Prevalence and Clinical Manifestations of Hereditary Angioedema in Untested Close and Distant Blood Relatives of Hereditary Angioedema Index Patients in a City, Turkey/Turkiye'de Bir Sehirde Indeks Herediter Anjioodem Hastalarinin Uzak ve Yakin Test Edilmemis Akrabalarinda Herediter Anjioodem Prevalans ve Klinik Belirtileri.
Objective: Hereditary angioedema (HAE) is a rare autosomal-dominant disease characterized by recurring attacks of nonpruritic, nonpitting edema caused by an inherited deficiency or dysfunction in the C1 esterase inhibitor (C1 INH). Symptoms present years before an accurate diagnosis is made. Our aim was to determine the prevalence and clinical manifestations of HAE in untested blood relatives of HAE index patients in a city of Duzce province, Turkey.
Methods: Overall, 4 index patients with HAE and 60/118 blood relatives enrolled in the study. The mean age of the enrolled untested subjects (29 female+31 male) was 41 years. The enrolled subjects underwent complement testing (C4, C1 INH antigen, and functional C1 INH). If the laboratory tests were abnormal, the enrolled subjects were questioned on clinical manifestations and scheduled for a follow-up visit.
Results: Except for 4 index cases, 60 relatives enrolled in the study underwent complement testing, and 36.6% of them were diagnosed Type 1 and 1.6% Type 2. HAE could not be ruled out in 6.6% of the subjects. In 55% of the untested blood relatives, the HAE disorder was ruled out. Of 23 (22; type 1+ 1; type 2) newly diagnosed subjects, 9 (39%) reported having experienced symptoms that may have been related to HAE, such as swelling in the face, genitourinary region, extremities or abdominal pain. The median age of 9 symptomatic patients was 42 (25-75) years, whereas newly diagnosed asymptomatic subjects had a median chronological age of 17 (9-74) years.
Conclusions: This study's findings reinforce the importance of screening family members and relatives of index patients with HAE to detect this hereditary condition.
Keywords: C1 esterase inhibitor, hereditary angioedema, screening, questionnaires, C4
Amac: Herediter Anjioodem (HAO), C1 esteraz inhibitor eksikligi veya fonksiyon bozuklugu nedeniyle tekrarlayan kasintisiz ve basmakla cukur-lasmayan odem ataklari ile seyreden otozomal dominant nadir bir hastaliktir. Sikayetler kesin teshis konulmadan cok once belirebilir. Bu calismada, amacimiz Turkiye'nin bir ilcesinde indeks HAO hastalarinin tani konulmamis akrabalarinda HAO siklik ve klinik bulgularini arastirmakti.
Yontemler: HAO tanisi almis 4 indeks hastanin 118 akrabasindan altmisi (29 kiz, 31 erkek) calismaya katildi. Katilanlarin ortalama yaslari 41 (4-5) yas idi. Kompleman testleri (C1 esteraz inhibitor antijen, C1 esteraz inhibitor fonksiyon ve C4 duzeyleri) calisilmak uzere kan ornekleri alindi. Anormal sonucu olanlar klinik bulgular acisindan sorgulandi ve takibe alindi.
Bulgular: Dort indeks HAO vakasi disinda calismaya katilan 60 kisiden alinan kan orneklerinde; olgularin %36,6'sinda Tip 1 HAO ve %1,6'sinda ise Tip 2 HAO hastaligi saptandi. Olgularin %6,6'sinda ise, HAO hastaligi dislanamadi. Daha once test edilemeyen akrabalarin %55'inde HAO hastaligi dislandi. Yeni tani konulan 23 (22; tip 1 + 1; tip 2) HAO hastasindan 9'unda (%39) yuz, ekstremite ve karinda HAO ile iliskili sislik semptomlarinin oldugu ogrenildi. Semptomatik 9 yeni hastanin yas ortalamasi 42 (25-75) yas, asemptomatik yeni hastalarin yas ortalamasi ise 17 (9-74) yas idi.
Sonuc: Bu calisma; indeks HAO hastalarinin tani konulmamis aile uyeleri ve akrabalarinda hastalik taramasinin onemini vurgulamaktadir.
