Electronic Theses and Dissertation

Penyakit Hirschsprung (HSCR) dapat meningkatkan resiko morbiditas dan mortalitas pada anak, kelainan menimbulkan obstruksi fungsional. Data epidemiologi dan ekspresi genetik HSCR pada populasi suku Aceh masih sangat terbatas, padahal insidensi kasus di Aceh lebih tinggi dibandingkan rata-rata nasional dan global. Penelitian ini merupakan studi observasional analitik dengan pendekatan cross-sectional. Sebanyak 57 pasien HSCR yang menjalani operasi di RSUD dr. Zainoel Abidin Banda Aceh diikut sertakan dalam penelitian. Data epidemiologi, manifestasi klinis, dan radiologis dikumpulkan secara sistematis. Jaringan usus aganglionik dan ganglionik diambil saat operasi, serta jaringan kontrol dari pasien dengan malformasi anorektal. Ekspresi mRNA gen RET, NRG1, SEMA3, dan RarB dianalisis menggunakan real-time PCR, dan hasilnya dinormalisasi terhadap gen housekeeping GADPH. Analisis statistik dilakukan untuk menilai hubungan antara ekspresi gen, profil genotip, dan fenotip klinis. Dari 57 pasien, mayoritas berjenis kelamin laki-laki 40 orang (70,2%) dan anak perempuan 17 (29,8%) tipe HSCR paling banyak adalah short segment (98,2%), terutama pada rectosigmoid, dengan manifestasi klinis kembung 100 %, muntah hijau 31,6%, meconium terlambat 86%, Soiling 93%, Saat pemeriksaan colok dubur buang air besar menyemprot (squirt sign) 77,2 %, riwayat penggunaan laksansia 61,4%, Gambaran Radiologis Kontras enema (KE) short segment 56 orang (98%) dan 1 orang total colon aganglionik (1,8%) Prosedur operasi TEPT Like Soave 33 orang (57,9%), TEPT Like Swenson 22 orang (38,6%), Soave Boyle dan Duhamel prosedur masing masing 1 orang (1,8%), letak umumnya rectosigmoid 56 orang (98,2%)Manifestasi klinis utama meliputi perut kembung (100%), mekonium terlambat (86%), dan squirt sign (77,2%). Ekspresi gen RET dan NRG1 lebih rendah signifikan pada jaringan aganglionik dibandingkan jaringan ganglionik dan control. Ekspresi gen NRG1 menunjukkan penurunan yang signifikan pada jaringan kolon aganglionik (ddCT = -1,15; Cl 95%: -2,78 hingga 0,25; fold change = 2,84; p = 0,02), sementara penurunan pada jaringan ganglionic tidak signifiukan secara statistic (ddCT = -1,13; Cl 95%: -2.40 hingga 0,14, p = 0,08. Ekspresi gen RET juga turun secara signifikan pada jaringan anganglionik dan ganglionic (ddCT = -1,26; 95% Cl: -3,15 hingga -0,23; fold change = 3,23; p = 0,02). Sedangkan SEMA3 dan RarB menunjukkan variasi bermakna. Gen SEMA3A menunjukkan penurunan yang signifikan pada jaringan yang aganglionik (ddCT = -1,61; 95% Cl: -3,05 hingga -0,16; fold change= 3,05; p = 0,03). Pada ekspresi gen RarB juga mengalami penurunan ekspresi yang signifikan pada jaringan aganglionik (ddCT = -1,65; 95%Cl: -2,85 hingga 0,45; fold change= 3,14; p < 001). Juga pada jaringan ganglionic (ddCT = -1,38; 95%Cl: -2,63 hingga -0,13; fold change = 2,60; p = 0,01). Gen SEMA3 dan RarB diekspresikan lebih banyak pada HSCR pertempuan. NRG1 diekspresikan lebih tinggi pada pasien HSCR laki-laki. Usia secara signifikan mempengaruhi ekspresi gen NRG1, dengan kadar terendah diamati pada individu di bawah 1 tahun. Terdapat hubungan signifikan antara riwayat keluarga dan jenis HSCR, serta keterlambatan diagnosis yang berkontribusi pada komplikasi. Faktor lingkungan seperti kesehatan ibu selama kehamilan juga berperan dalam kejadian HSCR. Penelitian ini menunjukkan bahwa faktor genetik, khususnya ekspresi gen RET dan NRG1, berperan penting dalam patogenesis HSCR pada suku Aceh.

