Letters to the Editor
78
familial melanoma [8,9], (2) The protein encoded by C4AQO is more efficient than those marked by other alleles: a decreased frequency of this allele (C4AQO) means an impaired immune surveillance and a consequent incapacity to control toxic factors responsible for the disap pearance of melanocytes in vitiligo and for persistent stimulation resulting in malignant deviation. In this way multiple familial mel anomas and their earlier occurrence |8, 9] in life arc better explained. However it remains obscure what these noxious factors are: we cannot exclude a virus acting directly [10, 11] on melanocytes insufficiently protected by an inefficient immune system with an altered comple ment, or indirectly, by further damaging the immune system [12]. It must be stated that a reduced or increased activity of the comple ment system should interact with different targets and not just with melanocytes. Indeed vitiligo is known to be associated with different autoimmune diseases: such an association is not evident in familial mel anoma but it should be searched for carefully to gain further support for our hypothesis. In fact a more active interaction between a particular complement phenotype and a specific antigenic target (normal or genetically abnormal melanocyte and also other tissues) could be expected since glycoproteins on the cell surface may offer a more or less accessible site for activation of C3 and C4 [ 1]. In conclusion, a genctical predisposition for familial melanoma [3. 4. 8] and for vitiligo [6, 13. 14] has been already demonstrated: our observation of reduced frequency of C4AQO in both diseases suggests the possibility of a common genetic marker, playing a role in the path ogenesis and/or in the evolution of these diseases and. in particular, acting as a resistance factor for familial melanoma and for vitiligo.
Acknowledgements We arc grateful to Dr. A.B. Lerner, MD, for his invitation to visit his department in Yale: it was a useful stimulus for our work. We are also grateful to Dr. M.T. Illeni of 1st. Nazionale per lo Studio e la Cura dei Tumori for kindly referring the patients with familial melanoma to us. Research partially supported by Fondazione ‘Pro Ricerca Derma tológica’.
G. Orecchia, MD L. Pcrfctti. MD M. Cuccia, PhD O. Finco. PhD Dipartimento di Genética e Microbiología dell’Universita di Pavia Via S. Epifanio 14. 27100 Pavia (Italy) Clínica Dermatológica dell'Universitá di Pavia P. Ic Golgi 2. 27100-Pavia (Italy)
References 1 Porter RR: Complement polymorphism, the major histocompati bility complex and associated diseases: A speculation. Mol Biol Med 1983;1:161-168. 2 Porter RR: The molecular genetics of the components of comple ment and autoimmune diseases. Biol Essays 1984;6:261-264.
3 Milton GW. Balch CM. Shaw HM: Clinical characteristics: in Balch CM. Milton GW (eds): Cutaneous melanoma. Philadelphia, Lippincott, 1985, pp 13-28. 4 Budowle B. Barger BO, BalchcsCM.ct al: Associations of proper din factor B with melanoma. Can J Genet Cytol 1982;5:247-251. 5 De Paoli F, Cuccia Belvedere M. Finco O, Illeni MT, Pellegris G, Cascinelli N: C4 and Bf polymorphism in familial malignant mel anoma. Med Biol Environ 1988;16:307-315. 6 Orecchia G, Martinetti M. Finco O. et al: Different genetic mark ers in early onset and adult onset of sproadic vitiligo. J Invest Der matol 1989:92:495. 7 Lerner AB, Kirkwood JM: Vitiligo and melanoma: Can genetically abnormal melanocytes result in both vitiligo and melanoma within a single family? J Am Acad Dermatol 1984;11:696-701. 8 Kopf AW, Mintzis M. Robson W, et al: Familial malignant mel anoma. Cutis 1976;17:873-876. 9 Bork K, Brauningcr W, Nake A: Increased frequency of multiple familial melanomas in hereditary familial melanoma. Dermatoló gica 1981;162:191-196. 10 Birkmayer GD, Balada BR, Miller F: Oncorna-viral information in human melanoma. Eur J Cancer 1974;10:419-424. 11 Parsons PG, Goss P, Pope JH: Detection in human melanoma cells lines of particles with some properties in common with RN A tumor viruses. Int J Cancer 1974;13:606-618. 12 Riley V. Spackman D: Melanoma enhancement by viral induced stress. Pigment Cell 1976;2:163-173. 13 Haider RM, Grimes PE, Cowan CA, et al: Childhood vitiligo. J Am Acad Dermatol 1987;16:948-954. 14 Foley LM, Lowe NJ. Misheloft E. et al: Association of HLA-DR4 with vitiligo. J Am Acad Dermatol 1983;8:39-40.
