Angioedema, Hereditary, Type I

A number sign (#) is used with this entry because hereditary angioedema types I and II are caused by heterozygous mutation in the C1 inhibitor gene (C1NH, SERPING1; 606860) on chromosome 11q. HAE caused by homozygous mutation in the C1NH gene has also been reported.

Another type of hereditary angioedema, HAE type III (610618), is caused by mutation in the gene encoding coagulation factor XII (F12; 610619) on chromosome 5q.

Description

Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. There are 2 classic types of the disorder. In type I, representing 85% of patients, serum levels of C1NH are less than 35% of normal (Cicardi and Agostoni, 1996; Bowen et al., 2001). In type II, the levels are normal or elevated, but the protein is nonfunctional. The 2 types are clinically indistinguishable.

See 300145 for a discussion of angioedema induced by ACE inhibitors.

Zuraw (2008) provided a detailed review of the clinical features, management, and pathogenesis of hereditary angioedema.

Clinical Features

Edema of the larynx and other portions of the airways is the most fearsome feature of this disorder. Visceral involvement with abdominal pain can lead to unnecessary laparotomy (Weinstock et al., 1987; Waytes et al., 1996).

Weinstock et al. (1987) described a family in which lifelong abdominal pain was the only manifestation of hereditary angioedema. A 40-year-old man, 2 of his brothers, his mother, and his daughter were affected. In addition to abdominal pain, nausea, diarrhea, and vomiting occurred, but there were no cutaneous, oropharyngeal, or respiratory manifestations. Barium studies during painful attacks showed transient intestinal wall edema.

In rare patients the deficiency is acquired, with symptoms first emerging well into adulthood. Jackson et al. (1986), Alsenz et al. (1987), and Malbran et al. (1988) described patients with acquired C1 inhibitor deficiency resulting from anti-C1NH autoantibodies. These patients had no evidence of an underlying disease, followed a benign course, and showed variable responses to therapy. Frigas (1989) described a patient with acquired C1 inhibitor deficiency who had no evidence of underlying disease 11 years after onset.

Muhlemann et al. (1987) found an increased frequency of thyroglobulin antibodies and thyroid microsomal antibodies in patients with hereditary angioedema. They reported the occurrence of systemic lupus erythematosus and glomerulonephritis in patients with this disorder.

Perricone et al. (1992) concluded that polycystic ovaries (PCO syndrome; 184700) or multifollicular ovaries occur with unusually high frequency in women with HANE. Weidenbach et al. (1993) reported a 25-year-old woman, with no family history of the disorder, in whom infectious mononucleosis appeared to precipitate the acute onset of HAE.

Yakushiji et al. (2007) reported a 35-year-old woman who presented with rapid onset of severe numbness and weakness of all 4 extremities. Detailed laboratory investigations revealed decreased serum levels of several complement components, including C2, C4, C1q, and C1INH. Nerve conduction studies indicated a sensorimotor axonal peripheral neuropathy. Peripheral nerve biopsies showed enlarged nerves with vasculitis and lymphocytic infiltration; most of the proliferating capillaries were strongly positive for anti-C1q, consistent with activation of the classic complement pathway. There was also a decrease of myelinated fibers and axonal degeneration. The patient's asymptomatic mother and sister were also found to have decreased serum C1INH, prompting the diagnosis of HAE, which was confirmed by genetic analysis. Yakushiji et al. (2007) noted that vasculitic neuropathy had not previously been described in patients with HAE.

Association with Lymphoproliferative Disorders

Angioedema due to acquired C1 inhibitor deficiency has been associated with benign or malignant B-cell lymphoproliferative disorders such as chronic lymphocytic leukemia, multiple myeloma, or essential cryoglobulinemia (Gelfand et al., 1979) and is due not to defective synthesis but to markedly increased catabolism of the C1 inhibitor protein. Frigas (1989) reported a patient with angioedema associated with a B-cell lymphoproliferative disorder that became evident 9 months after C1NH deficiency was diagnosed.

Diagnosis

Laurent et al. (1988) showed that sonographic demonstration of fluid in the abdomen in association with an attack of abdominal pain could be used in diagnosis.

Prenatal Diagnosis

Stoppa-Lyonnet et al. (1987) suggested that unique familial variants of the C1NH gene may be used for prenatal or early diagnosis of the disease. In 1 subject in an affected family, the C1 inhibitor level determined at birth in cord blood was inconclusive. Later the measurement showed a level in agreement with the diagnosis predicted by DNA analysis.

