Discussion
HAE is an uncommon autosomal dominant disorder characterized by
recurrent episodes of subcutaneous oedema, reduced complement C4 and low
antigenic and/or functional levels of C1-INH. HAE is a potentially
life-threatening medical condition. Depending on the C1-INH antigenic
and functional levels, HAE has been classified into 3 different
types.7 In majority (80-85%) there is a reduction of
both antigen and functional levels of C1-INH protein (type I HAE) and in
15-20% patients C1-INH antigen levels are normal or elevated but it is
dysfunctional (type II HAE). A rare form of hereditary angioedema (HAE
nlC1-INH) is characterized by normal levels and function of C1-INH
protein. HAE nlC1-INH is most commonly caused by mutation of coagulation
factor XII (F12 ) gene. Recent advances in the genetic studies
have identified some new genes that are associated with HAE nlC1-INH.
These include mutations in angiopoietin 1 gene (HAE-ANGPT1),plasminogen gene (HAE-PLG) and Kininogen-1gene.8,22–25 Acquired angioedema (AAE-C1-INH) has
mostly been reported in association with drugs, autoimmune diseases and
B-cell lymphoproliferative disorders.26 Patients with
AAE have older age at onset (4th or
5th decades of life). These patients have low levels
or abnormal function of C1-INH and low levels of C1q. The present study,
however, focussed on patients with type I HAE.
Published literature on HAE from developing countries is very
limited.13–19,27–29 To the best of our knowledge, no
long-term follow-up studies are available from India, especially in
children. Moreover, there are limited data on genetic profile of
patients with HAE from developing countries including India. Studies
conducted in China27 and Japan30reported that the incidence of HAE in Asian countries is less as
compared to studies from Latin American and Western countries such as
Brazil31, Hungary32,
Denmark33 and Germany.34 However,
precise epidemiologic figures are not available.35Table 3 shows an overview of published studies on type 1 and 2 HAE
including few paediatric studies.12,27,30–34,36–46
Diagnosis of HAE can be easily made from the characteristic oedema and
is supported by a positive family history. Low serum C4 level is a
cost-effective method of screening for HAE.2,3 In our
cohort, the characteristic swelling was present in all patients and low
C4 levels were detected in all. It has, however, been reported that C4
levels may occasionally be normal in HAE.2,9,36Assessment of serum C1-INH level (antigenic and functional) helps in
establishing an accurate diagnosis. All patients in the present study
had low C1-INH antigen levels.
Median age at onset of symptoms was 6.25 years in the present study
which is comparable with several other previously published studies
(Table 3). Median age at the time of diagnosis was 12 years with median
delay in diagnosis of 6.5 years. This is largely because of lack of
awareness amongst primary care physician and most patients were
initially managed elsewhere as allergic angioedema.
No definite triggers were discernible in most patients in the cohort
except few patients who identified blunt trauma, psychosocial stress and
exercise as potential triggers. Frequency of attacks were discernibly
less during pregnancy in 2 patients in our study. One of these 2
patients was continued on TA prophylaxis and she had an uneventful
pregnancy. The other patient experienced 2 first trimester abortions
while she was on TA prophylaxis even though she had no episodes of
angioedema during both pregnancies. Pregnancy has variable effect on the
clinical course of HAE.47–49 Attenuated androgens are
considered contraindicated during pregnancy and plasma derived C1-INH
and TA are considered safe. Mental stress has also been reported to be
an important trigger in these patients.7,50
There can be substantial inter-individual variation in the onset of
symptoms of HAE, duration of symptoms, frequency of attacks and severity
of symptoms. These differences can exist within the members of the same
family as was the case in several of our patients. In the Hungarian
cohort, the clinical attacks were found to be more severe in children
who had earlier age of disease onset.32 Recurrent
abdominal pain may be seen in 30-100% of patients with
HAE.27,31,51 It may be the initial presenting symptom
in 40-80% of children.16,52 In the presented study,
1/3rd of all patients reported having gastrointestinal
symptoms. Patients with predominant abdominal symptoms may inadvertently
be subjected to exploratory laparotomy.30 In one
study, 3 patients presented with oedematous abdominal attacks as initial
symptoms.32 One patient in the present cohort had a
history of exploratory laparotomy for acute surgical abdomen, several
years before he was diagnosed to have HAE.
