Klin. Wschr. 53,679-684 (1975) - © by Springer-Verlag 1975

Hereditary Angioneurotic Oedema A. A g o s t o n i , B. M a r a s i n i , G . C . M a r t i g n o n i , M. C i c a r d i Istituto di Patologia Medica I dell'UniversitA di Milano L. Levi Divisione Dermatologica dell'Ospedale di Monza

Hereditiires angioneurotisches Odem. Zusammenfassung. Es wird fiber 3 Familien mit hereditgrem angioneurotischem Odem berichtet. Die Serum-Ci-INH- und C4Spiegel wurden bei 23 Familienmitgliedern immunochemisch bestimmt : Bei 6 Personen mit typischen Symptomen yon HANE und einem Familienmitglied ohne Krankheitserscheinungen wurden niedrige CI-INH- und C4-Spiegel gefunden. Vergleichsweise sind die Normalbereiche der beiden Proteine ffir Erwachsene, Kinder und Neugeborene angegeben. Die Autoren weisen auf die Bedeutung und Wichtigkeit einer rechtzeitigen Diagnose und Therapie hin. Schl~sselw6rter:Heredit/ires angioneurotisches 0dem, C~-Inhibitor, filE-Globulin (C4).

Summary. Three families with hereditary angioneurotic oedema (HANE) are described. Serum CI-INH and C4 immunochemical determinations were performed on 23 members of the families: in 6 persons low CI-INH and C4 levels were found with typical symptoms of HANE, and in one asymptomatic subject. Normal ranges of both proteins for adults, children and newborns are given for comparative purposes. The importance of the early diagnosis and treatment is emphasized. Key words:Hereditary angioedema, Ci-inhibitor, /~lE-globulin (C4).

H e r e d i t a r y a n g i o n e u r o t i c o e d e m a ( H A N E ) is a familial disease w i t h a n a u t o s o m a l d o m i n a n t inheritance, c h a r a c t e r i z e d clinically by p a r o x y s m a l e d e m a i n v o l v i n g the skin, the m u c o s a o f the g a s t r o i n t e s t i n a l a n d the u p p e r r e s p i r a t o r y tracts, a n d o c c a s i o n a l l y the u r i n a r y t r a c t a n d the brain. R e p o r t s o n this c o n d i t i o n c a n be t r a c e d b a c k to the last c e n t u r y ( M i l t o n , 1876; D i n k e l a c k e r , 1882; Q u i n c k e , 1882; Strfibing, 1885) b u t it was dist i n g u i s h e d f r o m the allergic t y p e o f a n g i o e d e m a b y Osler in 1888 (Osler, 1888) w h o was the first to n o t e the c h a r a c t e r i s t i c genetic aspect. I n 1963, D o n a l d s o n ( D o n a l d s o n et al., 1963) r e p o r t e d t h a t H A N E p a t i e n t s l a c k e d the s e r u m i n h i b i t o r d i r e c t e d a g a i n s t the C ' 1esterase ( C I - I N H ) . A l t h o u g h the p r o t e i n level is a b n o r m a l l y small o r even a b s e n t in the m a j o r i t y o f the p e r s o n s affected, a few cases ( a b o u t 15%) s h o w n o r m a l C I - I N H c o n c e n t r a t i o n s , b u t these are bioc h e m i c a l l y inactive ( R o s e n et al., 1965 ; A x e l s s o n et al.,

1971; L a u r e l l et al., 1968). L o w levels o f s e r u m ritEg l o b u l i n (C4) are r e p o r t e d in m o r e t h a n 9 9 % o f H A N E p a t i e n t s ( R u d d y et all 1973). Such s e r u m p a t t e r n have been k n o w n to p r e c e d e the o n s e t o f s y m p t o m s for years ( D o n a l d s o n etal., 1964; P i c k e r i n g etal., 1968; D e n n e y , 1970). T h r e e H A N E families a r e discussed in this p a p e r a n d the findings in their s e r u m C I - I N H a n d C4 p a t t e r n are r e p o r t e d . F o r c o m p a r a t i v e p u r p o s e s a n d in the a i m o f facilit a t i n g the d i a g n o s i s o f H A N E b y p r o v i d i n g a n o r m a l s e r u m p a t t e r n o f C I - I N H a n d C4, the a u t h o r s r e p o r t on such d e t e r m i n a t i o n s in the b l o o d o f n o r m a l adults, c h i l d r e n a n d n e w b o r n infants.

