Brirish Journal of Dermatology (1979) 100, 207.
Case Reports
Hereditary angio-oedema: treatment with danazol REPORT OF A CASE GERHARD TAPPEINER*, HELMUT HINTNER*, JOSEF GLATZLf AND KLAUS WOLFF* •Department of Dermatology, and tDepartment of PediatxicS) University of Innsbruck, A-6020 Innsbruckj Austria Accepted for publication 19 June 1978
SUMMARY
An 8-year-oId boy with hereditary angio-oedema was treated with danazol under close endocrinological supervision. The boy's Ci esterase inhibitor (Ciinh) and C4 levels increased rapidly to near normal values under a daily dose of 400 mg and were maintained at about 50';,, of the normal by maintenance doses of 200 mg danazol every other day. Throughout the entire treatment period (i I months) the boy has been maintained free from attacks of angio-oedema. No hormonal imbalance was detected in the follow-up period. Our results indicate that danazol should be suitable for the treatment of HAE not only in adults but also in prepubescent children.
Hereditary angio-oedema (HAE), first described by Dinkelacker (1882) and Osier (1888), is characterized by episodes of oedema of the skin and mucous membranes, particularly of the oral cavity, larynx, pharynx and the gastrointestinal tract. These episodes occur suddenly and are usually selflimiting. Attacks can be precipitated by minor trauma or stress, but may occur without obvious provocation. Oedema of the intestinal mucosa may lead to colicky abdominal pain, and oedema of the laryngeal mucosa to acute airway obstruction. The latter complication is responsible for a considerable mortality, which has been estimated to be as high as 30",, (Frank, Gelfand & Atkinson, 1976). The disease is transmitted as an autosomal dominant trait (Osier, 1888). A defect of the serum inhibitor (Ciinh) of the activated form of the first complement component Ci,Ci esterase (Ci) and of plasmin, has been identified as the underlying cause of the disease (Donaldson & Evans, t963). Since Ci is constantly generated in the blood, either through the action of plasmin on Ci or 'spontaneously', the absence of Ciinh will permit uninhibited action of Ci on its substrate, the fourth Correspondence: Dr Gerhard Tappeiner, Department ol" Dermatology, University of Innsbruck, A-6020 Innsbruck, Austria. O0O7-O963/79/o2CX)-0207 $02.00 C) 1979 British Association of Dermatologists
207
2o8
G.Tappeiner et al.
complement component C4. C4 levels are therefore reduced in the serum of HAE patients. During a clinical attack, the activated C4 acts on its substrate, C2, the second complement component, which, in turn, leads to the liberation of a fragment from C2 (C2 kinin) which increases vasopermeabiiity and is thus believed responsible for the clinical manifestations of HAE (Donaldson, Rosen & Bing, 1977)Two biochemically distinct but clinically identical forms of the disease have been described (Rosen et al, 1975); in the common form, which accounts for about 80",, of cases, insufficient amounts of Ciinh are synthesized; in a variant form, normal or even elevated values of an antigcnically identical but functionally inactive protein are found in the serum. Until recently, the therapy of this condition was unrewarding. Fresh frozen plasma, containing Ciinh (Pickering et al, 1969) and partially purified Ciinh (Schulz, 1974) are helpful only during an attack or when an attack is anticipated, for instance, when surgery is to be performed. Plasmin inhibitors, such as epsilon-aminocaproic acid and tranexamic acid, have successfully been given prophylactically (Nilsson, Anderson & Bjorkman, 1966; Austen & Rosen, 1972; Blohme, 1972) but their value is seriously impaired by their side effects, such as increased predisposition to thrombosis, muscle fatigue and myositis. Androgens have also been employed as prophylactic agents (Spaulding, i960), but the side effects of long-term androgen therapy seriously limit their use. Recently, however, Gelfand et al. (1976) have shown that danazol*, a derivative of ethisterone, a pituitary gonadotropin inhibitor with only minimal androgenic properties (Potts, 1977) was dramatically effective in the treatment of 9 adults with HAE. This drug seems selectively to stimulate the production of functionally active Ciinh in either form of the disease, thus restoring to balance the complement and complement inhibitor system of patients with this condition. To our knowledge danazol has so far not been employed in the treatment of children with HAE and we therefore wish to report its successful use in the treatment of an 8-year-old boy. METHODS
Determinations of Ciinh and C4 levels were carried out using a standard radial immunodiffusion technique (Mancini, Carbonara& Heremans, 1965). Results were expressed as percent of normal as determined from a panel of fresh sera from randomly chosen healthy blood donors. Antiserum against Ciinh and radial immunodiffusion plates for C4 determination were purchased from Behringwerke, I" Total haemolytic complement was determined in a standard haemolytic system (Gewurz & Suyehira, 1976). In addition, the following laboratory tests were performed: routine haematology, urinary sediment and chemical analysis, clotting time, serum GOT, GPT, yGT, alkaline phosphatase, bilirubin, electrolytes, protein, creatinine and urea. Plasma levels of the following hormones were determined: ACTH, pituitary FSH and LH, cortisol, progesterone and testosterone. CASE REPORT
E.G., an 8-year-old white boy, gave a history of recurrent attacks of subcutaneous oedema on the face, trunk, genitalia and extremities; bouts of angio-ocdema of the larynx and pharynx produced marked respiratory distress and there was a history of recurring colicky abdominal pain. The attacks began when the patient was two years old; initially occurring only every 2 or 3 months, their frequency gradually increased to one attack per week at the time when the patient was first seen. Stress, a common cold, cold weather and trauma were reported as precipitating factors. •Danol", Winthrop Laboratories, Surbiton-on-Thames, Surrey. tBehringwerke, Marburg, FRG.
