Fetale Lageanomalien und Heterotaxien

Zusammenfassung

Lageanomalien und Heterotaxien sind mit einer Inzidenz von 1–1,5 auf 10 000 Geburten insgesamt selten und umfassen eine Vielzahl viszerokardialer Anomalien und Fehlbildungen. Vor allem Heterotaxien können mit komplexen kardialen und extrakardialen Fehlbildungen assoziiert sein, die sowohl den antenatalen als auch den postnatalen Verlauf entscheidend beeinflussen. Die pränatale Differenzierung zwischen den beiden klinischen Hauptvarianten Links- und Rechts-Isomerie gelingt durch die Beurteilung des Herzrhythmus, des Verlaufs und der Lage der Hohlvenen und deszendierenden Aorta sowie durch die Beurteilung der begleitenden Fehlbildungen. Eine exakte Diagnose ist Voraussetzung für eine adäquate Beratung der werdenden Eltern und zur Planung der postnatalen Versorgung. Feten mit Links-Isomerien weisen durch eine Kombination aus Bradykardie bei früh, oft im ersten Trimenon einsetzendem AV-Block und konsekutiver Herzinsuffizienz mit Hydrops fetalis eine hohe pränatale Mortalität auf, wohingegen Feten mit Rechts-Isomerie, bedingt durch die Komplexität der assoziierten kardialen Fehlbildungen und assoziierter Milzanomalien, eine höhere Mortalität in der Postnatalperiode aufweisen. Die Art der assoziierten Anomalien und deren Korrigierbarkeit bestimmen die spätere Morbidität der Kinder. Zusätzliche viszerale Anomalien wie Asplenie und Polysplenie mit konsekutiv verminderter Immunabwehr, die pränatal nie sicher ausgeschlossen werden können, komplizieren das Krankheitsbild.

Abstract

Disorders of laterality and heterotaxy syndromes are rare diseases with an incidence of 1–1.5/10 000 live births. They are associated with numerous viscerocardiac anomalies and malformations. In particular, heterotaxy syndromes are associated with complex cardiac and extracardiac malformations that have an important impact on the prenatal and postnatal course. A prenatal differentiation between the 2 main variants of heterotaxy – left and right isomerism – is possible by assessment of cardiac rhythm, anomalies of caval veins and descending aorta and concomittant cardiac and extracardiac anomalies. An exact diagnosis is mandatory for adequate counselling of the parents and planning of postnatal care. Left isomerism has a high intrauterine mortality, caused by early atrioventricular block with subsequent cardiac failure and hydrops. In contrast, right isomerism has a high postnatal mortality due to the more complex type of cardiac defects and splenic disorders. The type of associated cardiac and extracardiac anomalies determines the postnatal morbidity and mortality. Polysplenia and asplenia may be associated with immunological disorders, that cannot be ruled out in the prenatal period, and further complicate the postnatal course.

