Prenatal Down Sendromu Taramaları; Güncel Perspektif
Özet
Down sendromu (Trisomi 21), 21. kromozomun üç adet olmasıyla karakterize, entelektüel yetersizliğin en yaygın nedenlerinden biri olan kromozomal bir anomalidir. Öğrenme güçlüğünün yanı sıra konjenital kalp, Alzheimer ve Hirschsprung hastalıkları ile lösemi gibi ciddi sağlık sorunlarına yol açar. Canlı doğumlarda görülme sıklığı yaklaşık 319-1000'de birdir. İleri anne yaşı, bu anöploidi için en temel risk faktörünü oluşturmaktadır. Hastalığın prenatal tanısı; geleneksel serum analiti temelli tarama yöntemleri ve hücre dışı DNA (cell-free DNA) temelli taramalar olmak üzere iki ana yöntemle yürütülür. İlk trimesterde ense saydamlığı (NT), hCG ve PAPP-A ölçümlerini içeren kombine test uygulanırken, ikinci trimesterde 15-21. haftalar arasında dörtlü test tercih edilmektedir. İlk ve ikinci trimester sonuçlarını birleştiren entegre testler %94-96 ile oldukça yüksek bir tanı yeteneğine sahiptir. 2011 yılında kullanıma giren hücre dışı DNA testi (NIPT) ise maternal kanda saptanan fetüs kökenli serbest DNA parçalarını analiz ederek %99 gibi en yüksek Down sendromu yakalama oranını sunmaktadır. Günümüzde antenatal dönem taramalarında %100 spesifite ve sensitiviteye sahip non-invaziv bir yöntem bulunmamakla birlikte, cell-free DNA temelli taramalar mevcut en gelişmiş tanı değerine sahip seçenektir.
Down syndrome (Trisomy 21) is a chromosomal anomaly characterized by the presence of three copies of the 21st chromosome, serving as one of the most common causes of intellectual disability. In addition to learning difficulties, it leads to severe health problems such as congenital heart disease, Alzheimer's disease, leukemia, and Hirschsprung disease. Its incidence is approximately 1 in 319 to 1000 live births, and advanced maternal age is the primary risk factor. The prenatal diagnosis of the disease is carried out through two main methods: traditional serum analyte-based screenings and cell-free DNA-based screenings. While the combined test involving nuchal translucency (NT), hCG, and PAPP-A measurements is applied in the first trimester, the quadruple test is preferred between the 15th and 21st weeks in the second trimester. Integrated tests combining the first and second-trimester results provide a high detection rate of 94-96%. Introduced in 2011, the cell-free DNA test offers the highest Down syndrome detection rate at 99% by analyzing fetus-derived free DNA fragments in maternal blood. Currently, no non-invasive test possesses absolute specificity and sensitivity in the antenatal period; however, cell-free DNA-based methods provide the highest diagnostic value available.
Referanslar
Jones KL. Down syndrome. In: Smith's recognizable patterns of human malformation, 6th ed, Elsevier Saunders, Philadelphia 2006. p.7.
Epstein CJ. Down syndrome (Trisomy 21). In: The metabolic and molecular bases of inherited disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.1223.
Hall B. Mongolism in newborn infants. An examination of the criteria for recognition and some speculations on the pathogenic activity of the chromosomal abnormality. Clin Pediatr (Phila) 1966; 5:4.
Bull MJ, Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics 2011; 128:393.
Winders PC. Gross motor milestone statistics. In: Gross motor skills in children with Down syndrome: A guide for parents and professionals, Woodbine House, Baltimore 1997. p.228.
Kumin L. Speech and language skills in children with Down syndrome. MRDD Research Reviews 1996; 2:109.
Gruhn JR et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 365, 1466–1469 (2019).
Ghosh S, Feingold E & Dey SK Etiology of Down syndrome: evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am. J. Med. Genet. A 149, 1415–1420 (2009).