Materials and Methods CI-INH and C4 concentrations were determined in the sera of 23 subjects of three HANE families, in 57 normal children aged between 1 month and 12 years, and in the plasma of 13 newborns aged between 1 and 12 days. The control group consisted of 39 healthy individuals of either sex (age 21 to 30 years). Samples of venous blood were collected and then stored at - 2 0 ° C until examined. Ci-INH and C4 levels were determined by single radial immunodiffusion on cellulose acetate strips (Agostoni etal., 1970). Because standards with known CI-INH content were not avaib able, serum CI-INH levels were expressed as percentage of a normal serum pool. Serum concentrations of C4 were expressed in mg/ 100 ml, and to eliminate sex-related differences, as percentage of the normal mean value of the corresponding sex. The protein content in newborns, determined on plasma sampies, was referred to a normal plasma pool.

Results

1. Cl-INH and C4 Levels in Normal Subjects T h e m e a n + SE level o f s e r u m C I - I N H in n o r m a l a d u l t s was 99.46 + 2.71% o f a n o r m a l s t a n d a r d p o o l . N o significant difference was f o u n d b e t w e e n males a n d females.

A. A g o s t o n i et al. : H e r e d i t a r y A n g i o n e u r o t i c O e d e m a

680

totalled 41.85_+2.82 mg%. Both values were significantly higher in newborn infants than in older children (p < 0.001) and adults (p< 0.001). The results are summarized in Table 1.

The mean + SE level of serum C4 corresponded to 27.52+0.69mg%, these values are lower than those reported by Kholer (Kholer et al., 1967). The mean level of C4 was significantly higher in males (29.15 + 0.96) than in females (25.89 + 0.87) (p < 0.02). The mean + SE level of serum C i - I N H in normal children was 94.27 + 2 . 9 5 % of a normal standard pool. The mean + SE level of serum C4 was 24.13 _+ 1.13 mg%. Because no significant differences were observed neither for C I - I N H nor for C4 levels in children aged between 1 month to 12 years, subjects were grouped together. The C I - I N H levels were the same in adults as in children, while C4 concentrations were significantly higher in adults (p < 0.05). The mean + SE level of serum C I - I N H in newborns attained 124.05+5.98% of a normal pool, in the same subjects the mean _+SE level of serum C4

2. Cl-INHand C4 Levels in Members of HANE Families The results are summarized in Table 2. In all symptom-free family members but one (Family B, IV-17), serum C I - I N H and C4 concentrations were within the normal range. In the affected subjects both proteins were markedly decreased.

Case Reports Three Italian families are discussed and their pedigrees are shown in Fig. 1.

T a b l e 1. M e a n _+SE level o f s e r u m C i - I N H a n d C4 in n o r m a l adults, c h i l d r e n a n d n e w b o r n s . T h e v a l u e s o f C I - I N H as p e r c e n t a g e o f a n o r m a l s t a n d a r d pool. T h e v a l u e s o f C4 a r e expressed in rag/100

Adults Children Newborns

Age

N o o f cases

2 1 - 3 0 years 1 m o n t h - 12 y e a r s 1 - 12 d a y s

39 57 13

CI-INH 99.46_+2.71 94.27_+2.95 124.05+5.98 b

N o o f cases

C4

38 57 11

27.52_+0.69 24.13 -+ 1.13" 41.85+2.82 b

are expressed

a p < 0.05 b e t w e e n adults a n d children. b p < 0.001 b o t h v e r s u s a d u l t s a n d children.