Hereditary Angioedeina and Oral Contraception To the Editor Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by a quantitative or functional deficiency of Cl esterase inhibitor (Cl-INH) [1], Attacks of angioedema may be induced by a variety of factors, such as tissue trauma, infection, anx iety, and fatigue [1]. The condition apparently is further influenced by sexual hormones [2-4], Case Report. A 20-year-old previously healthy woman was given Diane® (containing 0.035 mg ethinyl estradiol and 2 mg cyproterone acetate) as treatment for acne. Three weeks after institution of the ther apy she experienced attacks of poorly circumscribed, nonpitting and nonpruritic cutaneous swellings, along with occasional abdominal pain. The edema involved particularly the extremities, the trunk and further pressure-exposed sites. The episodes lasted for up to 3 days and occurred weekly. After 2 months she changed to Trinordiol® (contain ing 0.05-0.125 mg levonorgestrel and 0.03-0.04 mg ethinyl estradiol) as oral contraceptive agent (OCA), but attacks persisted. She was therefore given Lutcnyl® (containing 5 mg of normegcstrol acetate) and she was free of symptoms until she discontinued OCA 2 months later. Responses to repeated pressure challenges were all the time nega tive. Extensive laboratory investigations, including search for autoan tibodies, did not reveal any abnormalities, except of the complement profile (table 1).
79
Letters to the Editor
.
Table 1 Complement profile 1 month after stop of OCA treatment Patient
Normal range
276
300 -516U/ml]
82 undetectable 1
70 -135% 80 —125%4 70 -130%5
0.04 114 115 0.93 0.07
0.11-0.26 g/1 75 -125% 67 -127% 0.75-1.40 g/1 0.14-0.35 g/1
gests that progestational agents, such as normegestrol acetate, may be of benefit in young women with hereditary angioedema requiring an oral contraception.
Functional assay C H s„
Functional Cl-INH Formation ofCl-INH-Clr complexes' Exog. Cls (amidolysis3) Exog. Cls (amidolysis) Protein concentrations6 Cl-INH Clr C2 C3/C3c C4
1 1 U corresponds to the amount of serum (ml), which lyses 50% of 3-106 optimally sensitized sheep erythrocytes within 45 min at 37 °C in a total volume of 0.5 ml. 2 This assay directly measures interaction of Cl-INH with its natural substrate, C lr, at physiologic concentrations of C lr and Cl-INH [according to 7], Based on inhibition by Cl-INH of amidolytic activity of exogenous Cls added to the sample to be tested, using commercially available test kits. 4 Kits from Beringwerke. Marburg, FRG. 5 Kits from Immuno, Vienna. Austria. 6 Assessed by ncphelometry or radial immunodiffusion using monospecific antisera.
Luca Borradori“, Odilc Marie“. Michel Rybojad“, Patrick Vexiaub, Patrice Morel“, Peter SpatlL “Departments of Dermatology and bEndocrinology Hopital Saint Louis University of Paris VII Paris (France); 'Central Laboratory of the Swiss Red Cross Transfusion Service Berne (Switzerland)
References 1 Guenther LC: Inherited disorders of complement. J Am Acad Der matol 1983;9:815-839. 2 Gordon EM. Ratnoff OD. Saito H, Donaldson VH. Pensky J. Jones PK: Rapid fibrinolysis, augmented Hageman factor (factor XII) titers, and decreased Cl esterase inhibitor titers in women taking oral contraceptives. J Lab Clin Med 1980;96:762-769. 3 Warin RP. Cunliffe WJ, Greaves MW, Wallington TB: Recurrent angioedema: Familial and oestrogen-induced. Br J Dermatol 1986; 115:731-734. 4 Böckers M. Bork K: Kontrazeption und Schwangerschaft beim hereditären Angioödem. Dtsche Med Wochenschr 1987; 112: 507- 509 .