Schlüsselwörter

Heterotaxie - Lageanomalie - Herzfehler - Isomerismus - pränatal

Key words

heterotaxy - disorders of laterality - isomerism - heart defect - prenatal

• Literatur

• 1 Lin AE, Ticho BS, Houde K et al. Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genet Med 2000; 2: 157-172
• 2 Okada Y, Nonaka S, Tanaka Y et al. Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell 1999; 4: 459-468
• 3 www.embryology.ch/allemand/hdisqueembry/triderm05.html
• 4 Hirokawa N, Tanaka Y, Okada Y. Cilia. KIF3 molecular motor and nodal flow. Curr Opin Cell Biol 2012; 24: 31-39
• 5 Tanaka Y, Okada Y, Hirokawa N. FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left–right determination. Nature 2005; 435: 172-177
• 6 Nakamura T, Mine N, Nakaguchi E et al. Generation of Robust Left-Right Asymmetry in the Mouse Embryo Requires a Self-Enhancement and Lateral-Inhibition System. Develop Cell 2006; 11: 495-504
• 7 Peeters H, Devriendt K. Human laterality disorders. Eur J Med Genet 2006; 49: 349-362
• 8 Kuehl KS, Loffredo C. Risk factors for heart disease associated with abnormal sidedness. Teratol 2002; 66: 242-248
• 9 Gebbia M, Ferrero GB, Pilia G et al. X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 1997; 17: 305-308
• 10 Ware SM, Peng J, Zhu L et al. Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet 2004; 74: 93-105
• 11 Mohapatra B, Casey B, Li H et al. Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet 2009; 18: 861-871
• 12 Kosaki R, Gebbia M, Kosaki K et al. Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet 1999; 82: 70-76
• 13 Bamford RN, Roessler E, Burdine RD et al. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 2000; 26: 365-369
• 14 Goldmuntz E, Bamford R, Karkera JD et al. CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. Am J Hum Genet 2002; 70: 776-780
• 15 Kosaki K, Bassi MT, Kosaki R et al. Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am J Hum Genet 1999; 64: 712-721
• 16 Otto EA, Schermer B, Obara T et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 2003; 34: 413-420
• 17 Calinescu-Tuleasca AM, Bottani A, Rougemont AL et al. Caroli disease, bilateral diffuse cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas: a ciliopathy caused by a homozygous NPHP3 mutation. Eur J Pediatr 2011; Aug 16. [Epub ahead of print]
• 18 Marion V, Stutzmann F, Gérard M et al. Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet-Biedl syndrome with situs inversus and insertional polydactyly. J Med Genet 2012; Apr 17. Epub ahead of print]
• 19 Leigh MW, Pittman JE, Carson JL et al. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med 2009; 11: 473-487
• 20 Kennedy MP, Omran H, Leigh MW et al. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation 2007; 115: 2814-2821
• 21 Zariwala MA, Knowles MR, Leigh MW. Primary Ciliary Dyskinesia. GeneReviews™ 2012 In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP. (eds.).
• 22 Berg JS, Evans JP, Leigh MW et al. Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia: implications for application to clinical testing. Genet Med 2011; 13: 218-229
• 23 Comstock CH, Smith R, Lee W et al. Right fetal cardiac axis: clinical significance and associated findings. Obstet Gynecol 1998; 91: 495-499
• 24 Walmsley R, Hishitani T, Sandor GS et al. Diagnosis and outcome of dextrocardiea diagnosed in the fetus. Am J Cardiol 2004; 94: 141-143
• 25 Bernasconi A, Azancot A, Simpson SM et al. Fetal Dextrocardia: diagnosis and outcome in two tertiary centres. Heart 2005; 91: 1590-1594
• 26 Lee SE, Kim HY, Jung SE et al. Situs anomalies and gastrointestinal abnormalities. J Pediatr Surg 2006; 41: 1237-1242
• 27 Blaas HG, Hals J, Bjornstad PG et al. Situs inversus viscerum with levocardia, without associated anomalies. Fetus 1991; 1: 75-93
