Podsumowanie

Nieimmunologiczny obrzęk płodu nadal stanowi istotne wyzwanie diagnostyczne. Prenatalne ustalenie przyczyny obrzęku umożliwia zaplanowanie optymalnego postępowania i ewentualne wdrożenie leczenia, a także pozwala na oszacowanie ryzyka powtórzenia się NIHF w kolejnych ciążach. Diagnostyka genetyczna, zwłaszcza ES, otwiera nowe możliwości w identyfikacji patogennych wariantów genetycznych, które mogą być przyczyną obrzęku. Wprowadzenie ES do diagnostyki prenatalnej pomaga w ustaleniu rozpoznania w przypadkach, w których inne metody nie przyniosły rezultatu, szczególnie u płodów z towarzyszącymi wadami strukturalnymi. Ponowna analiza danych w świetle aktualnej wiedzy może dodatkowo zwiększyć skuteczność diagnostyczną. Dalszy rozwój badań genetycznych, w tym GS, może się przyczynić do znacznego postępu w opiece nad pacjentkami z rozpoznanym NIHF.

ABSTRACT

Diagnostic challenges in non-immune hydrops fetalis with special regard to advanced genetic diagnostics

Hydrops fetalis is defined as the accumulation of fluid in at least two body cavities, such as the peritoneal cavity, pleural cavity or pericardial cavity, or in one body cavity and subcutaneous tissue. Foetal oedema can accompany multiple foetal defects or be detected in an otherwise healthy foetus. This article focuses on diagnostic and therapeutic possibilities in non–immune hydrops fetalis (NIHF), which accounts for 85-90% of cases of foetal oedema in developed countries. NIHF has a complex aetiology involvjng genetic, infectious, cardiac, hematological and metabolic causes. Despite diagnostic progress, the cause of NIHF cannot be ascertained in 20% of cases.

This article stresses the importance of prenatal diagnostics based on modern molecular genetic techniques, such as exome sequencing (ES) and whole-genome sequencing (GS). These techniques allow for the identification of genetic variants in monogenic diseases, such as RAS-opathies (e.g., Noonan syndrome) or bone dysplasias, that may be associated with hyodrops fetalis. The advent of ES has significantly improved diagnostic accuracy, especially in the presence of concomitant structural defects.

Additionally, we discuss a rare but very dangerous complication of NIHF in the form of so-called mirror syndrome (Ballantyne syndrome) in the expectant mother, who develops symptoms resembling those in the foetus. The onset of mirror syndrome represents a serious threat to both the mother and the foetus, increasing both foetal mortality and maternal morbidity.

In summary, advanced genetic techniques open new possibilities in the diagnosis and treatment of NIHF, which is of significant importance for the foetal prognosis and the planning of future pregnancies. Further progress in techniques such as GS can contribute to a better understanding of the underlying pathomechanisms and the development of more effective pre- and postnatal therapies.

Piśmiennictwo

1. Bellini C, Donarini G, Paladini D, et al. Etiology of non-immune hydrops fetalis: an update. Am J Med Genet A 2015;167A(5):1082-8. doi: 10.1002/ajmg.a.36988

2. Deng Q, Fu F, Yu Q, et al. Nonimmune hydrops fetalis: genetic analysis and clinical outcome. Prenat Diagn 2020;40(7):803-12. doi: 10.1002/pd.5691

3. Chen R, Liu M, Yan J, et al. Clinical characteristics of mirror syndrome: a retrospective study of 16 cases. J Obstet Gynaecol 2021;41(1):73-6. doi: 10.1080/01443615.2020.1718621

4. Hirata G, Aoki S, Sakamaki K, et al. Clinical characteristics of mirror syndrome: a comparison of 10 cases of mirror syndrome with non-mirror syndrome fetal hydrops cases. J Matern Fetal Neonatal Med 2016;29(16):2630-4. doi: 10.3109/14767058.2015.1095880

5. Sichitiu J, Alkazaleh F, de Heus R, et al. Maternal "mirror" syndrome: evaluating the benefits of fetal therapy. Prenat Diagn 2024;44(8):979-87. doi: 10.1002/pd.6589

6. Adani SN, Mohd Ashari NS, Johan MF, et al. Red blood cell alloimmunization in pregnancy: a review of the pathophysiology, prevalence and risk factors. Cureus 2024 ;16(5):e60158. doi: 10.7759/cureus.60158

7. Moise KJ Jr, Argoti PS. Management and prevention of red cell alloimmunization in pregnancy: a systematic review. Obstet Gynecol 2012;120(5):1132-9. doi: 10.1097/aog.0b013e31826d7dc1

8. Vlachodimitropoulou E, Shehata N, Ryan G, et al. Management of pregnancies with anti-K alloantibodies and the predictive value of anti-K titration testing. Lancet Haematol 2024;11(11):e873-7. doi: 10.1016/S2352-3026(24)00239-4