5
The father of our patient, 3 of her paternal uncles and 1 aunt had a history of repeated attacks of angioedema. occasionally in association with the intake of salicylates and insect bites. Comment. In the present case clinical features, complement profile and family history are consistent with a diagnosis of hereditary angioe dema. In this disorder, the first clinical manifestations often occur dur ing puberty and symptoms may be further elicited or aggravated by menstruation, suggesting a direct relationship between hormonal changes and angioedema. In addition, angioedematous attacks induced by OCA have been rarely described [2-5]. In line with previous reports, our patient experienced the first symptoms shortly after institution of the OCA therapy [2-5], The estro gen-related compounds contained in the OCA appear to precipitate the attacks [2-5]. Cyproterone acetate has not been shown to aggravate clinical manifestations in hereditary Cl-INH deficiency [6], however, it has been recently implicated in the development of angioedema in female patients with normal Cl-INH function [5]. Interestingly, the swellings disappeared while the patient was on normegestrol acetate, a progestogen derived from 17-OH progester one. In fact, in order to avoid the frequent side effects observed in female patients with Cl-INH deficiency receiving long-term prophy lactic therapy with attenuated androgens, such as danazol. clinical effi cacy of synthetic progestatins with anabolic properties has been recent ly assessed [8]. Our observation thus confirms that OCA containing estrogens may precipitate potentially dangerous attacks of edema, and further sug
Pichler WJ, Lehncr R, Späth PJ: Recurrent angioedema associated with hypogonadism or anti-androgen therapy. Ann Allergy 1989; 63:301-305. 6 JaminC, Intrator L, Laurent J. Lagrue G : L’acétate de cyprotérone n’est pas actif pour la prophylaxie de l’oedème angioneurotique héréditaire. Presse Méd 1985,14:1559. 7 Späth PJ. Wüthrich B. Butler R: Quantification of Cl-inhibitor functional activities by immunodiffusion assay in plasma of patients with hereditary angioedema - evidence of functionally critical level of C-l-inhibitor concentration. Complement 1984; 1:147. 8 Laurent J. Jamin C, Lagrue G: Oedème angioneurotique hérédi taire: la norgestriénone n’est pas active dans tous les cas. Presse Méd 1987; 16:2132.
About the Association of Lichen planus and Psoriasis Sir, We read with interest the report by Shiohara et al. about the coex istence of lichen planus and psoriasis in a single patient in a recent issue of Dermatológica [1]. Between September 1986 and February 1988 the Gruppo Italiano Studi Epidcmiologici in Dermatología (GISED) conducted a multi-
78
familial melanoma [8,9], (2) The protein encoded by C4AQO is more efficient than those marked by other alleles: a decreased frequency of this allele (C4AQO) means an impaired immune surveillance and a consequent incapacity to control toxic factors responsible for the disap pearance of melanocytes in vitiligo and for persistent stimulation resulting in malignant deviation. In this way multiple familial mel anomas and their earlier occurrence |8, 9] in life arc better explained. However it remains obscure what these noxious factors are: we cannot exclude a virus acting directly [10, 11] on melanocytes insufficiently protected by an inefficient immune system with an altered comple ment, or indirectly, by further damaging the immune system [12]. It must be stated that a reduced or increased activity of the comple ment system should interact with different targets and not just with melanocytes. Indeed vitiligo is known to be associated with different autoimmune diseases: such an association is not evident in familial mel anoma but it should be searched for carefully to gain further support for our hypothesis. In fact a more active interaction between a particular complement phenotype and a specific antigenic target (normal or genetically abnormal melanocyte and also other tissues) could be expected since glycoproteins on the cell surface may offer a more or less accessible site for activation of C3 and C4 [ 1]. In conclusion, a genctical predisposition for familial melanoma [3. 4. 8] and for vitiligo [6, 13. 14] has been already demonstrated: our observation of reduced frequency of C4AQO in both diseases suggests the possibility of a common genetic marker, playing a role in the path ogenesis and/or in the evolution of these diseases and. in particular, acting as a resistance factor for familial melanoma and for vitiligo.
Acknowledgements We arc grateful to Dr. A.B. Lerner, MD, for his invitation to visit his department in Yale: it was a useful stimulus for our work. We are also grateful to Dr. M.T. Illeni of 1st. Nazionale per lo Studio e la Cura dei Tumori for kindly referring the patients with familial melanoma to us. Research partially supported by Fondazione ‘Pro Ricerca Derma tológica’.
G. Orecchia, MD L. Pcrfctti. MD M. Cuccia, PhD O. Finco. PhD Dipartimento di Genética e Microbiología dell’Universita di Pavia Via S. Epifanio 14. 27100 Pavia (Italy) Clínica Dermatológica dell'Universitá di Pavia P. Ic Golgi 2. 27100-Pavia (Italy)
References 1 Porter RR: Complement polymorphism, the major histocompati bility complex and associated diseases: A speculation. Mol Biol Med 1983;1:161-168. 2 Porter RR: The molecular genetics of the components of comple ment and autoimmune diseases. Biol Essays 1984;6:261-264.