• 28 Talner CN. Report of the New England Regional Infant Cardiac Program, by Donald C. Fyler. Pediatrics 1980; 65 (Suppl) 375-461 Pediatrics 1998; 102: 258–259
• 29 Winer-Muram HT, Tonkin IL. The spectrum of heterotaxic syndromes. Radiol Clin North Am 1989; 27 (06) 1147-1170
• 30 Ho SY, Anderson RH, Allan L. Disposition of the atrioventricular conduction tissues in the heart with isomerism of the atrial appendages: its relation to congenital complete heart block. Jam Coll Cardiol 1992; 20: 904-910
• 31 Berg C, Geipel A, Kohl T et al. Atrioventricular block detected in fetal life – associated anomalies and potential prognostic markers. Ultrasound Obstet Gynecol 2005; 26: 4-15
• 32 Schmidt KG, Ulmer HE, Silverman NH et al. Perinatal outcome of fetal complete atrioventricular block: a multicenter experience. J Am Coll Cardiol 1991; 17: 1360-1366
• 33 Machado MV, Tynan MJ, Curry PV et al. Fetal complete heart block. Br Heart J 1988; 60: 512-515
• 34 Gembruch U, Hansmann M, Redel DA et al. Fetal complete heart block: antenatal diagnosis, significance and management. Eur J Obstet Gynecol Reprod Biol 1989; 31: 9-22
• 35 Berg C, Geipel A, Smrcek J et al. Prenatal diagnosis of cardiosplenic syndromes: a 10-year experience. Ultrasound Obstet Gynecol 2003; 22: 451-495
• 36 Berg C, Geipel A, Kamil D et al. The syndrome of left isomerism – sonographic findings and outcome in prenatally diagnosed cases. J Ultrasound Med 2005; 24: 921-931
• 37 Peoples WM, Moller JH, Edwards JE. Polysplenia: a review of 146 cases. Pediatr Cardiol 1983; 4: 129-137
• 38 Rose V, Izukawa T, Moes CA. Syndromes of asplenia and polysplenia. A review of cardiac and non-cardiac malformations in 60 cases with special reference to diagnosis and prognosis. Br Heart J 1975; 37: 840-852
• 39 Ruscazio M, Van Praagh S, Marrass AR et al. Interrupted inferior vena cava in asplenia syndromes and a review of the hereditary patterns of visceral situs abnormalities. Am J Cardiol 1998; 81: 111-116
• 40 Chang J, Brueckner M, Touloukian RJ. Intestinal malrotation and fixation abnormalities in heterotaxis: early detection and management. J Pediatr Surg 1993; 28: 1281-1285
• 41 Choi M, Borenstein H, Hornberger L et al. Heterotaxy syndrome: the role of screening for intestinal rotation abnormalities. Arch Dis Child 2005; 90: 813-815
• 42 Gillajm T, McCrindle BW, Smallhorn JF et al. Outcomes of left atrial isomerism over a 28-year period at a single institution. J Am Coll Cardiol 2000; 36: 908-916
• 43 Carmi R, Magee CA, Neill CA et al. Extrahepatic biliary atresia and associated anomalies: etiologic heterogeneity suggested by distinctive patterns of associations. Am J Med Genet 1993; 45: 683-693
• 44 Murray CP, Yoo SJ, Babyn PS. Congenital extrahepatic portosystemic shunts. Pediatr Radiol 2003; 33: 614-620
• 45 Berg C, Geipel A, Kamil D et al. The syndrome of right isomerism – prenatal features and outcome. Ultraschall in Med 2006; 27: 225-233
• 46 Wu MH, Wang JK, Lin JL et al. Supraventricular tachycardia in patients with right atrial isomerism. J Am Coll Cardiol 1998; 32: 773-779
• 47 Ticho BS, Goldstein AM, Van Praagh R. Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures. Am J Cardiol 2000; 85: 727-734
• 48 Uemura H, Ho SY, Devine WA et al. Atrial appendages and venoatrial connections in hearts with visceral heterotaxy. Ann Thorac Surg 1995; 60: 561-569
• 49 Phoon CK, Neill CA. Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 1994; 73: 581-587
• 50 Lim JSL, McCrindle BW, Smallhorn JF et al. Clinical features, management, and outcome of children with fetal and postnatal diagnosis of isomerism syndromes. Circulation 2005; 112: 2454-2461