Biochemical Features

Three types of C1 esterase inhibitor were described by Rosen et al. (1971) in different families with angioneurotic edema. Immunologically, one group had levels of inhibitor (an alpha-2 neuraminoglycoprotein) 17.5% of normal, a second group had levels 111% of normal, and a third group represented by affected persons in a single kindred had levels more than 400% of normal. Although immunologically identical, the three types of inhibitor differed in electrophoretic and other characteristics from the normal and from each other.

Pathogenesis

From immunofluorescence studies, Johnson et al. (1971) concluded that deficient hepatic synthesis of C1 inhibitor is the basis of the deficiency in plasma inhibitor.

Cicardi et al. (1982) reported on 104 cases in 31 families. In 22%, functionally defective C1 esterase inhibitor was present (HANE type II). In 78%, both antigen levels and functional activity of C1 esterase inhibitor were low (HANE type I).

Quastel et al. (1983) studied the catabolism of C1 inhibitor in HANE I. The fact that serum concentrations of a structurally normal C1 inhibitor is 5 to 31% of normal rather than the 50% expected in heterozygotes is explained, the authors suggested, by the presence of only one functional gene and increased catabolism of the protein. On the basis of in vivo turnover studies, Quastel et al. (1983) suggested that there is activation of C1 or other protease systems in which this protein acts as an inhibitor. This, in turn, could lead to consumption of normal C1 inhibitor that falls below normal.

Although the hepatocyte is the main site of synthesis of the inhibitor, cultured human peripheral blood monocytes also synthesize and secrete this protein. Cicardi et al. (1987) found that in the supernatant of such cells, the inhibitor was present at levels of about 20% of normal, whereas intracellular reduction approached 50%. The Northern blot analysis showed inhibitor mRNA to be present at about half-normal concentrations. One of the patients showed a genetically abnormal mRNA (1.9 kb) in addition to the normal mRNA (2.1 kb).

To ascertain the mechanism for decreased synthesis of C1 inhibitor in certain patients with type I HANE, Kramer et al. (1993) studied expression of C1NH in fibroblasts in which the mutant and wildtype mRNA and protein could be distinguished because of deletion of exon 7 (606860.0001). In the mutant cells, the amount of wildtype mRNA was expressed at 52% of normal, whereas the mutant mRNA was 27% of normal. Rates of synthesis of both wildtype and mutant proteins were lower than predicted from the mRNA levels. There was no evidence of increased C1NH protein catabolism. Thus, there appear to be multiple levels of control of C1NH synthesis in type I HANE. Pretranslational regulation results in less than 50% of the mutant truncated 1.9-kb mRNA; translational regulation results in decreased synthesis of both wildtype and mutant proteins. These data suggested a transinhibition of wildtype C1NH translation by mutant mRNA and/or protein.

In an editorial, Cicardi and Agostoni (1996) used an instructive diagram to demonstrate the pathophysiology of hereditary angioedema.

Inheritance

A considerable number of kindreds with angioneurotic edema transmitted in a typical autosomal dominant pattern have been described. In the family studied by Trigg (1961), about twice as many males as females were affected. A family studied by Donaldson and Rosen (1964) had previously been reported by Heiner and Blitzer (1957). Cohen (1961) described a family with many cases in 5 generations. Although reported as giant urticaria, the same family was studied by Rosen et al. (1965) and shown to have a defect in a component of complement. Agostoni and Cicardi (1992) pointed out that in more than 20% of those with hereditary angioedema, the mutations are de novo and therefore there is no family history of the disease.

Verpy et al. (1996) found a homozygous mutation (606860.0013) in a promoter for the C1NH gene in 2 affected members of a family. In this family, homozygosity correlated with low C1 inhibitor levels and severe HANE. In contrast, heterozygotes for this mutation had C1 inhibitor within the normal range, although often at its lower level, and were free of angioedema attacks. These results suggest autosomal recessive inheritance of this mutation. Other patients with HAE caused by homozygous mutation in the C1NH gene have been reported (see, e.g., 606860.0015 and 606860.0017 reported by Blanch et al., 2006 and Bafunno et al., 2013, respectively).

Mapping

Theriault et al. (1989, 1990) used in situ hybridization to map the human C1 inhibitor gene (606860) to chromosome 11q11-q13.1.

Clinical Management

Nzeako et al. (2001) and Winkelstein and Colten (1989) reviewed the clinical features and therapy of HANE.