3 Milton GW. Balch CM. Shaw HM: Clinical characteristics: in Balch CM. Milton GW (eds): Cutaneous melanoma. Philadelphia, Lippincott, 1985, pp 13-28. 4 Budowle B. Barger BO, BalchcsCM.ct al: Associations of proper din factor B with melanoma. Can J Genet Cytol 1982;5:247-251. 5 De Paoli F, Cuccia Belvedere M. Finco O, Illeni MT, Pellegris G, Cascinelli N: C4 and Bf polymorphism in familial malignant mel anoma. Med Biol Environ 1988;16:307-315. 6 Orecchia G, Martinetti M. Finco O. et al: Different genetic mark ers in early onset and adult onset of sproadic vitiligo. J Invest Der matol 1989:92:495. 7 Lerner AB, Kirkwood JM: Vitiligo and melanoma: Can genetically abnormal melanocytes result in both vitiligo and melanoma within a single family? J Am Acad Dermatol 1984;11:696-701. 8 Kopf AW, Mintzis M. Robson W, et al: Familial malignant mel anoma. Cutis 1976;17:873-876. 9 Bork K, Brauningcr W, Nake A: Increased frequency of multiple familial melanomas in hereditary familial melanoma. Dermatoló gica 1981;162:191-196. 10 Birkmayer GD, Balada BR, Miller F: Oncorna-viral information in human melanoma. Eur J Cancer 1974;10:419-424. 11 Parsons PG, Goss P, Pope JH: Detection in human melanoma cells lines of particles with some properties in common with RN A tumor viruses. Int J Cancer 1974;13:606-618. 12 Riley V. Spackman D: Melanoma enhancement by viral induced stress. Pigment Cell 1976;2:163-173. 13 Haider RM, Grimes PE, Cowan CA, et al: Childhood vitiligo. J Am Acad Dermatol 1987;16:948-954. 14 Foley LM, Lowe NJ. Misheloft E. et al: Association of HLA-DR4 with vitiligo. J Am Acad Dermatol 1983;8:39-40.
Hereditary Angioedeina and Oral Contraception To the Editor Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by a quantitative or functional deficiency of Cl esterase inhibitor (Cl-INH) [1], Attacks of angioedema may be induced by a variety of factors, such as tissue trauma, infection, anx iety, and fatigue [1]. The condition apparently is further influenced by sexual hormones [2-4], Case Report. A 20-year-old previously healthy woman was given Diane® (containing 0.035 mg ethinyl estradiol and 2 mg cyproterone acetate) as treatment for acne. Three weeks after institution of the ther apy she experienced attacks of poorly circumscribed, nonpitting and nonpruritic cutaneous swellings, along with occasional abdominal pain. The edema involved particularly the extremities, the trunk and further pressure-exposed sites. The episodes lasted for up to 3 days and occurred weekly. After 2 months she changed to Trinordiol® (contain ing 0.05-0.125 mg levonorgestrel and 0.03-0.04 mg ethinyl estradiol) as oral contraceptive agent (OCA), but attacks persisted. She was therefore given Lutcnyl® (containing 5 mg of normegcstrol acetate) and she was free of symptoms until she discontinued OCA 2 months later. Responses to repeated pressure challenges were all the time nega tive. Extensive laboratory investigations, including search for autoan tibodies, did not reveal any abnormalities, except of the complement profile (table 1).
79
Letters to the Editor
.
Table 1 Complement profile 1 month after stop of OCA treatment Patient
Normal range
276
300 -516U/ml]
82 undetectable 1
70 -135% 80 —125%4 70 -130%5
0.04 114 115 0.93 0.07
0.11-0.26 g/1 75 -125% 67 -127% 0.75-1.40 g/1 0.14-0.35 g/1
gests that progestational agents, such as normegestrol acetate, may be of benefit in young women with hereditary angioedema requiring an oral contraception.