Coppede F Risk factors for Down syndrome. Arch. Toxicol 90, 2917–2929 (2016).
Hunter JE et al. The association of low socioeconomic status and the risk of having a child with Down syndrome: a report from the National Down Syndrome Project. Genet. Med 15, 698–705 (2013).
Keen C et al. The association between maternal occupation and Down syndrome: a report from the national Down syndrome project. Int. J. Hyg. Environ. Health 223, 207–213 (2020)
Merkatz IR, Nitowsky HM, Macri JN, et al: An association between low maternal serum α- fetoprotein and fetal chromosomal abnormalities. Am J Obstet Gynecol 148(7):886, 1984
DiMaio MS, Baumgarten A, Greenstein RM, et al: Screening for fetal Down’s syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels. N Engl J Med 317(6):342, 1987
Cartier L, Murphy-Kaulbeck L; GENETICS COMMITTEE. Counselling considerations for prenatal genetic screening. J Obstet Gynaecol Can. 2012 May;34(5):489-493.
Stevenson DA, Carey JC: Contribution of malformations and genetic disorders to mortality in a children’s hospital. Am J Med Genet (Part A) 126(4):393, 2004.
Wellesley D, Dolk H, Boyd PA, et al: Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe. Eur J Hum Genet 20(5):521, 2012
Alldred SK, Deeks JJ, Guo B, et al. Second trimester serum tests for Down's Syndrome screening. Cochrane Database Syst Rev 2012; :CD009925.
American College of Obstetricians and Gynecologists: Cell-free DNA screening for fetal aneuploidy. Committee Opinion No. 640, September 2015, Reaffirmed 2017c
Wald NJ, Rodeck C, Hackshaw AK, et al. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 2003; 7:1.
Alldred SK, Takwoingi Y, Guo B, et al. First and second trimester serum tests with and without first trimester ultrasound tests for Down's syndrome screening. Cochrane Database Syst Rev 2017; 3:CD012599.
Norton ME, Jelliffe-Pawlowski LL, Currier RJ: Chromosomal abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol 124(5):979, 2014
Kazerouni NN, Currier RJ, Flessel M, et al: Detection rate of quadruple-marker screening determined by clinical follow-up and registry data in the statewide California program, July 2007 to February 2009. Prenat Diagn 31(9):901, 2011
Malone FD, Canick JA, Ball RH, et al: First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 353(19):2005b
Natoli JL, Ackerman DL, McDermott S, Edwards JG. Prenatal diagnosis of Down syndrome: a systematic review of termination rates (1995-2011). Prenat Diagn 2012; 32:142.
Quezada MS, Gil MM, Francisco C, et al: Screening for trisomies 21, 18, and 13 by cell-free DNA analysis of maternal blood at 10–11 weeks. Ultrasound Obstet Gynecol 45(1):36, 2015
Gil MM, Quezada MS, Revello R, et al: Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 45(3):249, 2015
Morris JK, Alberman E. Trends in Down's syndrome live births and antenatal diagnoses in England and Wales from 1989 to 2008: analysis of data from the National Down Syndrome Cytogenetic Register. BMJ 2009; 339:b3794.
Zhang H, Gao Y, Jiang F, et al. Non-invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146,958 pregnancies. Ultrasound Obstet Gynecol 2015; 45:530.
Practice Bulletin No. 163: Screening for Fetal Aneuploidy. Obstet Gynecol. 2016 May. 127 (5):e123-37.
Odibo AO, Stamilio DM, Nelson DB, et al. A cost-effectiveness analysis of prenatal screening strategies for Down syndrome. Obstet Gynecol 2005; 106:562.