Erythema marginatum could be an early manifestation of HAE and may
precede a disease flare. It may easily be confused with urticaria and is
more commonly reported in children and with type 1 and 2
HAE.7,53 Erythema marginatum was seen in 3 patient in
the present series.
In children, the only recommended drugs for management of acute episode
of HAE are C1-INH concentrate.7 Solvent detergent
–treated plasma (SDP) or fresh frozen plasma (FFP) may be considered
when C1-INH therapy is not available.7 As C1-INH
concentrate is not readily available commercially in our country, we had
to administer FFP in our patients with laryngeal oedema and patients
showed prompt resolution of symptoms. FFP may be considered as on demand
therapy in countries where C1-INH therapy is not easily
available.21
Patients and their parents were explained about need of long-term
prophylaxis and available treatment options. All patients opted for long
term prophylaxis as effective on demand treatment is not available in
India and access to FFP in emergency situations may not be always be
possible. TA has favourable side effect profile when compared to
attenuated androgens. However, studies carried out in the past have
reported safety of attenuated androgens even in prepubertal
children.7,50 In India, we do not have access to
plasma derived C1-INH therapy. Therefore, we considered attenuated
androgens (stanozolol) as the agent of choice for long term prophylaxis
of HAE. Most patients in our cohort showed reduction in frequency and
severity of HAE attacks with stanozolol prophylaxis. However, few
patients continued to have disease flare and even severe airway
obstruction requiring plasma therapy while they were taking stanozolol
prophylaxis. It has been observed that attenuated androgens are more
effective than TA.7 However, TA was considered an
upfront therapy in several patients in the present study considering
their side effect profile and these patients showed good response to
therapy.
Patients with HAE are prone to develop disease flare and occasionally
life-threatening laryngeal oedema during surgical procedures especially
dental surgeries.7 Plasma derived C1-INH therapy is
recommended to be used as short-term prophylaxis during these
procedures. Use of attenuated androgens and FFP have also been suggested
if C1-INH is not available.54,55 We successfully used
stanozolol and FFP for short term prophylaxis in 2 patients in the
present series.
Genetic profile of patients with HAE has been studied for the first time
in India. We found mutations in the SERPING1 gene in 11 out of 20
families who were screened. Nine of these 11 families had a novel
pathogenic variant in the SERPING1 gene. Missense mutations in
exon 7 and 8 were the most common mutations in our cohort. Mutation
spectrum in SERPING1 gene is quite heterogeneous and more than
450 mutations spread over the entire gene have been reported so
far.33,56–59 Missense mutations have been reported to
be the most common mutations in SERPING1gene.8,60–62 while some populations have reported
that nonsense or frameshift mutations are most
common.33 Missense mutations in exon 8 have also been
reported to be the most common mutation in certain
populations.60,61,63 Few authors have also reported a
genotype-phenotype correlation and have shown that non-sense, frameshift
and deletion mutations are associated with a more severe disease
phenotype.56,64 However, several other authors have
reported no genotype-phenotype correlation and have suggested that
polymorphisms in bradykinin receptor or contact system proteins may be
responsible for this phenotypic heterogeneity.33,60 In
the present study, we observed no genotype-phenotype correlation. Family
members with same mutations were noted to have wide variation in age of
symptom onset and disease severity suggesting a variable
penetrance.8
We did Sanger sequencing for all 8 exons of SERPING1 gene, however, 9
out of 20 families were not found to have any pathogenic variant. All
these families had characteristic clinical manifestations of HAE with
low C4 and low C1-INH. All except 2 of these patients also had
suggestive family history. We could have missed mutations in the
promoter region and deep-intronic regions of the SERPING1 gene in
these patients. Recently a deep intronic novel pseudoexon activating
mutation in the intron 6 of SERPING1 gene has been reported in a
family with HAE.65 Therefore, some of the patients
with HAE in this study may have this deep intronic mutation or a variant
in the promoter region of the gene.