Spaulding (1960) and Dennehy (1970) described apparently effective prophylaxis with testosterone, and Frank et al. (1972) reported that epsilon aminocaproic acid is efficacious in treatment. The therapeutic benefit of Danazol, an 'impeded' androgen, is of interest from the point of view of the basic defect in this disorder (Gelfand et al., 1976). Danazol also raises the levels of the deficient protein in alpha-1-antitrypsin deficiency (Gadek et al., 1980) and in hemophilias A and B (Gralnick and Rick, 1983). Cicardi et al. (1982) found concentrates of C1 inhibitor to be effective and without side effects in the treatment of severe acute attacks. Androgen derivatives were useful for long-term prophylaxis.

Sheffer et al. (1988) reported that stanozolol is a safe and effective agent. Borum and Howard (1998) stated that prophylactic therapy with attenuated androgens or antifibrinolytic agents is useful, and that plasma concentrate of C1NH is the treatment of choice in an acute episode.

Waytes et al. (1996) concluded that infusions of vapor-heated C1 inhibitor concentrate are a safe and effective means of both preventing attacks of hereditary angioedema and treating acute attacks. The concentrate was vapor-heated to inactivate hepatitis and human immunodeficiency viruses.

Zuraw et al. (2010) conducted 2 randomized trials to evaluate nanofiltered C1 inhibitor concentrate with placebo for treatment of an acute attack of angioedema. A total of 68 subjects (35 in the C1 inhibitor group and 33 in the placebo group) were given 1 or 2 intravenous injections of the study drug (1,000 units each). The primary endpoint was the time to the onset of unequivocal relief. In this study, the median time to the onset of unequivocal relief from an attack was 2 hours in the subjects treated with C1 inhibitor concentrate but longer than 4 hours in those given placebo (P = 0.02). The second study was a crossover trial involving 22 subjects with hereditary angioedema that compared prophylactic twice-weekly injections of nanofiltered C1 inhibitor concentrate (1,000 units) with placebo during two 12-week periods. The primary endpoint was the number of attacks of angioedema per period, with each subject acting as his or her own control. In this study, the number of attacks per 12-week period was 6.26 with C1 inhibitor concentrate given as prophylaxis, as compared with 12.73 with placebo (P less than 0.001); the subjects who received the C1 inhibitor concentrate also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling.

Cicardi et al. (2010) performed a double-blind, placebo-controlled clinical trial in which patients with hereditary angioedema presenting with an acute attack were randomly assigned in a 1-to-1 ratio to receive subcutaneous ecallantide at a dose of 30 mg or placebo. Patients were evaluated using treatment outcome scores and change from baseline in the mean symptom complex severity score. The primary endpoint was the treatment outcome score 4 hours after study-drug administration. A total of 71 of the 72 patients completed the trial. The median treatment outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in the placebo group (interquartile range (IQR), 0.0 to 100.0 in both groups; P = 0.004). The median change in the mean symptom complex severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (P = 0.01). The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (P = 0.14). There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events.

Cicardi et al. (2010) described 2 double-blind, randomized, multicenter trials in which they evaluated the effect of icatibant, a selective bradykinin B2 receptor (113503) antagonist, in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST)-1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary endpoint was the median time to clinically significant relief of symptoms. A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary endpoint was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P = 0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P less than 0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.

In an accompanying editorial to the articles by Zuraw et al. (2010), Cicardi et al. (2010), and Cicardi et al. (2010), Morgan (2010) suggested that the existence of several agents available to treat hereditary angioedema will significantly improve survival for affected individuals.

Wuillemin (2011) commented on the studies of Zuraw et al. (2010), Cicardi et al. (2010), and Cicardi et al. (2010) and noted the availability of a pasteurized C1 inhibitor preparation in several European countries. He also mentioned the successful experience in Switzerland of C1 inhibitor concentrate self-administration, with regular practical training, for hereditary angioedema patients, and concluded that self-administration leads to better medical outcome and enhanced quality of life. Zuraw (2011) concurred. Morgan (2011) noted that guidelines and requirements for possession and self-administration of C1 inhibitor would exclude many patients, including children, and that practitioners fear that drug use would escalate as patients treat minor swellings or false prodromes. He suggested that the Swiss experience might provide reassurance about these matters, and that available data should be disseminated.

Referring to the studies of Cicardi et al. (2010) and Cicardi et al. (2010), Giavina-Bianchi et al. (2011) stated that the registration in only a few countries of formulations of C1 esterase-inhibitor concentrate is not an adequate justification to use a placebo comparison drug, and called for studies comparing icatibant and ecallantide with C1 esterase-inhibitor concentrate. Cicardi and Banerji (2011) replied that since their studies were performed in accordance with both the Declaration of Helsinki and expert consensus, they considered them ethically acceptable.