Nicolaides KH, Azar G, Byrne D, Mansur C, Marks K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ 1992;304:867-869
M. Pan, Y.N. Liu, L.L. Xu, D.Z. Li, First-trimester cystic hygroma and neurodevelopmental disorders: the association to remember, Taiwan J Obstet Gynecol, 59 (6) (2020 Nov 1), pp. 960-962
Cleary-Goldman J, D’Alton ME, Berkowitz RL: Prenatal diagnosis and multiple pregnancy. Semin Perinatol 29(5):312, 2005
Savva GM, Walker K, Morris JK. The maternal age-specific live birth prevalence of trisomies 13 and 18 compared to trisomy 21 (Down syndrome). Prenat Diagn 2010; 30:57.
Cuckle H, Morris J. Maternal age in the epidemiology of common autosomal trisomies. Prenat Diagn 2021; 41:573.
Cignini P, Maggio Savasta L, Gulino FA, et al: Predictive value of pregnancy-associated plasma protein-A (PAPP-A) and free beta-hCG on fetal growth restriction: results of a prospective study. Arch Gynecol Obstet 293(6):1227, 2016
Goetzl L, Krantz D, Simpson JL, et al: Pregnancy-associated plasma protein A, free beta-hCG, nuchal translucency, and risk of pregnancy loss. Obstet Gynecol 104(1):30, 2004
Alldred SK, Deeks JJ, Guo B, et al. Second trimester serum tests for Down's Syndrome screening. Cochrane Database Syst Rev 2012; :CD009925.
Haddow JE, Palomaki GE, Knight GJ, et al. Second trimester screening for Down's syndrome using maternal serum dimeric inhibin A. J Med Screen 1998; 5:115.
Wald NJ, Cuckle H, Brock JH, et al: Maternal serum-alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Report of UK Collaborative Study on alpha-fetoprotein in relation to neural-tube defects. Lancet 1(8026):1323, 1977
Benn PA, Leo MV, Rodis JF, et al: Maternal serum screening for fetal trisomy 18: a comparison of fixed cutoff and patient-specific risk protocols. Obstet Gynecol 93 (5 Pt 1):707, 1999
Hackshaw AK, Wald NJ. Repeat testing in antenatal screening for Down syndrome using dimeric inhibin-A in combination with other maternal serum markers. Prenat Diagn 2001; 21:58.
Sheets KB, Crissman BG, Feist CD, et al. Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors. J Genet Couns 2011; 20:432.
Reichler A, Hume RF Jr, Drugan A, et al: Risk of anomalies as a function of level of elevated maternal serum α-fetoprotein. Am J Obstet Gynecol 171(4):1052, 1994
Dugoff L, Hobbins JC, Malone FD, et al: Quad screen as a predictor of adverse pregnancy outcome. Obstet Gynecol 106(2):260, 2005
Kazerouni NN, Currier RJ, Hodgkinson C, et al. Ancillary benefits of prenatal maternal serum screening achieved in the California program. Prenat Diagn 2010; 30:981.
Craig WY, Haddow JE, Palomaki GE, Roberson M. Major fetal abnormalities associated with positive screening tests for Smith-Lemli-Opitz syndrome (SLOS). Prenat Diagn 2007; 27:409.
Craig WY, Haddow JE, Palomaki GE, et al. Identifying Smith-Lemli-Opitz syndrome in conjunction with prenatal screening for Down syndrome. Prenat Diagn 2006; 26:842.
Langlois S, Armstrong L, Gall K, et al: Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols. Prenat Diagn 29(10):966, 2009
Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 2003;7:1-77
Cuckle HS, Malone FD, Wright D, et al: Contingent screening for Down syndrome–results from the FaSTER trial. Prenat Diagn 28(2):89, 2008
Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med 2015; 372:1589.
Palomaki GE, Kloza EM, O'Brien BM, et al. The clinical utility of DNA-based screening for fetal aneuploidy by primary obstetrical care providers in the general pregnancy population. Genet Med 2017.
Bianchi DW, Parker RL, Wentworth J, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014; 370:799.
Antepartum fetal surveillance. Practice Bulletin No. 229. American College of Obstetricians and Gynecologists . Obstet Gynecol 2021 ; 137 : 1135 – 37 .