Danazoltreatment of HAE
209
The family history revealed similar symptoms in the boy's father. He had experienced frequent attacks of oedema in his childhood, but the signs and symptoms of the disease had gradually subsided during and immediately after puberty so that at the time of examination not more than two minor attacks of oedema occurred per year. No other family member was reported to have similar symptoms (Fig. I).
FIGURE I. Family tree of our patient, E.G. (arrow). The black symbols denote family members with proven HAE, the white symbols those without. The shaded symbols represent those who were not available for study but reportedly had no history of attacks of angio-oedema.
The serum levels of Ciinh and C4 were 30^',, and 24",, of the normal, respectively, in the propositus and 30",j and 33",, in his father, which confirmed that both had the common form of HAE. Total haemolytic complement was normal in both the mother and sister, who gave no history of angio-oedema and also had normal serum levels of Ciinh and C4. Other family members were unavailable for study. 400 T
400/200o,a 200 200aa mq danozol
lOO-i
60
120
150 ?\Q
FIGURE 2. Levels of Ciinh and C4 in our patient E.G. prior to and following treatment with danazol. The open columns show the C4 levels, the solid columns the Ciinh levels. Asterisks denote attacks of angio-oedema. Treatment was started on day zero. The daily danazol dosage is given by the figures above the bars, 'a.d.' denotes alternate day medication.
210
G.Tappeiner et al. TREATMENT
The dose of danazol administered to our patient, the clinical response and the effect of this treatment on the serum levels of Ciinh are shown in Fig. 2. Since exaa data on the dose requirements for HAE in children were not available and Gelfand (1976) had employed a dose of 600 mg in adults, treatment was provisionally started with 400 mg danazol daily and Ciinh levels were monitored regularly. There was a rapid increase of the Ciinh levels from 30*?,, before treatment to 60% after 3 days and to 80",, after 2 weeks of treatment. C4 levels increased accordingly and, clinically, attacks of angiooedema subsided. After the Ciinh level had reached normal values and the patient was still free of disease, the daily dose of danazol was lowered first to alternating doses of 200 mg and 400 mg, subsequently to 200 mg daily, and finally, 200 mg every other day (Fig. 2). One mild attack occurred while the patient was on the last regimen, but therapy was continued as before and there was no recurrence of angio-oedema. The Ciinh levels in the patient's serum, which had increased to normal levels during the high dose regimen, decreased again as the dosage of danazol was reduced, but were kept at about 50",, of the normal with a maintenance dose of 200 mg on alternate days. At the time of writing the patient has remained free of disease for 11 months and is now maintained on 200 mg of danazol given every other day. Clinical examinations and laboratory studies revealed no abnormal changes before and during danazol treatment. Alkaline phosphatase was at the upper limit of normal (700 iu; normal range for the age 120-700 iu), due to bone phosphatase as shown by isoenzyme studies, and coincided with a period of growth. The competitive radioligand assay of Creange & Potts (1974) revealed increased and danazol-dose dependent serum levels of what behaved in this assay like progesterone (43 7 ng/ml at 400/200 mg danazol on alternating days, 7-7 ng/ml at 200 mg danazol daily). Since danazol can interfere with this test (Lloyd-Jones et al.., 1977) the significance of this finding is questionable. Attempts to determine pregnanes during danazol treatment were unsuccessful because of a contaminating substance in the urine that was shown to be non-steroidal by mass spectroscopy.