T a b l e 2. S e r u m levels o f C i - I N H a n d C4 (expressed as p e r c e n t a g e o f the n o r m a l m e a n ) in m e m b e r s o f families A, B a n d C. A g e w h e n s y m p t o m s s t a r t e d a n d the m a i n s y m p t o m s a r e g i v e n

Family A

Family B

Family C

C i - I N H C4

A g e o f onset of symptoms

Prevailing symptom

Glottidal edema

II-6" III-13 I I I - 16 a

40 127 22

48 177 23

childhood childhood

abdominal cutaneous

+

IV-21 IV-22

126 168

114 132

-

-

79 79 99 22 56 82 22

106 97 63 14 97 120 15

childhood -

cutaneous -

II-3 II-4 II-5 II-6"

88 102 142 48

138 89 67 34

childhood

abdominal

-

III-9 III-10 III-11 III-13 I I I - 13 a

100 81 102 86 15

133 96 86 102 30

childhood

cutaneous

+

IV-15 IV-16 a

72 13

66 39

15 years

cutaneous

-

II-3 II-4 II-5 III-14 a III-15 III-16 IV-17 a

a H A N E patients.

+

+

A.Agostoni etal. : Hereditary Angioneurotic Oedema

Family A Case 1 (III-16). The proband is a 33 year-old woman. Since her early age she suffered from swelling of the limbs and recurrent episodes of abdominal pain. Only occasionally she did notice a possible triggering factor such as local trauma or emotional stress. At the age of 19 she had her first of the numerous episodes of laryngeal oedema in association with tooth extraction. On five occasions such attacks have warranted tracheostomy. On two later occasions the attacks were aborted by treatment with a kallikrein inhibitor (Trasylol-Bayer) intravenously. During the last year the patient was intermittently treated with tranexamic acid (AMCA): again she had mild localised swellings of the skin or abdominal pain, but no longer any laryngeal oedema. Case 2 0I-6). 68 year-old man, the patient's father. He complained of abdominal pain since infancy, but only recently has he experienced swelling of the skin. Last year he had an attack of laryngeal edema which was successfully treated by Trasylol infusions. One of the patient's cousins (III-11) and one brother (III-14) died of laryngeal oedema. An other brother (III-15) died of acute laryngeal oedema at the age of 20 months with the diagnosis of "diphtheria". Three other members of this family have HANE (Patients I-l, II-4 and II-5) and two died of laryngeal oedema (I-l, II-5).

FAMILY

681

A

II

6 7-

III

3

11

-12 13

IV I"/

19

18

FAMILY

22

B

III 7

21

20

8

9

10

~15 11 12 13 141~~6

iV 17

FAMILY

C

Family B Case 1 (III-14). The proband of this family is a 26 year-old man who has suffered from oedema of the skin since the age of 6 years. From that age until 24 he was free of symptoms. Over the last two years, he suffered two episodes of laryngeal oedema, the last one was associated with severe abdominal colic and vomiting, and ceased after an intravenous infusion of Trasylol. Treatment with AMCA was started at the age of six months, and since then he has never suffered from angioedema. Case 2 (II-6). The patient's mother died at the age of 37 from laryngeal edema. She has been known to have suffered from HANE symptoms localised in any part of the body. Case 3 (IV-17). The patient's daughter, a 3 year-old girl, despite very low amounts of serum CI-INH and C4, has never suffered from episodes typical of HANE.