Kata kunci: Hirschsprung, epidemiologi, ekspresi gen, RET, NRG1, SEMA3, RarB, suku Aceh, mRNA, real-time PCR

Hirschsprung disease can increase risk of morbidity and mortality in children, as the disorder causes functional obstruction. Epidemiological and genetic expression data on HSCR in Acehnese ethnic population are still very limited, even though the incidence rate in Aceh is higher than nasional ang global avereges. This study is observational analytic study using a cross-sectional approach. A total of 57 HSCR patients who underwent surgery at Dr. Zainoel Abidin Hospital in Banda Aceh were included in study. Demografic, clinical and histopatological data were collected systematically. Both aganglionic and ganglionic tissues colon or rectal were sampled from HSCR and controle sample from each pasient with anorectal malformation. mRNA expression of RET, NRG1, SEMA3, and RarB genes was measured using real-time PCR, normalized against the housekeeping gene GADPH. Statiscal analysis was performed to asses the relationship between gene expression, genotip profiles, and clinical phenotype. Among the 57 patients, the majority were male (70,2%) and mosh had short-segment HSCR (98,2%), primarily involving the rectosigmoid region. Clinical manifestations included abdominal distention (100%), vomiting of green bile (31,6%), delayed meconium passage (86%), Soiling (93%) and positive squirt sign (77,2%). On contras enema imaging, short segment was faound in 98% of case, while total colon aganglionosis was found in 1,8%. Surgical procedures include TEPT-like Soave in 57,9% of patient, TEPT-like Swenson in 38,6% and a small number underwent Duhamel or Soave-Boyle Procedures. Expression of RET and NRG1 was signifintly lower in aganglionic compare to ganglionic tissue. NRG1 showed a significant decrese in aganglinic tissue (ddCT = -1.15; 95%Cl: -2.78 to 0.25; fold change = 2,84; p = 0,02) while the decrease in ganglionic tissue was not statistically no significant (ddCT = -0,43; 95% Cl: -2,40 to 0,14; p = 0,08). RET expression was also significantly lower in aganglionik tissue (ddCT = -1.16; 95% Cl: -3.15 to -0.23: fold change = 3.23; p = 0,02), while SEMA3 and RarB showed variable expression. SEMA3 showed reduced expression in aganglionic tissue (ddCT = -1,05; 95% Cl: -2,85 to 0,45; fold change 3.14; p = 0,01) and in ganglionic tissue (ddCT = -1.38; 95% Cl: -2.63 to - 0.13; fold change = 2,60; p = 0,01). RARB expression was also reduced expression in aganglionic tissue (ddCT = -1.65; 95% Cl: -2.85 to 0.45; fold change = 3.14; p < 0.01) and in ganglionic (ddCT = -1.38; 95%Cl: -2.63 to -0.13; fold change = 2,60; p = 0,01). The SEMA3 dan RarB genes were expressed more in female HSCR patients. NRG1 was expressed at higher levels in male HSCR patients. Age significantly affected NRG1 gene expression, with lowest levels observed in individuals under 1 years of age. Significant association were found between family history, HSCR type, and delayed diagnosis with complications. Environmental factors, such as maternal health during pregnancy, also played a role in HSCR development. This study indicated that genetic factors, particularly RET and NRG1 expresion, play a crucial role in the pathogenesis of HSCR among the Acehnese population. Keywords: Hirscsprung, epidemiology, gene expression, RET, NRG1, SEMA3, RarB, Acehnese, mRNA, real-time PCR