DISCUSSION
Although the report of Gelfand et al. (1976) indicated that danazol may be the drug of choice for the treatment of HAE in adults and thus changed prevailing concepts on the treatment for this condition, there have so far been no reports on its use for the therapy of HAE in children. To our knowledge, the only group of children treated with danazol so far were patients with precocious puberty (Smith & Harris, 1977) in which condition the therapeutic effect of the drug is thought to be due to a pituitary gonadotropin inhibitory effect (Potts, 1977). No data are available on the effects of danazol on hormone functions of endocrinologically normal prepubescent children but there exists a possibility that it might affect pituitary function. Although no serious side effects of this drug have been seen so far (Potts, 1977; Spooner, 1977), its employment in our patient, an endocrinologically normal boy, was a matter of some concern. A risk-benefit ratio decision in favour of danazol treatment was reached in view of the fact that the condition of our patient had become considerably worse over the last few months and life-threatening episodes of laryngcal oedema had repeatedly occurred. The clinical effectiveness of the treatment and the absence of side effects have so far justified its use. Our experience with this therapy now spans 11 months during which time the patient has been kept free of disease, employing the maintenance dose of danazol described above. With this dose the patient's Ciinh level has remained about 5O'\> of the normal value, which is thought to be the threshold level below which attacks of angio-oedema can occur (Frank, Gelfand & Atkinson, 1976). Preliminary evidence from six studies cited by Blackmore (1977) suggests that the minimal clinically
Danazoltreatment of HAE
2il
effective dose of danazol in adults is 300 mg daily. Although exact figures are not given, this on a body weight basis would have to be much more than the 200 mg given every other day, which our patient who weighs 41 kg reqtiires. Based on an average body surface of i 73 m', this would be 173 mg/m- daily for adults, whereas our patient with a body surface area of 1-35 m- takes 148 mg/mevery other day. A larger series will be necessary, however, to determine whether children with HAE consistently require comparatively less danazol for maintenance therapy than adults. So far, our patient has tolerated this therapy very well and there is no evidence of hormonal imbalance or liver toxicity. A problem may arise when the patient enters puberty when close monitoring of clinical and hormonal parameters will be essential. It is in this context that the history of the patient's father appears interesting: he had sufFered from frequent and severe attacks up to the age of 14, but in the following 5 years his condition had spontaneously improved. He now has only very minor attacks so that even he considers treatment unnecessary. The reason for this improvement is not clear, but its coincidence with the age of pubescence suggests that increased androgen production may have been the cause, although improvement of the condition of male HAE patients with puberty is not a regular feature of the disease. This may be taken to suggest that spontaneous improvement and thus discontinuation of therapy may also be possible in our patient after puberty. Although more patients will have to be studied to prove this point, the experience with danazol therapy for HAE in our patient indicates that presently this is the drug of choice not only in adults, but also in children with HAE. ACKNOWLEDGMENTS
We thank Dr Horst Struckmeyer, Department of Pediatrics and Dr Siegfried Schwarz, Department of Experimental Pathology, both of University of Innsbruck, for performing the hormone assays and Winthrop Austria, Vienna for providing danazol. This study was supported in part by grant Nr. 3228 from the 'Fonds zur Forderung der wissenschaftlichen Forschung', Vienna and a research grant from Schering AG, Berlin. REFERENCES BLACKMOBE, W.P. (1977) Danazol in the treatment of hereditary angio-oedema. Journal of Imerrmtiona! Medical Research, 5, Suppl. 3, 38. BLOHME, G . (1972) Treatment of hereditary angioneurotic oedema with tranexamic acid: a random double-blind cross-over study. Acta medica scandinavica. 192,293. CREANGE, J.E. & POTTS, G . O . C1974) A competitive radioligand assay for Danazol (i7-a-pregn-4-en-2O-Yno (2, 3, -d) Isoxazol-17-OL) using pregnant guinea-pig plastna. Steroids, 23,411. DiNKKLACKER, E. (1882) Ober akutes Oedem. Diss, Kiel. DONALDSON, V.H. & EVANS, R.R. (1963) A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C l ziici3L%c. American Journal of Medicine, •i^,-^-]. DONALDSON, V.H., ROSEN, F.S. & BING, D.H. (1977) Role of the second component of complement (C2) and
plasmin in kinin release in hereditary angioneurotic edema (H.A.N.E.) plasma. Transactions of the American Association of Physicians, 90, 174. FRANK, M.M., GELFAND, J.A. & ATKINSON, J.P. {1976) Hereditary angio-oedema: the clinical syndrome and its
management. Annals of Internal Medicine, 84, 580. GKLFAND, J.A., SHERINS, R.J., ALLING, D.W. & FRANK, M.M. (1976) Treatment of hereditary angio-oedema
with danazol: Reversal of clinical and biochemical abnormalities. New England Journal of Medicine, 295, 1444. GEWURZ, H . & SUYEHIRA, L.A. (1976) Complement. In: Manual of Clinical Immunology (Ed. by N.R. Rose and H. Friedman). Amer. Soc. Microbiol., Washington. LLOVD-JONES, J.G., LABROSS, A . , WILLIAMS-ROSS, R.W., JR, EDELSON, J. & DAVISON C . (1977) Danazol plasma
concentration in man. Journal of International Medical Research, 5, Suppl. 3, 18.