Family C Case 1 (III- 19). The proband, a 44 year-old woman. She suffered from abdominal pain as long as she can remember. At the age of 13 she began to have acute

ii

III IV

4

91

d]s

"

12

15

÷

÷

14

16

Fig. l. Pedigrees of families A, B and C with hereditary angioneurotic oedema Female Male C) Unaffected [] Q~ Not studied, asymptomatic ~" [] • Symptomatic, have defect j Not studied, symptomatic [] Q Asymptomatic, have defect [] ÷ • + Death from laryngeal oedema [] + + Death possibly due to HANE [] + Q) + Death from unknown cause Sex not known Propositus

oedema in the limbs, genitalia and larynx. On several occasions such attacks had warranted tracheostomy. While only in some cases a clear relationship between

682

A. Agostoni et al. : Hereditary Angioneurotic Oedema

oedema and antecedent trauma or emotional stress was noted, it seems that there is always a prodromal phase lasting about 24 hours, which is characterised by a marked depression. The last episode of laryngeal oedema has been successfully treated by Trasylol infusion. AMCA was started in spring 1974: the intervals between HANE attacks seem to be longer. Case 2 (II-6). The patient's father, a 65 year-old man. He has a history of recurrent abdominal pain and circumscribed episodic oedema of the skin and he is free of symptoms since the age of 62. Case 3 (IV-16). The patient's daughter, 17 year-old girl, affected by congenital cataract. She had her first attack typical of HANE at the age of 15. The last episode of oedema involving face, arm and leg has apparently followed a mild local trauma. On that occasion AMCA and Trasylol were given without success.

Plasma transfusions successfully used to abort acute attacks already in progress (Pickering et al., 1969) have the theoretical disadvantage that substrate for C1 is transfused together with the inhibitor. Recent studies, however, confirmed the efficacy of such treatment in potentially life-threatening episodes of HANE (Cohen et al., 1972; Wfithrich et al., 1972; Beck et al., 1973; Misgeld et al., 1973; Ohela et al., 1973; Pickering, 1973). Data on the use of kallikrein inhibitor so far reported are only few (Donaldson, 1968; Juhlin et al., 1968): while in two patients of our series, attacks of laryngeal oedema promptly ceased after Trasylol infusions (Agostoni et al., 1973), recently such treatment failed to abort a severe swelling involving face and limbs. Although a really effective therapy should theoretically be represented by infusions of purified C' 1-esterase inhibitor, recently tried in two subjects (Brackertz et al., 1973a; Brackertz et al., 1973b), it is at present impractical because the protein is available for experimental use only.

Treatment

A wide variety of drugs (e.g. adrenalin, aspirin, cortisone, antihistamines, morphine, bromides, etc.) was recorded by Landerman (Landerman, 1962) and all agents were found ineffective in either preventing or aborting HANE attacks. Some successful prophylaxis of symptoms was reported using epsilon-aminocaproic acid (EACA) or its analogues as well as trans-4-(aminomethyl) cyclohexane carboxilic acid (tranexamic acid or AMCA). However the large dose of EACA required is a great inconvenience (Frank et al., 1972; Korsan-Bengtsen etal., 1969; Sheffer etal., 1972). AMCA, which can be administered at a much lower concentration, is less liable to produce side effects (Blohmb etal., 1972; Sheffer et al., 1972). The administration of methyltestosterone in small doses appeared to prevent swelling in certain HANE patients (Spaulding, 1960), but the side effects of this drug seriously compromise its use. Recently a new drug, suramin, an inhibitor of complement system was given in a prophylactic purpose (Fong et al., 1972; Brackertz et al., 1973a): further trials of this agent appear warranted because the available clinical data do not permit a definitive statement. For the treatment of acute attacks three possible methods of therapy are available: a) infusion of freshfrozen plasma, b) infusion of a plasmin and kallikrein inhibitor (Trasylol), and c) infusion of purified C' 1esterase inhibitor.