9. Kagan KO, Hoopmann M, Geipel A, et al. Prenatal parvovirus B19 infection. Arch Gynecol Obstet 2024;310(5):2363-71. doi: 10.1007/s00404-024-07644-6

10. Bijok J, Warakomska M, Massalska D, et al. Foeto-maternal haemorrhage: an unexpected challenge. J Obstet Gynaecol 2017;37(6):818-20. doi: 10.1080/01443615.2017.1289159

11. Chen CP. Chromosomal abnormalities associated with fetal pleural effusion (I): general overview. Taiwan J Obstet Gynecol 2024;63(2):165-7. doi: 10.1016/j.tjog.2024.01.009

12. Chen CP. Chromosomal abnormalities associated with fetal pleural effusion (II): specific and non-specific chromosome aberrations. Taiwan J Obstet Gynecol 2024;63(2):168-73. doi: 10.1016/j.tjog.2024.01.010

13. Massalska D, Bijok J, Ilnicka A, et al. Triploidy – variability of sonographic phenotypes. Prenat Diagn 2017;37(8):774-80. doi: 10.1002/pd.5080

14. Chen CP. Syndromic and single gene disorders associated with fetal pleural effusion (I): Noonan syndrome, RASopathy and congenital lymphatic anomalies. Taiwan J Obstet Gynecol 2024;63(2):174-7. doi: 10.1016/j.tjog.2024.01.011

15. Pevec U, Rozman N, Gorsek B, et al. RASopathies: presentation at the genome, interactome and phenome levels. Mol Syndromol 2016;7(2):72-9. doi: 10.1159/000445733

16. Kucińska-Chahwan A, Roszkowski T, Nowakowska B, et al. Genetic causes of the skeletal system abnormalities diagnosed by prenatal sonography with the use of exome sequencing: single institution experience. Ultrasound Obstet Gynecol 2021. doi: 10.1002/uog.23722

17. Epstein Weiss T, Erez O, Hazan I, et al. Characterization of pregnancy outcome of women with an offspring with inborn errors of metabolism: a population-based study. Front Genet 2022;13:1030361. doi: 10.3389/fgene.2022.1030361

18. Herzeg A, Borges B, Lianoglou BR, et al. Intrauterine enzyme replacement therapies for lysosomal storage disorders: current developments and promising future prospects. Prenat Diagn 2023;43(13):1638-49. doi: 10.1002/pd.6460

19. Chong JX, Buckingham KJ, Jhangiani SN, et al. The genetic basis of mendelian phenotypes: discoveries, challenges and opportunities. Am J Hum Genet 2015;97(2):199‐215. doi: 10.1016/j.ajhg.2015.06.009

20. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405‐24. doi: 10.1038/gim.2015.30

21. Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet 2019;393(10173):758-67. doi: 10.1016/S0140-6736(18)32042-7

22. Best S, Wou K, Vora N, et al. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn 2018;38(1):10-9. doi: 10.1002/pd.5102

23. Lord J, McMullan DJ, Eberhardt RY, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 2019;393(10173):747‐57. doi: 10.1016/S0140-6736(18)31940-8

24. Al-Kouatly HB, Makhamreh MM, Rice SM, et al. High diagnosis rate for nonimmune hydrops fetalis with prenatal clinical exome from the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study. Genet Med 2021;23(7):1325-33. doi: 10.1038/s41436-021-01121-0

25. Sparks TN, Lianoglou BR, Adami RR, et al.; University of California Fetal–Maternal Consortium; University of California, San Francisco Center for Maternal–Fetal Precision Medicine. Exome sequencing for prenatal diagnosis in nonimmune hydrops fetalis. N Engl J Med 2020;383(18):1746-56. doi: 10.1056/NEJMoa2023643

26. Mone F, Eberhardt RY, Hurles ME, et al. Fetal hydrops and the Incremental yield of Next-generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta-analysis. Ultrasound Obstet Gynecol 2021;58(4):509-18. doi: 10.1002/uog.23652

27. Liu C, Huang Y, Wang Y, et al. Exome sequencing for nonimmune hydrops fetalis and clinical utility of data reanalysis. QJM 2024:hcae187. doi: 10.1093/qjmed/hcae187

28. Kucińska-Chahwan A, Geremek M, Roszkowski T, et al. Implementation of exome sequencing in prenatal diagnosis and impact on genetic counseling: the Polish experience. Genes 2022;13(5):724. doi: 10.3390/genes13050724

29. Westenius E, Sahlin E, Conner P, et al. Diagnostic yield using whole-genome sequencing and in-silico panel of 281 genes associated with non-immune hydrops fetalis in clinical setting. Ultrasound Obstet Gynecol 2022;60(4):487-93. doi: 10.1002/uog.24911

Do góry