Anahtar kelimeler: C1 esteraz inhibitor, herediter anjioodem, tarama, anket, C4
Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by an inherited deficiency or dysfunction of the plasma protein C1 esterase inhibitor (C1 INH). It is characterized by recurring attacks of nonpruritic, nonpitting subcutaneous edema, or submucosal edema of the small/large intestines or upper/lower airways (1). Symptoms typically present during childhood; however, the diagnosis could be delayed for a decade or more, even in developed countries (2-5). The offspring (children) of a diseased parent with a mutation of the C1 INH gene will have a 50% chance of inheriting the HAE disorder. Because of the scarcity of the disease, clinicians do not think of HAE in the first plan of their differential diagnosis (6). Additionally, despite its high probability due to familial predisposition, many family members of HAE patients are not searched for the disease. With new and effective therapeutic products, screening of family members has increasingly been given emphasis as a means to diminish the significant morbidity and mortality related to HAE (7).
This study was designed to determine the prevalence and occurrence of clinical manifestations of hereditary angioedema (HAE) in previously unevaluated blood relatives of known (index) patients with HAE in a few villages of a city in a province (Duzce) in Turkey.
In the beginning, after this study was approved by the relevant ethics committee (number: 162 214 662/050.01.04/90), we informed the local administration about our survey and got their approval as well. Later, we reached out to the recorded 4 (index) cases diagnosed with HAE and their untested relatives. A pedigree drawing was performed for the 4 index cases diagnosed with HAE (Figure 1). In addition, through public meetings with the permission of the local administration, the patients and relatives were informed about the disease. Besides close relatives of the index cases, distant relatives of the index case were also of interest. Close and distant blood relatives that wanted to enroll in the study were identified. These patients and their relatives were first informed of the nature of the study by telephone and were then visited. During this visit, the untested relatives were given a questionnaire (Table 1). The questionnaire was used to collect information on the demographics, screening status of blood relatives according to the HAE index patient, pregnancy, medication use, and past medical history including specific questions about swelling and symptoms that could be consistent with an angioedema attack. During the visit, permission by filling the informed consent form was obtained from all the blood relatives of the 4 index cases who agreed to enroll in the study. During this visit, after completing the questionnaire, blood samples were drawn and complement tests were performed to verify the diagnosis. If the complement testing (C4, C1 INH antigen level, and C1 INH activity) was normal in a suspected person, the diagnosis of HAE was excluded, and the results were provided to them. If the complement test results were abnormal or HAE could not be ruled out, the subjects were telephoned. They were asked the same questionnaire about the symptoms of HAE, the time of the onset of symptoms, swelling attacks, and drug use, and new complement testing was planned. In addition, through correspondence with the local health authorities, the medical/laboratory records of the newly diagnosed HAE patients were passed to their family physicians. (A diagram of participation from the index cases to the identification of untested relatives with laboratory results compatible with the diagnosis of HAE is shown in Figure 2).
Fresh serum blood samples were collected in a red top Vacutainer tube for complement testing. Within six hours of blood collection, 3 mL of serum from the untested relatives was obtained and stored at -20[degrees]C. Frozen serum samples were tested within 72 hours for C4, antigenic and functional C1 INH levels. C4 was evaluated using the Cobas C4-2 kit (Roche, Rotkreuz, Switzerland) by Cobas c 501 nephelometry (C4 reference range: 0.1-0.4 g/L), and the C1 INH antigen level was measured using the N AS C1IN kit (Siemens, Marburg Germany) by BN Prospec nephelometry (C1 INH antigen normal range: 0.21-0.39g/L). The functional C1 INH was measured using a chromogenic Berichrom C1-Inhibitor kit (Siemens, Marburg Germany) by BCS coagulometer (C1 INH function normal range: 70-130%). Results were defined as low for C4: [less than or equal to]0.1g/L, antigenic C1 INH: [less than or equal to]0.21g/L, and functional C1 INH: [less than or equal to]%70 (8-10).
Figure 3. Distribution of symptoms in newly diagnosed patients in our survey Symptoms Extremity swelling 0.56 Abdominal pain 0.44 Face swelling 0.33 Genitourinary swelling 0.11 Note: Table made from bar graph.
Questions were developed by collaborating with HAE experts to characterize the current state of screened subjects for HAE disorder. Nine questions were categorized into several broad areas, including patient characteristics, burden of disease, and treatment options (Table 1).