Discussion

Although HANE is a rare disorder, the prognostic implications make it an important disease that must be recognized by the physician. The clinical diagnosis is often difficult because the prevalent abdominal symptoms may be the presenting symptom of more common diseases. On the other hand, barium-meal examination, only if performed during the attack of an abdominal colic, shows a marked thickening of the mucosal folds in the small intestine. Moreover, angioedema of the skin rarely is pathognomic of HANE: swelling is episodic, localized, the affected area is firm, nonpruritic. Frequency and duration of episodes differ from patient to patient, and, in a same patient, from attack to attack. Laryngeal oedema is the most dramatic manifestation and it is the cause of death in 2 0 25% of cases (Freeman, 1971; Landerman, 1962). Mortality rate from glottidal oedema in affected members of the same family varies from 6 to 54% (Tedesco, 197l). HANE patients live in a continuous fear of laryngeal oedema, leading them to consult one doctor after another, to submit to numerous laboratory and physical investigations and to try many ineffective drugs. These observations indicate the critical need to recognize the disease by providing easy and reliable means of diagnosis. At present diagnosis is based on the following methods: 1) enzymatic assay of serum CI-INH, 2)

A.Agostoni

et al.

: Hereditary Angioneurotic Oedema

immunochemical determination of serum Ci-INH, and 3) immunochemical determinations of natural substrates of C' 1-esterase, C4 and C2. It has been said that the enzymatic test is the best criterion of diagnosis (Hartmann et al., 1974). However, according to other observations (Ohela et al., 1973; Ruddy et al., 1973), serum C4 immunochemical assay is as useful as enzymatic CI-INH estimation. In fact, the percentage of HANE patients with normal serum level of C4 is less than 1% (Ruddy et al., 1973). Moreover, such immunochemical method is fast and suitable, owing to the small amount of sample necessary for analysis and the low cost of the apparatus. Furthermore, also in the series of patients recently reported by Hartmann (Hartmann et al., 1974), while serum CI-INH and C2 levels are often within the normal range, serum C4 is present in an abnormally small amount in all the patients. In our opinion it is important to provide the clinician with a normal pattern of both serum proteins, either in the case of adults or children or even newborns. In fact, it is necessary to carry out such blood test on children of subjects with hereditary angioneurotic oedema as early as possible in order to provide a correct diagnosis and an useful treatment at the onset of symptoms. It is likely that some cases of sudden death for unknown cause or even "diphteria" in children of families with HANE history might be referred to unrecognized hereditary angioedema of the larynx.