• 51 Fyler DC, Buckley LP, Hellenbrand WE et al. Report of the New England Regional Infant Cardiac Programme. Pediatrics 1980; 65 (suppl) 376-461
• 52 Rubino M, Van Praagh S, Kadoba K et al. Systemic and pulmonary venous connections in visceral heterotaxy with aspenia. Diagnostic and surgical consideration based on 72 autopsied cases. J Thorac Cardiovasc Surg 1995; 110: 641-650
• 53 Hashmi A, Abu-Sulaiman R, McCrindle BW et al. Management and outcomes of right atrial isomerism: a 26-year experience. J Am Coll Cardiol 1998; 31: 1120-1126
• 54 Patel CR, Lane JR, Muise KL. In utero diagnosis of obstructed supracardiac total anomalous pulmonary venous connection in a patient with right atrial isomerism and asplenia. Ultrasound Obstet Gynecol 2001; 17: 268-271
• 55 Huggon IC, Cook AC, Smeeton NC et al. Atrioventricular septal defects diagnosed in fetal life: associated cardiac and extra-cardiac abnormalities and outcome. J Am Coll Cardiol 2000; 36: 593-601
• 56 Wren C, Macartney FJ, Deanfield JE. Cardiac rhythm in atrial isomerism. Am J Cardiol 1987; 59: 1156-1158
• 57 Shenker L, Reed KL, Anderson CF et al. Congenital heart block and cardiac anomalies in the absence of maternal connective tissue disease. Am J Obstet Gynecol 1987; 157: 248-253
• 58 Baschat AA, Gembruch U, Knopfle G et al. First-trimester fetal heart block: a marker for cardiac anomaly. Ultrasound Obstet Gynecol 1999; 4: 311-314
• 59 Jaeggi ET, Hornberger LK, Smallhorn FJ et al. Prenatal diagnosis of a complete atrioventricular heart block associated with structural heart disease: combined experience of two tertiary care centers and review of the literature. Ultrasound Obstet Gynecol 2005; 26: 16-21
• 60 Moller JH, Nakib A, Anderson RC et al. Congenital cardiac disease associated with polysplenia. A developmental complex of bilateral “left-sidedness”. Circulation 1967; 36: 789-799
• 61 Salomon LJ, Baumann C, Delezoide Al et al. Abnormal abdominal situs: what and how should we look for?. Prenatal diagn 2006; 26: 282-285
• 62 Ivemark BI. Implications of agenesis of the spleen in the pathogenesis of conotruncal anomalies in childhood. Acta Paediatr 1955; 44 (Suppl) 7-110
• 63 Ho SY, Cook A, Anderson RA et al. Isomerism of the atrial appendages in the fetus. Pediatr Pathol 1991; 11: 589-608
• 64 Van Praagh S, Kakou-Guikahue M, Hae-Seong K et al. Atrial situs in patients with visceral heterotaxy and congenital heart disease: conclusions based on finding in 104 postmortem cases. Coeur 1988; 19: 484-502
• 65 Yoo SJ, Lee YH, Cho KS et al. Sequential segmental approach to fetal congenital heart disease. Cardiol Young 1999; 9: 430-444
• 66 Phoon CK, Villegas MD, Ursell PC et al. Left atrial isomerism detected in fetal life. Am J Cardiol 1996; 77: 1983-1088
• 67 Sheley RC, Nyberg DA, Kapur R. Azygous continuation of the interrupted inferior vena cava: a clue to prenatal diagnosis of the cardiosplenic syndromes. J Ultrasound Med 1995; 14: 381-387
• 68 Okoye BO, Bailey DM, Cusick EL et al. Prophylactic gastropexy in the asplenia syndrome. Pediatr Surg Int 1997; 12: 28-29
• 69 Nakada K, Kawaguchi F, Wakisaka M et al. Digestive tract disorders associated with asplenia/polysplenia syndrome. J Pediatr Surg 1997; 32: 91-94
• 70 Wu MH, Wang JK, Lue HC. Sudden death in patients with right isomerism (asplenism) after palliation. J Pediatr 2002; 140: 93-96
• 71 Waldman JD, Rosenthal A, Smith AL et al. Sepsis and congenital asplenia. J Pediatr 1977; 90: 555-559
• 72 Walkinshaw SA, Welch CR, McCormack J et al. In utero pacing for fetal congenital heart block. Fetal Diagn Ther 1994; 9: 183-185
• 73 Assad RS, Zielinsky P, Kalil R et al. New lead for in utero pacing for fetal congital heart block. J Thorac Cardiovasc Surg 2003; 126: 300-302