Data from our study group were pooled and presented as descriptive (summary) statistics using the IBM Statistical Package for the Social Sciences 21.0 (IBM Statistics; Armonk, NY, USA) software package program in the form of group means, rates, and proportions.
One hundred and eighteen blood relative subjects were identified from pedigree charts of 4 index patients with HAE. Nine out of 118 blood relatives of HAE patients had already died. Six of them were diagnosed with HAE before death. From the remaining 109 living relatives, 64 (including 4 index cases) elected to enroll in the study and underwent complement testing. Forty-five untested blood relatives did not want to enroll in the study. Twenty-nine enrolled blood relatives (29/60: 48.3%) were female, and 31/60 (51.6%) of them were male. The median age of all untested subjects, including the index cases, was 41 (range: 4-75) years (Table 2).
Prevalence of HAE in Close and Distant Relatives
C1 INH antigen levels were significantly low in 22/60 (36.6%) of the untested blood relatives of 4 index patients. These subjects were thought to have Type 1 HAE disorder. The C1 INH activity was significantly low in just 1/60 (1.6%) untested subject. This one was thought to have Type 2 HAE disease. In the remaining 4 subjects, HAE could not be ruled out during the study due to borderline low complement results. These suspicious results will be repeated in the near future. As a result, of the 60 relatives who enrolled in the study and underwent complement testing, 36.6% of them were found to have laboratory results indicative of Type 1 and 1.6% of them has results indicative of type 2 HAE. The complement tests could not rule out the diagnosis of HAE (indeterminate cases) in 4 patients (4/60: 6.6%). In 33/60 (55%) of the untested blood relatives, the HAE disorder was ruled out (Table 2).
The median age of the 4 patients (indeterminate cases) whose complement tests could not rule out the diagnosis of HAE was 33.5 (range: 4-71) years. The mean C1 INH protein levels of these subjects was detected as 0.17[+ or -]0.01 g/L (0.20, 0.15, 0.17, and 0.17 g/L). The C1 INH activity and C4 levels were within normal limits. There was not a symptom that might have been related to HAE in the indeterminate cases. This suggests that indeterminate cases/subjects might need some more time to develop symptoms since the median age of the 9 symptomatic patients was 42 years. Complement testing of these patients will be performed again.
According to the index cases, 10/23 newly diagnosed patients (43.5%) were first-degree relatives and 13/23 (56.5%) of them were more distant (second/third degree) relatives. In the 60 subjects who enrolled in our study, 17 of them were first-degree relatives, and the remaining 43 were more distant relatives. The HAE diagnosis rate in the first degree relatives of the index cases was 58.8% (10/17), and it was 30.2% (13/43) in the more distant relatives (Table 2).
History of Symptoms
Of 23 (22; type 1 + 1; type 2) newly diagnosed subjects, 9 (39.1%) subjects reported symptoms that may be related to HAE, such as swelling in the face, genitourinary region or extremities, and abdominal pain. These 9 symptomatic patients reported a few swelling episodes per year persisting for a couple of days. The attacks were mostly reported to be triggered by stress and/or trauma. Most of the 9 patients did not recall the time when the first attack happened. Swelling in extremities was observed in 5 (55.5%) of them, swelling in the face (lip) was reported in 4 (44.4%), swelling in the testis in 1 (11.1%), and abdominal pain was reported in 3 (33.3%) of them (Figure 3). The median age of the 9 symptomatic patients was 42 (range: 25-75) years, whereas the newly diagnosed asymptomatic subjects had a median chronological age of 17 (range: 9-74) years (Table 2).
Hereditary angioedema (HAE), caused by C1-INH deficiency, is a rare disease with an estimated frequency of 1:10.000-1:150.000 (11, 12). The clinical features of HAE consist of recurrent episodes of edema, which usually last for 2-5 days. The skin, gastrointestinal tract, and upper airway are most commonly affected in the recurrent edema attacks (13). A diagnosis of HAE should be suspected in any patient with recurrent angioedema attacks on the skin as well as upper airways or abdominal pain.
