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Genetische und molekularbiologische Aspekte des Blasenekstrophie-Epispadie-Komplexes (BEEK)

Genetic and molecular biological aspects of the bladder exstrophy-epispadias complex (BEEC)

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Zusammenfassung

Der Blasenekstrophie-Epispadie-Komplex (BEEK) stellt einen infraumbilikalen Mittelliniendefekt dar. Seine Inzidenz variiert in Abhängigkeit vom ethnischen Hintergrund, dem Geschlecht und der phänotypischen Ausprägung; in der Mitteleuropäischen Bevölkerung liegt sie bei 1:20.000 bis 1:80.000. Bisher konnte kein für den BEEK verantwortlicher Gendefekt identifiziert werden und assoziierte chromosomale Aberrationen oder genetische Syndrome wurden bisher nur in wenigen Kasuistiken beschrieben. Epidemiologische Daten deuten darauf hin, dass dem Krankheitsbild ein komplex genetischer bzw. multifaktorieller Erbgang zugrunde liegt. Eine spezifische teratogene Noxe für die Entstehung des BEEK beim Menschen konnte bisher nicht identifiziert werden.

Das Wiederholungsrisiko für BEEK beträgt innerhalb von Familien mit einem Betroffenen 0,5–3%. Dies entspricht einem gegenüber der Allgemeinbevölkerung 200- bis 800fach erhöhten Risiko. Aufgrund der geringen Fallzahl betroffener Geschwisterpaare und geeigneter Multiplexfamilien (mehrere Betroffene, im Idealfall über mehrere Generationen) sind klassische Kopplungsanalysen zur Suche verantwortlicher Gene nicht durchführbar. Durch die Auswahl möglichst vieler, geeigneter Kandidatengene stellen Segregationsanalysen in Verbindung mit Assoziationsstudien (viele Familien mit einem Betroffenen und gleichen ethnischen Hintergrundes) eine Alternative zur Identifikation verantwortlicher Gene bzw. genomischer Regionen dar.

Neue Untersuchungsmethoden wie die sog. Matrix-CGH (comparative genomic hybridisation) sind hier sehr viel versprechend, wie dies am Beispiel der CHARGE-Assoziation gezeigt werden konnte. In Anbetracht der geringen Inzidenz des BEEK wird eine erfolgreiche Gensuche nur durch eine intensive Kooperation der operativen und nichtoperativen Fächer erreicht werden können.

Abstract

The bladder exstrophy and epispadias complex (BEEC) is an anterior midline defect with variable expression involving the infraumbilical abdominal wall including the pelvis, urinary tract, and external genitalia. The incidence varies with regard to ethnical background, sex, and phenotypic expression, and an incidence of 1:20,000 to 1:80,000 has been observed in the middle European population. No gene defect has been attributed to BEEC thus far and chromosomal aberrations or genetic syndromes associated with BEEC have only rarely been reported. According to epidemiological data, a complex genetic as well as a multifactorial mode of inheritance could underlie BEEC. However, no single teratogenic agent or environmental factor has been identified, which could play a dominant role in the expression of the BEEC.

A risk of recurrence of 0.5–3% has been described in families with one affected subject. These values correspond to an increased recurrence risk estimated to be as high as 200- to 800-fold when compared to the common population. Due to the paucity of affected sib pairs and suitable multiplex families, conventional linkage analysis to identify candidate genes causally related with BEEC appears to be unfeasible. Large association studies and consecutive linkage disequilibrium mapping should therefore lead to the identification of candidate genes. Also new methods including matrix-based comparative genomic hybridization (CGH) are promising and have successfully been used in the past (e.g., CHARGE association). Moreover, the low incidence of the BEEC requires close cooperation between clinicians in the operative and nonoperative specialties as well as geneticists for successful gene search.

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Danksagungen

Für die Erstellung des Befundes der bisher nicht beschriebenen Translokation zwischen den Chromosomen 2 und 9 bei einem Patienten mir klassischer Blasenekstrophie möchten wir uns bei Fr. Prof. Weber, Diagnostisches Labor der Zytogenetik, Institut für Humangenetik, Universitätsklinikum Bonn, bedanken. Außerdem möchten wir uns bei Dr. Simeon Boyadjiev Boyd, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Hospital, 733 N. Broadway, BRB 469, Baltimore MD 21205, USA, im Rahmen unserer gemeinsamen Kooperation, für die konstruktive Diskussion bei der Erstellung des Manuskriptes bedanken.

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  1. Institut für Klinische Biochemie, Universitätsklinikum, Bonn

    M. Ludwig

  2. Klinik mit Poliklinik für Kinder und Jugendliche, Friedrich-Alexander-Universität, Erlangen-Nürnberg

    B. Utsch

  3. Institut für Humangenetik, Universitätsklinikum, Bonn

    H. Reutter

  4. Institut für Klinische Biochemie, Universitätsklinikum, Sigmund-Freud-Straße 25, 53105, Bonn

    M. Ludwig

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Ludwig, M., Utsch, B. & Reutter, H. Genetische und molekularbiologische Aspekte des Blasenekstrophie-Epispadie-Komplexes (BEEK). Urologe 44, 1037–1044 (2005). https://doi.org/10.1007/s00120-005-0863-z

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