Results:
In this study, we included 32 patients (21 male and 11 female) from 23
families who were diagnosed to have HAE. Median age at onset of symptoms
was 6.25 years (range 1–25 years) and median age at diagnosis was 12
years (range 2-43 years) with median delay in diagnosis of 6.5 years
(range 0-28 years). Clinical manifestations of patients in this study
are detailed in Table 2. All patients had swelling over face (eyelids
and/or lips) (Supplemental Figure 1). Recurrent episodes of erythema
marginatum preceding a flare of disease were noted in 4 patients.
Although abdominal symptoms were noted in almost 1/3rdof patients, only 1 patient presented with acute surgical abdomen and
underwent exploratory laparotomy. No patient in this study had central
nervous system complaints. Stress, exercise and blunt trauma were the
only identifiable triggers for flare of symptoms. However, most patients
reported no definite trigger for their episodes. All patients had low
serum complement C4 levels and low serum C1-INH levels. C1INH activity
was also low in all patients in who it was tested. Thus, all patients in
the present study had type 1 HAE.
Most common differential diagnosis at presentation was allergic
angioedema. Patients who were diagnosed to have allergic angioedema had
itching or redness over the swelling and had history of response to
antihistaminic drugs and/or corticosteroids that were prescribed
elsewhere. All these features were absent in patients who were diagnosed
to have HAE. However, 1 patient presented with recurrent episodes of
periorbital puffiness and fever. A clinical possibility of HAE was
considered initially as C1-INH levels were low. However, because of
recurrent episodes of fever accompanying the periorbital puffiness and
elevated inflammatory parameters (erythrocyte sedimentation rate and
C-reactive protein), a clinical possibility of autoinflammatory syndrome
was also considered. Next generation sequencing revealed a pathogenic
variant in the TNFRSF1A gene that encodes for Tumour Necrosis
Factor receptor (TNFR1) protein.
SERPING1 gene sequencing could be carried out in 29 patients from
20 families till the time of this analysis. Of these, 17 patients from
11 families were found to have a pathogenic variant in theSERPING1 gene, while no pathogenic variant was detected in 12
patients from 9 families. Most mutations in the SERPING1 gene in our
cohort were located in exon 7 and exon 8 (in 4 and 3 families
respectively). Missense mutations were most common and seen in 5/11
families while non-sense, frameshift and splice site mutations were seen
in 2/11 families each (Figure 2 and Figure 3). Nine out of these 11
families had a novel mutation while in remaining 2 families a previously
reported mutation was identified. In addition, 20 benign polymorphisms
in SERPING1 gene were observed in 14 patients from 13 families
(Supplementary Table 1). Intron 6 polymorphism
(c.1029+20A>G) was most common (in 6 patients) followed by
exon 8 polymorphism (c.1438 G>A; p.Val480 Met) and intron 3
polymorphism (c.251-106 T>G) [in 4 patients each].
Most patients who were diagnosed prior to 2015 were initiated on
stanozolol (2 mg per day) or danazol (200 mg/day). However, over last 4
years, patients were initiated on either a combination of stanozolol and
TA or TA alone. Depending on the response, stanozolol was either
discontinued after 6 months to 1 year or continued at a dose of 0.5-2 mg
per day. Stanozolol had to be initiated in patients who failed to
respond to TA alone (Table 2). Four patients who were initially given
stanozolol and TA, stopped taking treatment after 25 years of age
because they had minimal attacks thereafter.
Short term prophylaxis was used in 2 patients. First patient was a
6-year-old girl who was diagnosed to have type 1 HAE in 2015. She was
given short term prophylaxis in 2018 as she had to undergo radical
excision of mandibular cyst. She was managed by increasing the dose of
stanozolol and by giving FFP infusions [10 ml/kg/dose]. Second
patient was a 29-year-old female who was diagnosed to have HAE in 2001.
She conceived in 2018 and remained asymptomatic during pregnancy despite
any prophylaxis. She was planned for an elective cesarean section in
view of non-progress of labor. She was managed with FFP (2 units) before
and during cesarean section and stanozolol 2 mg/day (initiated on the
day of cesarean section). Both patients tolerated the procedure well.
On demand therapy was used for acute episodes of laryngeal edema only.
FFP (10 ml/kg, maximum 2 units) infusion was used for 15 such episodes.
All patients showed prompt response and resolution of symptoms with
single dose of FFP.
Four patients reported virilization (menstrual irregularities, hirsutism
and hoarseness of voice) after taking stanozolol. One patient also
developed hypertension and excess weight gain. None of the patients
treated with attenuated androgens showed any evidence of hepatic or
haematological abnormalities. Other than one patient who had 2
spontaneous abortions during first trimester while she was being
continued on TA prophylaxis, no side effects related to TA therapy were
reported in this study.
One patient in our cohort died due to the disease. She was taking
stanozolol and TA as long-term prophylaxis. She developed an acute
episode of laryngeal oedema and collapsed before her parents could
access FFP infusion. Another patient in this study died due to road
traffic accident. In addition, at least 3 families could recall the
death of one of their family members who died due to an episode of
laryngeal oedema in the past.
Mean follow-up period in this study is 57 months (+ 81.5, range
4-288). The total follow-up period of the entire cohort is 1824
patient-months.