212
G.Tappeiner et al.
MANCINI, G., CARBONARA, A . O . & HEREMANS, J.F. (1965) Itrmiunochcmical quantification of antigens by single radial immunodiffusion. Immunochemistryf 2, 235. NiLSSON, I.M., ANDERSSON, L . & BjORKMAN, S.E. (1966) Epsilon-aminocaproic acid (E-ACA) as a therapeutic agent based on 5 years' clinical experience. Acta medica scandinavica, (Suppl.) 44S, i. OsLER, W. (1888) Hereditary angio-neurotic oedema. American Journal of Aiedical Science, 95,362. PICKERING, R.J., KELLY, J.R., GOOD, R.A. & GEWURZ, H . (1969) Replacement therapy in hereditary angio-
oedema—successful treatment of two patients with fresh frozen plasma. Lancet, i, 326. POTTS, G.O. (1977) Pharmacology of dana?.ol. Journal of International Medical Research, 5, Suppl. 3,1. ROSEN, F.S., CHARACHE, P., PENSKY, J. & DONALDSON, V . H . (1965) Hereditary angioneurotic oedema: two
genetic variants. Science, 148, 957. SCHULZ, K.-H. (1974) Hereditares Quincke-Oedem. Neuere Wege der Thcrapie. Hautarzt, 25, 12. SHEFFER, A.L., AUSTEN, K . F . & ROSEN, F . S . (1972) Tranexamic acid therapy in hereditary angioneurotic edema. New EnglandJournal of Medicine, 287,452. SMITH, C . S . & HARRIS, F . (1977) Preliminary experience with danazol in children with precocious puberty. Journal of International Medical Research, 5, Suppl. 3,109. SPAULDING, W.B. (1960) Methyltestosterone therapy for hereditary episodic edema (hereditary angioneurotic edema). Annals of Internal Medicine, 53, 739. SPOONER, J.B. (1977) Classification of side-effects to danazol therapy, ^OUTMO/ of International Medical Research, 5, Suppl. 3, 15.
Case Reports
Hereditary angio-oedema: treatment with danazol REPORT OF A CASE GERHARD TAPPEINER*, HELMUT HINTNER*, JOSEF GLATZLf AND KLAUS WOLFF* •Department of Dermatology, and tDepartment of PediatxicS) University of Innsbruck, A-6020 Innsbruckj Austria Accepted for publication 19 June 1978
SUMMARY
An 8-year-oId boy with hereditary angio-oedema was treated with danazol under close endocrinological supervision. The boy's Ci esterase inhibitor (Ciinh) and C4 levels increased rapidly to near normal values under a daily dose of 400 mg and were maintained at about 50';,, of the normal by maintenance doses of 200 mg danazol every other day. Throughout the entire treatment period (i I months) the boy has been maintained free from attacks of angio-oedema. No hormonal imbalance was detected in the follow-up period. Our results indicate that danazol should be suitable for the treatment of HAE not only in adults but also in prepubescent children.