Functional assay C H s„
Functional Cl-INH Formation ofCl-INH-Clr complexes' Exog. Cls (amidolysis3) Exog. Cls (amidolysis) Protein concentrations6 Cl-INH Clr C2 C3/C3c C4
1 1 U corresponds to the amount of serum (ml), which lyses 50% of 3-106 optimally sensitized sheep erythrocytes within 45 min at 37 °C in a total volume of 0.5 ml. 2 This assay directly measures interaction of Cl-INH with its natural substrate, C lr, at physiologic concentrations of C lr and Cl-INH [according to 7], Based on inhibition by Cl-INH of amidolytic activity of exogenous Cls added to the sample to be tested, using commercially available test kits. 4 Kits from Beringwerke. Marburg, FRG. 5 Kits from Immuno, Vienna. Austria. 6 Assessed by ncphelometry or radial immunodiffusion using monospecific antisera.
Luca Borradori“, Odilc Marie“. Michel Rybojad“, Patrick Vexiaub, Patrice Morel“, Peter SpatlL “Departments of Dermatology and bEndocrinology Hopital Saint Louis University of Paris VII Paris (France); 'Central Laboratory of the Swiss Red Cross Transfusion Service Berne (Switzerland)
References 1 Guenther LC: Inherited disorders of complement. J Am Acad Der matol 1983;9:815-839. 2 Gordon EM. Ratnoff OD. Saito H, Donaldson VH. Pensky J. Jones PK: Rapid fibrinolysis, augmented Hageman factor (factor XII) titers, and decreased Cl esterase inhibitor titers in women taking oral contraceptives. J Lab Clin Med 1980;96:762-769. 3 Warin RP. Cunliffe WJ, Greaves MW, Wallington TB: Recurrent angioedema: Familial and oestrogen-induced. Br J Dermatol 1986; 115:731-734. 4 Böckers M. Bork K: Kontrazeption und Schwangerschaft beim hereditären Angioödem. Dtsche Med Wochenschr 1987; 112: 507- 509 .
5
The father of our patient, 3 of her paternal uncles and 1 aunt had a history of repeated attacks of angioedema. occasionally in association with the intake of salicylates and insect bites. Comment. In the present case clinical features, complement profile and family history are consistent with a diagnosis of hereditary angioe dema. In this disorder, the first clinical manifestations often occur dur ing puberty and symptoms may be further elicited or aggravated by menstruation, suggesting a direct relationship between hormonal changes and angioedema. In addition, angioedematous attacks induced by OCA have been rarely described [2-5]. In line with previous reports, our patient experienced the first symptoms shortly after institution of the OCA therapy [2-5], The estro gen-related compounds contained in the OCA appear to precipitate the attacks [2-5]. Cyproterone acetate has not been shown to aggravate clinical manifestations in hereditary Cl-INH deficiency [6], however, it has been recently implicated in the development of angioedema in female patients with normal Cl-INH function [5]. Interestingly, the swellings disappeared while the patient was on normegestrol acetate, a progestogen derived from 17-OH progester one. In fact, in order to avoid the frequent side effects observed in female patients with Cl-INH deficiency receiving long-term prophy lactic therapy with attenuated androgens, such as danazol. clinical effi cacy of synthetic progestatins with anabolic properties has been recent ly assessed [8]. Our observation thus confirms that OCA containing estrogens may precipitate potentially dangerous attacks of edema, and further sug
Pichler WJ, Lehncr R, Späth PJ: Recurrent angioedema associated with hypogonadism or anti-androgen therapy. Ann Allergy 1989; 63:301-305. 6 JaminC, Intrator L, Laurent J. Lagrue G : L’acétate de cyprotérone n’est pas actif pour la prophylaxie de l’oedème angioneurotique héréditaire. Presse Méd 1985,14:1559. 7 Späth PJ. Wüthrich B. Butler R: Quantification of Cl-inhibitor functional activities by immunodiffusion assay in plasma of patients with hereditary angioedema - evidence of functionally critical level of C-l-inhibitor concentration. Complement 1984; 1:147. 8 Laurent J. Jamin C, Lagrue G: Oedème angioneurotique hérédi taire: la norgestriénone n’est pas active dans tous les cas. Presse Méd 1987; 16:2132.
About the Association of Lichen planus and Psoriasis Sir, We read with interest the report by Shiohara et al. about the coex istence of lichen planus and psoriasis in a single patient in a recent issue of Dermatológica [1]. Between September 1986 and February 1988 the Gruppo Italiano Studi Epidcmiologici in Dermatología (GISED) conducted a multi-
![[Hereditary angioedema].](/assets/img/hold.png)