There have also been recent reports of attacks manifesting as headaches, temporary neurologic deficits, swelling and spasms of the urethra and bladder, joint swelling, chest tightness and pain, and renal colic (14, 15). Laryngeal edema is the most serious complication and can become life threatening, but it is a relatively rare event. Only 0.9% of all edema episodes of HAE disease involved laryngeal edema (16). In this study, symptoms such as swelling in the face, genitourinary region or extremities, and abdominal pain were present in our tested subjects. We found symptoms that might have been related to HAE in 39% of subjects. As mentioned above, the newly described clinical findings, such as headaches, described in the literature and outside the classic findings were not observed. A history of laryngeal edema development was not reported in our newly diagnosed patients. Symptoms appeared at an advanced age (median: 42 years) in our study population.
Although HAE is an autosomal dominant disorder, approximately 25% of disorders inherited in this manner may represent de novo mutations (17). HAE is a genetically heterogeneous disease, with more than 100 C1 INH gene mutations described to date spanning all the exons and exon/intron boundaries (18). However, genetic testing is rarely necessary, and, in fact, a negative test result cannot be used to exclude the diagnosis because new mutations that have not been previously identified are possible. In addition, a positive test result is consistent with the diagnosis but cannot be used to predict the natural history of the disease because the same genotypes present with various phenotypes (19). Laboratory testing (complement testing: C4, C1 INH activity, and C1 INH antigen level) is needed to confirm or rule out the diagnosis of HAE (11, 20). Even if a patient does not exhibit HAE symptoms, a confirmed diagnosis will allow them to prepare for the possibility of a future attack. The early diagnosis will also provide patients with the necessary education and knowledge to manage the HAE disorder during their daily life, including identification and avoidance of triggers and how to properly react to lethal complications, such as an airway obstruction (19). In this study, 14/23 (61%) of the newly diagnosed subjects did not have any symptoms/signs suggestive of HAE in their past medical history until our survey. Proving their diagnosis of HAE during our study will let unscreened blood relatives be aware of the disease and prepare for a possible HAE attack in the future.
Hereditary angioedema is caused by mutations in the C1-INH gene that result in reduced C1-INH antigen levels (type I) or dysfunction (type II) of the C1-INH protein (21). Unique among the inherited deficiencies of the complement system, HAE types I and II are inherited as an autosomal dominant disorder, with equal occurrence in men and women. Low levels of the C1 INH protein and decreased function of the protein distinguish type I HAE, which accounts for approximately 80% to 85% of all HAE cases. Type II HAE, which occurs in 15% to 20% of patients, results from decreased functional activity of the C1 INH gene but with a normal C1 INH protein level in the serum (22, 23). Recently, a new subtype of HAE, type III, has been described in the literature (19, 24). Type III HAE was out of the scope of this study. In this study, 22 out of 23 (95.6%) patients diagnosed by the complement tests had type 1 HAE disorder, and 1/23 (4.3%) of the patients was diagnosed as type 2 HAE. This is consistent with the literature.
Because of the rarity of HAE disease and the fact that its symptoms overlap with those of other forms of angioedema and, in cases of abdominal attack, it can appear to be a surgical emergency, it is frequently misdiagnosed. Consequently, HAE patients may experience considerable delays in diagnosis (5, 25, 26). Without an accurate diagnosis, HAE patients may not receive an appropriate treatment that can effectively manage their attacks. Inappropriate treatment could result in higher morbidity and mortality, adverse events, and unnecessary surgical interventions (27, 28). Especially, delayed treatment of laryngeal swelling can cause death (11, 13). Zanichelli et al. (28) reported that the median age of the first symptoms was 12.0 years, and the corresponding median age at diagnosis was 24.3 years (29). In our survey, the median age at diagnosis of untested blood relatives was too late (41 years). The median age at diagnosis was 42 years in symptomatic patients, and 17 years in asymptomatic patients.
Although HAE is inherited as an autosomal dominant disorder, it is known that testing family members and close/distant relatives for the disorder is not common practice worldwide. It is prudent to test family members or relatives of affected individuals to ensure appropriate education and treatment of HAE. This will decrease the time from the initial symptoms to diagnosis. Screening family members/ blood relatives for HAE may also be cost-effective by decreasing the number of physicians seen and the number of unnecessary tests and procedures ordered. Detecting the median age at diagnosis as 42 years in this study proves that screening/testing family members and close/distant blood relatives of these index patients for the HAE disorder must be a common practice. Ten out of 23 newly diagnosed patients (44%) were first-degree relatives of the index cases and 13/23 (57%) of them were more distant relatives. Of the subjects who enrolled in the study, 17 of them were first-degree relatives and 43 tested subjects were more distant relatives. The HAE diagnosis rate in first degree relatives was 59% (10/17), and it was at 30% (13/43) in the more distant (second and third degree) relatives (Table 2).
