8635/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
derm.theclinics.com
A SHORT HISTORY
426
Vahlquist & Tasanen
Table 1 Estimated number of EB families in the Nordic countries (no data available from Iceland)
Sweden Norway Finland Denmark Total
Population Size (Millions)
(Total)
EBS
JEB
DDEB
RDEB
9 5 5 5 24
(93) (80) (37) (19) (229)
13 30 24 9 76
53 27 3 4 87
9 13 8 3 33
18 10 2 3 33
From Kero M. Occurrence of epidermolysis bullosa in Finland. Acta Derm Venereol 1984;64:57–62; Gedde-Dahl T. Epidermolysis bullosa: a clinical, genetic and epidemiological study. Oslo (Norway): Scandinavian University Books; 1971. p. 180; and Gedde-Dahl T. Epidemiology of epidermolysis bullosa in Scandinavia [abstract]. Acta Derm Venerol 2002;82:238.
a telephone call or an e-mail contact within days after the delivery, whereby a preliminary diagnosis is discussed over digital pictures. Concurrently, a specially trained nurse is alerted to assist the hospital staff and the family by visiting the birthplace. A skin biopsy is taken and send to the laboratory of Professor Leena Bruckner-Tuderman’s department in Freiburg, Germany (http://www.netzwerk-eb. de/index_eng.html) for immunofluorescence (IF)analysis of candidate proteins. In case of suspected JEB, a blood sample is send for screening of the LAMB3 hotspot mutation, whereas in suspected EBS, a screening of keratin mutation is made usually in collaboration with a research laboratory. Only rarely do we take biopsies for electron microscopy analysis. In Finland, the diagnostics and follow-up of patients with EB is focused in the dermatology clinics of 5 university hospitals where there is at least 1 dermatologist specialized in inherited skin diseases, especially Tampere University Hospital has long traditions in this field. After the birth, babies with severe EB are usually transferred to the pediatric intensive care units of the university hospitals, and dermatologists visit the newborns within 1 or 2 days after birth. Similar to Sweden, the diagnosis of EB in Finland is also based on IF-analysis of skin biopsies that is performed in Freiburg. The mutation analysis of patients with EB is made in collaboration with geneticists, and most of the samples are analyzed in Freiburg. Similar approaches are used in Denmark and in Norway where Rikshospitalet (in Oslo) is the leading center.
dental problems there are 2 specialized centers in Sweden (Jo¨nko¨ping and Gothenburg) to which patients are referred. Similar services are available in Norway at Rikshospitalet in Oslo together with the TAKO-center. Psychological support and lengthy discussions (sometimes via interpreter) about the disease and its consequences are essential and should be provided as soon as feasible. Wound management is taught to parents, adult patients, and in some cases also to accompanying hospital staff. When desirable, contacts are made between the family and the appropriate patient organization (eg, DebRA-Sweden, DebRA-Norway, DebRA-Finland). A special service for young patients that is very much appreciated by the families is provided by the A˚grenska and Frambue rehabilitation centers in Sweden and Norway, respectively. EB families are invited to stay for 1 week at these centers where they will meet specialists of all kinds teaching them about the disease and how to cope and deal with EB. The program also includes lectures and group discussions about the biology of skin and various inheritance patterns. General principles for wound care and future prospects for novel therapies are discussed. In Finland, there are no rehabilitation centers for patients with EB or other rare skin diseases; instead, the Finnish Central Organization for Skin Patients (Iholiitto ry) is organizing regularly rehabilitation courses for adult and young patients with EB and their families.
OTHER COLLABORATORS AND PATIENT EDUCATION
Every 3 years the Nordic EB Association arranges a 2-day symposium to which doctors, nurses, dentists and social workers dealing with patients with EB are invited. These meetings are rotated among the 4 Nordic countries, and the faculty
Pediatricians, physical therapists, geneticists, and dieticians are contacted whenever needed. For
EDUCATION OF HOSPITAL STAFF
Epidermolysis Bullosa Care in Scandinavia involves leading experts on EB from Scandinavia and abroad. This activity is also supported by the Nordic EB forum, which is a Web site where questions about EB can be asked and new information is distributed to professionals.
