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.