Hereditary angio-oedema (HAE), first described by Dinkelacker (1882) and Osier (1888), is characterized by episodes of oedema of the skin and mucous membranes, particularly of the oral cavity, larynx, pharynx and the gastrointestinal tract. These episodes occur suddenly and are usually selflimiting. Attacks can be precipitated by minor trauma or stress, but may occur without obvious provocation. Oedema of the intestinal mucosa may lead to colicky abdominal pain, and oedema of the laryngeal mucosa to acute airway obstruction. The latter complication is responsible for a considerable mortality, which has been estimated to be as high as 30",, (Frank, Gelfand & Atkinson, 1976). The disease is transmitted as an autosomal dominant trait (Osier, 1888). A defect of the serum inhibitor (Ciinh) of the activated form of the first complement component Ci,Ci esterase (Ci) and of plasmin, has been identified as the underlying cause of the disease (Donaldson & Evans, t963). Since Ci is constantly generated in the blood, either through the action of plasmin on Ci or 'spontaneously', the absence of Ciinh will permit uninhibited action of Ci on its substrate, the fourth Correspondence: Dr Gerhard Tappeiner, Department ol" Dermatology, University of Innsbruck, A-6020 Innsbruck, Austria. O0O7-O963/79/o2CX)-0207 $02.00 C) 1979 British Association of Dermatologists
207
2o8
G.Tappeiner et al.
complement component C4. C4 levels are therefore reduced in the serum of HAE patients. During a clinical attack, the activated C4 acts on its substrate, C2, the second complement component, which, in turn, leads to the liberation of a fragment from C2 (C2 kinin) which increases vasopermeabiiity and is thus believed responsible for the clinical manifestations of HAE (Donaldson, Rosen & Bing, 1977)Two biochemically distinct but clinically identical forms of the disease have been described (Rosen et al, 1975); in the common form, which accounts for about 80",, of cases, insufficient amounts of Ciinh are synthesized; in a variant form, normal or even elevated values of an antigcnically identical but functionally inactive protein are found in the serum. Until recently, the therapy of this condition was unrewarding. Fresh frozen plasma, containing Ciinh (Pickering et al, 1969) and partially purified Ciinh (Schulz, 1974) are helpful only during an attack or when an attack is anticipated, for instance, when surgery is to be performed. Plasmin inhibitors, such as epsilon-aminocaproic acid and tranexamic acid, have successfully been given prophylactically (Nilsson, Anderson & Bjorkman, 1966; Austen & Rosen, 1972; Blohme, 1972) but their value is seriously impaired by their side effects, such as increased predisposition to thrombosis, muscle fatigue and myositis. Androgens have also been employed as prophylactic agents (Spaulding, i960), but the side effects of long-term androgen therapy seriously limit their use. Recently, however, Gelfand et al. (1976) have shown that danazol*, a derivative of ethisterone, a pituitary gonadotropin inhibitor with only minimal androgenic properties (Potts, 1977) was dramatically effective in the treatment of 9 adults with HAE. This drug seems selectively to stimulate the production of functionally active Ciinh in either form of the disease, thus restoring to balance the complement and complement inhibitor system of patients with this condition. To our knowledge danazol has so far not been employed in the treatment of children with HAE and we therefore wish to report its successful use in the treatment of an 8-year-old boy. METHODS
Determinations of Ciinh and C4 levels were carried out using a standard radial immunodiffusion technique (Mancini, Carbonara& Heremans, 1965). Results were expressed as percent of normal as determined from a panel of fresh sera from randomly chosen healthy blood donors. Antiserum against Ciinh and radial immunodiffusion plates for C4 determination were purchased from Behringwerke, I" Total haemolytic complement was determined in a standard haemolytic system (Gewurz & Suyehira, 1976). In addition, the following laboratory tests were performed: routine haematology, urinary sediment and chemical analysis, clotting time, serum GOT, GPT, yGT, alkaline phosphatase, bilirubin, electrolytes, protein, creatinine and urea. Plasma levels of the following hormones were determined: ACTH, pituitary FSH and LH, cortisol, progesterone and testosterone. CASE REPORT
E.G., an 8-year-old white boy, gave a history of recurrent attacks of subcutaneous oedema on the face, trunk, genitalia and extremities; bouts of angio-ocdema of the larynx and pharynx produced marked respiratory distress and there was a history of recurring colicky abdominal pain. The attacks began when the patient was two years old; initially occurring only every 2 or 3 months, their frequency gradually increased to one attack per week at the time when the patient was first seen. Stress, a common cold, cold weather and trauma were reported as precipitating factors. •Danol", Winthrop Laboratories, Surbiton-on-Thames, Surrey. tBehringwerke, Marburg, FRG.