RESEARCH AND NEW IDEAS ABOUT THERAPY Norway has a long tradition of EB research (see the section ‘‘A short history’’) and more recent activities.5,6 In Finland, the current topics of the EB research include the molecular mechanisms of EB mutations and EB-associated squamous cell carcinomas.7,8 In Denmark and Sweden, there is a special interest in keratin mutations causing EBS.9,10 A new therapeutic concept was developed in Sweden to reduce hidrosis-induced precipitation of foot blisters in EBS. The idea to use plantar injections of botulinum toxin to prevent hyperhidrosis was originally described in patients with pachyonychia congenita,11 but this therapy has also proved beneficial in cases of EBS with ‘‘summer blisters.’’ A double-blind placebo controlled study of botulinum toxin in EBS is underway.
SUMMARY Specialized EB care in Scandinavia is mainly provided by dermatologists, pediatricians, and dentists working together in a team. This type of health service is facilitated in Sweden by the establishment of a national center for genodermatoses in Uppsala 10 years ago and by working in a network with many international collaborators (the European GENESKIN project). The increasing number of EB families with foreign ethnic backgrounds and language problems is a challenge to the health service, especially in Sweden, and demands increased facilities. Also, the high expectations by parents of children with JEB and RDEB about new, revolutionizing therapies (stem cell therapy, bone marrow transplantation, gene therapy) are challenges that can only be met by international collaboration and more research in specialized centers for EB. A close collaboration with patient organizations and various charity organizations will be very helpful in this respect.
ACKNOWLEDGMENTS The valuable discussions with Dr Anette Bygum Odense, Denmark and Dr Dorte Koss-Harness, Oslo, Norway are gratefully acknowledged.
REFERENCES 1. Kero M. Occurrence of epidermolysis bullosa in Finland. Acta Derm Venereol 1984;64:57–62. 2. Ryyna¨nen M, Knowlton RG, Parente G, et al. Human type VII collagen: genetic linkage of the gene (COL7A1) on chromosome 3 to dominant dystrophic epidermolysis bullosa. Am J Hum Genet 1991;49: 797–803. 3. Lai-Cheong JE, Liu L, Sethuraman G, et al. Five new homozygous mutations in the KIND1 gene in Kindler syndrome. J Invest Dermatol 2007;127(9): 2268–70. 4. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 2008; 58(6):931–50. 5. Koss-Harnes D, Høyheim B, Jonkman MF, et al. Lifelong course and molecular characterization of the original Dutch family with epidermolysis bullosa simplex with muscular dystrophy due to a homozygous novel plectin point mutation. Acta Derm Venereol 2004;84(2):124–31. 6. Koss-Harnes D, Høyheim B, Anton-Lamprecht I, et al. A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol 2002; 118(1):87–93. 7. Huilaja L, Hurskainen T, Autio-Harmainen H, et al. Glycine substitution mutations cause intracellular accumulation of collagen XVII and its affect posttranslational modifications. J Invest Dermatol 2009; 129:2302–6. 8. Kivisaari AM, Kallajoki M, Mirtti T, et al. Transformation-specific matric metalloproteinase (MMP)-7 nad MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas. Br J Dermatol 2008;158:778–85. 9. Chamcheu JC, Pavez-Lorie` E, Akgul B, et al. Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress conditions. J Dermatol Sci 2009; 53:198–206. 10. Sørensen CB, Andresen BS, Jensen UB, et al. Functional testing of keratin 14 mutant proteins associated with the three major subtypes of epidermolysis bullosa simplex. Exp Dermatol 2003;12(4): 472–9. 11. Swartling C, Vahlquist A. Treatment of pachyonychia congenita with plantar injections of botulinum toxin. Br J Dermatol 2006;154:763–5.
427