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Cohen, G., Peterson, A. : Treatment of hereditary angioedema with frozen plasma. Ann. Allergy 30, 690 (1972) Dennehy, J.J. : Hereditary angioneurotic edema. Report of a large kindred with defect in C1 esterase inhibitor and review of the literature. Ann. Intern. Med. 73, 55 (1970) Diukelacker, E.: Uber akutes ()dem. Diss., Kiel, 1882, cited by Osler W. Donaldson, V.H., Evans, R.R. : A biochemical abnormality in hereditary angioneurotic edema : absence of serum inhibitor of C' 1esterase. Am. J. Med. 35, 37 (1963) Donaldson, V.H., Rosen, F.S. : Action of complement in hereditary angioneurotic oedema: the role of CI esterase. J. Clin. Invest. 43, 2204 (1964) Donaldson, V.H. : Mechanism of activation ofC'l esterase in hereditary angioneurotic edema plasma in vitro : the role of Hageman factor, a clot-promoting agent. J. exp. reed. 127, 411 (1968) Editorial: Hereditary angioneurotic oedema. Lancet I, 1044 (1973) Fong, J.S.C., Good, R.A. : Suramin - a potent reversible and competitive inhibitor of complement system. Clin. exp. Immunol. 10, 127 (1972) Frank, M.M., Sergent, J.S., Kane, M.A., Alling, D.V.: Epsilon aminocaproic acid therapy of hereditary angioneurotic edema. A double-blind study. New Engl. J. Med. 286, 808 (1971) Hartmann, L., Br6cy, H., Ollier, M.P., Rethore, O. : Une maladie mol~culaire: l'oed~me angioneurotique h~r6ditaire. Etude de seize families. Biombdicine 20, 294 (1974) Juhlin, L., Michaelsson, G.: Use of a kallikrein inhibitor in the treatment of urticaria and hereditary angioneurotic edema. Acta derm.-venereol. 49, 37 (1969) Kholer, P.F., M/iller-Eberhard, J.H.: Immunochemical quantitation of the third, fourth and fifth components of human complement: concentrations in the serum of healthy adults. J. Immunol. 99, 1211 (1967) Korsan-Bengtsen, K., Ysander, L., Blohm~, G., Tibblin, E. : Extensive muscle necrosis after long-term treatment with aminocaproic acid (EACA) in a case of hereditary periodic edema. Acta reed. scand. 185, 341 (1969) Landerman, N.S. : Hereditary angioneurotic edema. I. Case reports and review of the literature. J. Allergy 33, 316 (1962) Laurell, A.-B., Lindegren, J., Malmros, I., Mgtrtenson, H. : Enzymatic and immunochemical estimation of C1 esterase inhibitor in sera from patients with hereditary angioneurotic edema. Scand. J. Clin. Lab. Invest. 24, 221 (1968) Milton, J.L. : On giant urticaria. Edinbourgh Med. J. 22, 513 (1876) Misgeld, V., Schultz-Ehrenburg, U.: Zum Quincke-Odem (hereditfires Angio6dem). Med. Klin. 68, 693 (1973) Ohela, K., RS.sgnen, J.A., Wager, O.: Hereditary angio-neurotic edema. Genealogical and immunological studies. Ann. Clin. Res. 5, 174 (1973) Osler, W. : Hereditary angio-neurotic edema. Am. J. med. Sci. 95, 362 (1888) Picketing, R.J., Gewurz, H., Kelly, J.R., Good, R.A. : The complement system in hereditary angioneurotic edema. A new perspective. Clin. exp. Immunol. 3, 423 (1968) Pickering, R.J., Kelly, J.R., Good, R.A., Gewurz, H. : Replacement therapy in hereditary angioedema. Successful treatment of two patients with fresh frozen plasma. Lancet II, 326 (1969) Pickering, R.J. : Hereditary angioneurotic edema. Lancet I, 41 (1973) Quincke, H. : ~ber akutes umschriebenes Haut6dem. Monatschr. prackt. Dermat. 1, 129 (1882) Rosen, F.S., Charache, P., Pensky, J., Donaldson, V.H. : Hereditary angioneurotic edema: two genetic variants. Science 148, 957 (1965)

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Ruddy, S., Austen, K.F. : Inherited abnormalities of the complement system in man. In: "The metabolic basis of inherited diseases ", p. 1655, Stanbury, J.B., Wyngaarden, J.B., Fredrickson, D.S., Eds., McGraw-Hill Book Company, New York (1973) Sheffer, A.L., Austen, K.F., Rosen, F.S. : Tranexamic acid therapy in hereditary angioneurotic edema. New Engl. J. Med. 287, 452 (1972) Spaulding, W.B.: Methyltestosterone therapy for hereditary eposodicedema(hereditaryangionenroticedema). Ann. Intern, Med, 53, 739 (1960) Striibing, P. : ~ber akutes (angioneurotisches) Odem. Ztschr. klin. Med. 9, 381 (1885)

Tedesco, F..: I1 sistema del complementa in patologia umana. Rec. Progr. Med. 51, 501 (1971) Wtithrich, B., Grob, P. : Hereditfires Angio-Odem: neuere Therapiem6glichkeiten. Schweiz. Med. Wschr. 102, 349 (1972) Angelo Agostoni, M.D. Istituto di Patologia Medica I dell'UniversitY. Via Pace 15 20122 Milano Italy

Hereditary angioneurotic oedema.

Three families with hereditary angioneurotic oedema (HANE) are described. Serum CI-INH and C4 immunochemical determinations were performed on 23 membe...
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