This study shows us that screening untested close and distant family members for the HAE disorder is very prudent and should be done. Validating their diagnosis of HAE will let the untested relative subjects be aware of the disorder earlier in life and prepare for a possible HAE attack in the near future.
HAE is a rare otosomal dominant disease caused by an inherited deficiency or dysfunction of the plasma protein C1 INH.
Despite its high probability of familial predisposition, many family members of HAE patients are not usually searched for the disease.
With new and effective therapeutic products, screening of family members has increasingly been given emphasis as a means to diminish the significant morbidity and mortality related to HAE.
Inappropriate treatment could result in higher morbidity and mortality, adverse events, and unnecessary surgical interventions. Especially, delayed treatment of laryngeal swelling can cause death.
Ethics Committee Approval: Ethics committee approval was received for this study from the ethics committee of Sakarya University.
Informed Consent: Written informed consent was obtained from patients and patients' parents who participated in this study.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept - O.O., B.E.; Design - O.O., B.E.; Supervision - O.O., B.E.; Resources - O.O., B.E.; Materials - O.O., B.E.; Data Collection and/or Processing - O.O., B.E.; Analysis and/or Interpretation - O.O., B.E.; Literature Search - O.O., B.E.; Writing Manuscript - O.O., B.E.; Critical Review - O.O., B.E.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: This study was supported by Centurion Pharma, Istanbul, Turkey.
Etik Komite Onayi: Bu calisma icin etik komite onayi Sakarya Universitesi'den alinmistir.
Hasta Onami: Yazili hasta onami bu calismaya katilan hastalardan ve hastanin ailesinden alinmistir.
Hakem Degerlendirmesi: Dis bagimsiz.
Yazar Katkilari: Fikir - O.O., B.E.; Tasarim - O.O., B.E.; Denetleme - O.O., B.E.; Kaynaklar - O.O., B.E.; Malzemeler - O.O., B.E.; Veri Toplanmasi ve/veya Islemesi - O.O., B.E.; Analiz ve/veya Yorum - O.O., B.E.; Literatur Taramasi - O.O., B.E.; Yaziyi Yazan - O.O., B.E.; Elestirel Inceleme - O.O., B.E.
Cikar Catismasi: Yazarlar cikar catismasi bildirmemislerdir.
Finansal Destek: Bu calisma Centurion Pharma, Istanbul, Turkiye tarafindan desteklenmistir.
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Oner Ozdemir (1), Bahri Elmas (2)
(1) Department of Pediatric Allergy-Immunology, Sakarya University School of Medicine, Training and Research Hospital, Sakarya, Turkey
(2) Department of Pediatrics, Sakarya University School of Medicine, Training and Research Hospital, Sakarya, Turkey
Address for Correspondence / Yazisma Adresi: Oner Ozdemir E-mail: firstname.lastname@example.org
Received Date / Gelis Tarihi: 14.01.2016 Accepted Date / Kabul Tarihi: 16.05.2016
This study was presented in the 22th National Allergy and Clinical Immunology Congress, 28 November - 2 December 2015, Antalya, Turkey.
Bu calisma 22. Ulusal Allerji ve Klinik Immunoloji Kongresinde sunulmustur, 28 Kasim - 02 Aralik 2015, Antalya, Turkiye.
This study was presented in the International Primary Immunodeficiencies Congress (IPIC), 5 -6 November 2015, Budapest, Macaristan.
Bu calisma Uluslararasi Primer Immun Yetmezlik Kongresi'nde sunulmustur, 5-6 Kasim 2015, Budapeste, Macaristan.
This study was presented in the Annals of Allergy Asthma Immunology 115 (5); Supplement: S Pages: A123-A123 Meeting Abstract: P295 Published: November 2015.
Bu calisma Annals of Allergy Asthma Immunology kitapciginda ozet bildiri olarak yayinlanmistir.
This study was presented in the MOJ Immunol 3(2): 00075. DOI: 10.15406/moji.2016.03.00075.