Danazoltreatment of HAE
209
The family history revealed similar symptoms in the boy's father. He had experienced frequent attacks of oedema in his childhood, but the signs and symptoms of the disease had gradually subsided during and immediately after puberty so that at the time of examination not more than two minor attacks of oedema occurred per year. No other family member was reported to have similar symptoms (Fig. I).
FIGURE I. Family tree of our patient, E.G. (arrow). The black symbols denote family members with proven HAE, the white symbols those without. The shaded symbols represent those who were not available for study but reportedly had no history of attacks of angio-oedema.
The serum levels of Ciinh and C4 were 30^',, and 24",, of the normal, respectively, in the propositus and 30",j and 33",, in his father, which confirmed that both had the common form of HAE. Total haemolytic complement was normal in both the mother and sister, who gave no history of angio-oedema and also had normal serum levels of Ciinh and C4. Other family members were unavailable for study. 400 T
400/200o,a 200 200aa mq danozol
lOO-i
60
120
150 ?\Q
FIGURE 2. Levels of Ciinh and C4 in our patient E.G. prior to and following treatment with danazol. The open columns show the C4 levels, the solid columns the Ciinh levels. Asterisks denote attacks of angio-oedema. Treatment was started on day zero. The daily danazol dosage is given by the figures above the bars, 'a.d.' denotes alternate day medication.
210
G.Tappeiner et al. TREATMENT
The dose of danazol administered to our patient, the clinical response and the effect of this treatment on the serum levels of Ciinh are shown in Fig. 2. Since exaa data on the dose requirements for HAE in children were not available and Gelfand (1976) had employed a dose of 600 mg in adults, treatment was provisionally started with 400 mg danazol daily and Ciinh levels were monitored regularly. There was a rapid increase of the Ciinh levels from 30*?,, before treatment to 60% after 3 days and to 80",, after 2 weeks of treatment. C4 levels increased accordingly and, clinically, attacks of angiooedema subsided. After the Ciinh level had reached normal values and the patient was still free of disease, the daily dose of danazol was lowered first to alternating doses of 200 mg and 400 mg, subsequently to 200 mg daily, and finally, 200 mg every other day (Fig. 2). One mild attack occurred while the patient was on the last regimen, but therapy was continued as before and there was no recurrence of angio-oedema. The Ciinh levels in the patient's serum, which had increased to normal levels during the high dose regimen, decreased again as the dosage of danazol was reduced, but were kept at about 50",, of the normal with a maintenance dose of 200 mg on alternate days. At the time of writing the patient has remained free of disease for 11 months and is now maintained on 200 mg of danazol given every other day. Clinical examinations and laboratory studies revealed no abnormal changes before and during danazol treatment. Alkaline phosphatase was at the upper limit of normal (700 iu; normal range for the age 120-700 iu), due to bone phosphatase as shown by isoenzyme studies, and coincided with a period of growth. The competitive radioligand assay of Creange & Potts (1974) revealed increased and danazol-dose dependent serum levels of what behaved in this assay like progesterone (43 7 ng/ml at 400/200 mg danazol on alternating days, 7-7 ng/ml at 200 mg danazol daily). Since danazol can interfere with this test (Lloyd-Jones et al.., 1977) the significance of this finding is questionable. Attempts to determine pregnanes during danazol treatment were unsuccessful because of a contaminating substance in the urine that was shown to be non-steroidal by mass spectroscopy.