To test the efficacy and safety of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in prevention of hereditary angioedema attacks, Banerji et al. (2018) conducted a phase 3 randomized, double-blind, parallel-group, placebo-controlled clinical trial at 41 sites in Canada, Europe, Jordan, and the US for 26 weeks in 125 patients aged 12 years and older (mean age 40.7 years). All 3 lanadelumab treatment regimens produced significantly significant reductions in the mean attack rate, number of attacks requiring acute treatment, and number of moderate or severe attacks compared with placebo. A total of 38.1% of patients treated with lanadelumab were attack-free over the entire treatment period. The majority (93.3%) of adverse events were related to the injection site. Banerji et al. (2018) concluded that their results supported the use of lanadelumab as a prophylactic therapy for hereditary angioedema.

Management in Pregnancy

Chappatte and De Swiet (1988) gave an account of pregnancy in 2 patients with HANE. They suggested that prophylaxis against attacks should not be used during pregnancy and that severe attacks should be treated with purified C1NH concentrate.

Cox and Holdcroft (1995) discussed the management of pregnancy and delivery in a 20-year-old primiparous woman with a history of type I HAE first diagnosed at age 12. She had been treated with an attenuated androgen in low dose (danazol and then amicar), which raised her C1 esterase inhibitor level and controlled her symptoms. Danazol rendered the patient oligomenorrheic. Since it is also teratogenic (Duck and Katayama, 1981), it was withdrawn under hospital observation when she decided to start a family. The recurrent symptoms were controlled with intravenous administration of C1 esterase inhibitor. Vaginal delivery in HAE may be impeded by perineal edema and abdominal pain may obscure obstetric disorders. In this case, successful spontaneous vaginal delivery was achieved using prophylactic C1 esterase inhibitor and epidural analgesia.

Molecular Genetics

Stoppa-Lyonnet et al. (1987) studied DNA from multiple members of 2 families with hereditary angioedema and from 6 unrelated patients. Their results indicated that a defective structural gene was responsible for the disease. In a patient with type I HANE, Ariga et al. (1989) found a deletion in exon 7 (606860.0001) of the C1NH gene. In 2 unrelated families with HANE type II, Levy et al. (1990) demonstrated a G-to-A change in codon 436 of the C1NH gene, resulting in an alanine-to-threonine residue change (606860.0002).

Patients with HANE type I appear to have a deletion of the C1 inhibitor gene or a truncated transcript because of a stop codon, whereas patients with HANE type II have a single base substitution. The 2 forms are clinically indistinguishable.

Guarino et al. (2006) reported 2 brothers with type I hereditary angioedema in whom they identified heterozygosity for a nonsense mutation in the C1NH gene (606860.0014). Clinical and laboratory findings of both parents and relatives were normal. The mutation occurred on the maternally transmitted chromosome, but was not detected in DNA derived from the mother's buccal cells, urinary cells, hair roots, or cultured fibroblasts, suggesting that the mother was a true gonadal mosaic.

History

Quincke (1882) first described (and named) angioneurotic edema. Osler (1888), while in Philadelphia, was first to describe the hereditary form.

Dennehy (1970) called attention to the fact that Nathaniel Hawthorne was apparently familiar with this disorder for in his 'House of the Seven Gables' he described a family with members who gurgled in the throat and chest when excited and who would sometimes die this way, ever since a curse to choke on blood had been placed on 1 of their ancestors. Dennehy (1970) interpreted the following passage as an indication that Hawthorne recognized that a hereditary disease, not a curse, was responsible for the deaths: 'This mode of death has been an idiosyncrasy with his family, for generations past....Old Maule's prophecy was probably founded on a knowledge of this physical predisposition in the Pyncheon race.'

Six years before Quincke (1882) introduced the term angioneurotic edema, Milton (1876) described 1 of his patients with angioedema in the following words: 'So soon as ever she came into the room I recognized the affection, for there lay, across the face from temple to temple, an oblong tumor almost closing both eyes.'

Robson et al. (1979) demonstrated that HANE is not linked to HLA or PGM1 on chromosome 6 and not linked to C6, which had not been assigned. Linkage to markers on 1p (Rh), 4q (MNSs), 9q (ABO), 16q (Hp), and 7 (Km) was also excluded. Furthermore, HANE was not linked to Gm. Linkage to HLA was excluded by Eggert et al. (1982). In family linkage studies, Olaisen et al. (1985) obtained 'a clear hint' that the HANE locus may be distal to F13A (134570) on 6p; the maximum lod score with F13A was 1.0 at a recombination fraction of 10%.