Bu calisma MOJ Immunology Kitapciginda ozet bildiri olarak yayinlanmistir.
Cite this article as: Ozdemir O, Elmas B. Prevalence and Clinical Manifestations of Hereditary Angioedema in Untested Close and Distant Blood Relatives of Hereditary Angioedema Index Patients in a City, Turkey. JAREM 2017; 7: 51-7.
Table 1. The questionnaire of our survey Volunteer (candidate)'s Name / Last name: .... Age: .... Sex: ... ID Number: ... Village / Neighborhood: .... Address: ... Phone: 0.... 1- Are you one of the untested blood relatives of HAE index patients? Yes ( ) No ( ) 2- Did you have any hand-arm-foot-eye-lip swelling without urticaria? Swelling: repeated; unknown cause; longer than 24 hours? Yes ( ) No ( ) 3- Did you have any trauma-, stress-triggered or unknown swelling? Yes ( ) Which region:.... No ( ) 4- Have you been referred to any health center with similar complaints? Yes ( ) Diagnosis:....... No ( ) 5- Is there any person in the family diagnosed with HAE? Yes ( ) Degree of relationship:...... No ( ) 6- Do you have a family member who died from HAE disease and/or complications? Yes ( ) Degree of relationship:...... No ( ) 7- Do you have another disease (autoimmune, connective tissue disease, vasculitis, etc.)? Yes ( ) Which disease:..... No ( ) 8- Are you pregnant? Yes ( ) No ( ) 9- Do you use any medications? Yes ( ) (androgens, antifibrinolytic, fresh frozen plasma, etc.) No ( ) Table 2. Clinical, demographic and laboratory findings of screened untested relatives of HAE index patients Case Age Sex C4 C1 Esterase C1 Esterase Type (g/L) Inhibitor Inhibitor Activity (%) (g/L) 1 46 F 0.12 45 0.02 I 2 42 F 0.03 34 0.05 I 3 25 M 0.06 38 0.12 I 4 51 F 0.40 86 0.13 I 5 75 F 0.03 38 0.06 I 6 41 M 0.12 51 0.09 I 7 41 M 0.07 32 0.05 I 8 55 M 0.07 34 0.08 I 9 32 M 0.37 99 0.17 I 10 18 F 0.05 38 0.06 I 11 58 F 0.23 60 0.33 II 12 74 M 0.11 35 0.08 I 13 26 F 0.06 41 0.07 I 14 9 M 0.10 37 0.16 I 15 14 F 0.07 46 0.09 I 16 13 M 0.07 40 0.08 I 17 13 F 0.06 43 0.09 I 18 16 F 0.06 34 0.08 I 19 11 F 0.12 45 0.09 I 20 52 M 0.10 44 0.09 I 21 10 M 0.09 44 0.10 I 22 46 M 0.05 37 0.05 I 23 42 F 0.09 36 0.06 I 24 51 M 0.20 78 0.21 Indeterminate 25 71 M 0.25 85 0.15 Indeterminate 26 4 M 0.21 92 0.17 Indeterminate 27 16 F 0.23 87 0.17 Indeterminate 28 42 F 0.10 39 0.06 I (Index case) 29 41 F 0.15 31 0.31 II (Index case) 30 46 F 0.03 21 0.05 I (Index case) 31 25 F 0.26 81 0.19 I (Index case) Case Relationship Swelling of parents Symptoms 1 Yes Face (lip)- Extremity 2 No Extremity 3 No Face - Abdominal pain 4 Yes Face (lip) 5 No Extremity 6 Yes Abdominal pain 7 Yes Extremity- Abdominal pain 8 No Genitourinary- Extremity 9 No Face (lip) 10 No No 11 No No 12 No No 13 No No 14 No No 15 No No 16 No No 17 No No 18 No No 19 No No 20 No No 21 No No 22 Yes No 23 No No 24 Yes No 25 No No 26 Yes No 27 No No 28 No Extremity 29 No Extremity 30 No Extremity- Face (eye, lip) 31 No Face (lip) F: female; M: male
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|Title Annotation:||Original Investigation / Ozgun Arastirma|
|Author:||Ozdemir, Oner; Elmas, Bahri|
|Publication:||Journal of Academic Research in Medicine|
|Date:||Aug 1, 2017|
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