DISCUSSION
Although the report of Gelfand et al. (1976) indicated that danazol may be the drug of choice for the treatment of HAE in adults and thus changed prevailing concepts on the treatment for this condition, there have so far been no reports on its use for the therapy of HAE in children. To our knowledge, the only group of children treated with danazol so far were patients with precocious puberty (Smith & Harris, 1977) in which condition the therapeutic effect of the drug is thought to be due to a pituitary gonadotropin inhibitory effect (Potts, 1977). No data are available on the effects of danazol on hormone functions of endocrinologically normal prepubescent children but there exists a possibility that it might affect pituitary function. Although no serious side effects of this drug have been seen so far (Potts, 1977; Spooner, 1977), its employment in our patient, an endocrinologically normal boy, was a matter of some concern. A risk-benefit ratio decision in favour of danazol treatment was reached in view of the fact that the condition of our patient had become considerably worse over the last few months and life-threatening episodes of laryngcal oedema had repeatedly occurred. The clinical effectiveness of the treatment and the absence of side effects have so far justified its use. Our experience with this therapy now spans 11 months during which time the patient has been kept free of disease, employing the maintenance dose of danazol described above. With this dose the patient's Ciinh level has remained about 5O'\> of the normal value, which is thought to be the threshold level below which attacks of angio-oedema can occur (Frank, Gelfand & Atkinson, 1976). Preliminary evidence from six studies cited by Blackmore (1977) suggests that the minimal clinically
Danazoltreatment of HAE
2il
effective dose of danazol in adults is 300 mg daily. Although exact figures are not given, this on a body weight basis would have to be much more than the 200 mg given every other day, which our patient who weighs 41 kg reqtiires. Based on an average body surface of i 73 m', this would be 173 mg/m- daily for adults, whereas our patient with a body surface area of 1-35 m- takes 148 mg/mevery other day. A larger series will be necessary, however, to determine whether children with HAE consistently require comparatively less danazol for maintenance therapy than adults. So far, our patient has tolerated this therapy very well and there is no evidence of hormonal imbalance or liver toxicity. A problem may arise when the patient enters puberty when close monitoring of clinical and hormonal parameters will be essential. It is in this context that the history of the patient's father appears interesting: he had sufFered from frequent and severe attacks up to the age of 14, but in the following 5 years his condition had spontaneously improved. He now has only very minor attacks so that even he considers treatment unnecessary. The reason for this improvement is not clear, but its coincidence with the age of pubescence suggests that increased androgen production may have been the cause, although improvement of the condition of male HAE patients with puberty is not a regular feature of the disease. This may be taken to suggest that spontaneous improvement and thus discontinuation of therapy may also be possible in our patient after puberty. Although more patients will have to be studied to prove this point, the experience with danazol therapy for HAE in our patient indicates that presently this is the drug of choice not only in adults, but also in children with HAE. ACKNOWLEDGMENTS
We thank Dr Horst Struckmeyer, Department of Pediatrics and Dr Siegfried Schwarz, Department of Experimental Pathology, both of University of Innsbruck, for performing the hormone assays and Winthrop Austria, Vienna for providing danazol. This study was supported in part by grant Nr. 3228 from the 'Fonds zur Forderung der wissenschaftlichen Forschung', Vienna and a research grant from Schering AG, Berlin. REFERENCES BLACKMOBE, W.P. (1977) Danazol in the treatment of hereditary angio-oedema. Journal of Imerrmtiona! Medical Research, 5, Suppl. 3, 38. BLOHME, G . (1972) Treatment of hereditary angioneurotic oedema with tranexamic acid: a random double-blind cross-over study. Acta medica scandinavica. 192,293. CREANGE, J.E. & POTTS, G . O . C1974) A competitive radioligand assay for Danazol (i7-a-pregn-4-en-2O-Yno (2, 3, -d) Isoxazol-17-OL) using pregnant guinea-pig plastna. Steroids, 23,411. DiNKKLACKER, E. (1882) Ober akutes Oedem. Diss, Kiel. DONALDSON, V.H. & EVANS, R.R. (1963) A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C l ziici3L%c. American Journal of Medicine, •i^,-^-]. DONALDSON, V.H., ROSEN, F.S. & BING, D.H. (1977) Role of the second component of complement (C2) and
plasmin in kinin release in hereditary angioneurotic edema (H.A.N.E.) plasma. Transactions of the American Association of Physicians, 90, 174. FRANK, M.M., GELFAND, J.A. & ATKINSON, J.P. {1976) Hereditary angio-oedema: the clinical syndrome and its
management. Annals of Internal Medicine, 84, 580. GKLFAND, J.A., SHERINS, R.J., ALLING, D.W. & FRANK, M.M. (1976) Treatment of hereditary angio-oedema
with danazol: Reversal of clinical and biochemical abnormalities. New England Journal of Medicine, 295, 1444. GEWURZ, H . & SUYEHIRA, L.A. (1976) Complement. In: Manual of Clinical Immunology (Ed. by N.R. Rose and H. Friedman). Amer. Soc. Microbiol., Washington. LLOVD-JONES, J.G., LABROSS, A . , WILLIAMS-ROSS, R.W., JR, EDELSON, J. & DAVISON C . (1977) Danazol plasma
concentration in man. Journal of International Medical Research, 5, Suppl. 3, 18.
212
G.Tappeiner et al.
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