Zusammenfassung
Das Ausmaß der ursächlichen Wirkung genetischer Faktoren bei der Entstehung von orofazialen
Spaltbildungen hängt von der Art der Fehlbildung ab und setzt eine Unterscheidung
in vier verschiedene Gruppen voraus. Zum einen muss unterschieden werden zwischen
isolierten und syndromalen Spaltbildungen, zum anderen muss differenziert werden zwischen
Lippen-Kiefer-Gaumenspalten und Gaumenspalten. Handelt es sich bei der orofazialen
Spaltbildung um ein Teilsymptom eines übergeordneten Syndroms, richtet sich die Erblichkeit
nach der des Syndroms. Hierbei kann es sich um Chromosomenstörungen, monogene Krankheiten
oder auch nicht mendelnde Syndrome handeln. Die isolierte Spaltbildung ist sehr wahrscheinlich
multifaktoriell bedingt. Bei multifaktoriell bedingten Erkrankungen führt die kumulative
Wirkung von genetischen Varianten an mehreren Genorten zu einer genetischen Prädisposition
und bedingt eine „Empfänglichkeit“ für die Entstehung einer Fehlbildung. Es müssen
jedoch bestimmte Umwelteinflüsse hinzukommen, so dass das Zusammenwirken von genetischen
und umweltbedingten Faktoren zur Entwicklung der Fehlbildung führen kann. Durch Kopplungsanalysen
ergaben sich Hinweise auf mehrere Chromosomenregionen, die eine Rolle bei der Entwicklung
von orofazialen Spalten spielen könnten. Kandidaten-Gene, von denen ein Teil in diesen
chromosomalen Bereichen liegen, sind zur Zeit Gegenstand der Forschung.
Genetical Aspects of Cleft Lip with or without
Cleft Palate and Cleft Palate
The causative role of genetic factors in clefting depends on type of orofacial clefts.
They can be divided in non-syndromic and syndromic clefts, and in cleft lip with or
without cleft palate and cleft palate only. When the cleft occurs as one component
of a multiple congenital anomaly syndrome, the heredity depends on the syndrome's
cause. Syndromes have chromosomal, monogenic or non-mendelian origins. Non-syndromic
clefts are very likely to be multifactorial. In multifactorial diseases a genetic
predisposition reflects the cumulative effect of genetic variation at multiple loci
and leads to susceptibility to disease. Environmental triggers must be present to
bring out the disease by gene-environmental interactions. Linkage studies found suggestions
of several chromosomal loci to play a role in clefting. Candidate genes, some of them
mapping to these regions, are currently under investigation.
Schlüsselwörter
Lippen-Kiefer-Gaumenspalte - Gaumenspalte - multifaktoriell - isoliert - syndromal
Key words
Cleft Lip and Palate - Cleft Palate - Multifactorial - Isolated - Syndromic
Literatur
- 1
Jones M C.
Etiology of facial clefts: prospective evaluations of 428 patients.
Cleft Palate.
1988;
25
16-20
- 2
Prescott N J, Lees M M, Winter R M, Malcolm S.
Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft
palate in a two stage genome scan of affected sib-pairs.
Hum Genet.
2000;
106
345-350
- 3
Schutte B C, Murray J C.
The many faces and factors of orofacial clefts.
Hum Mol Genet.
1999;
8
1853-1859
- 4
Carinci F, Pezzetti F, Scapoli L, Martinelli M, Carinci P, Tognon M.
Genetics of nonsyndromic cleft lip and palate: a review of international studies and
data regarding the Italian population.
Cleft Palate Craniofac J.
2000;
37
33-40
- 5
Ardinger H H, Buetow K H, Bell G I, Bardach J, VanDemark D R, Marray J C.
Association of genetic variation of the transforming growth factor-alpha gene with
cleft lip and palate.
Am J Hum Genet.
1989;
45
348-353
- 6
Chenevix-Trench G, Jones K, Green A, Martin N.
Further evidence for an association between genetic variation in transforming growth
factor alpha and cleft lip and palate.
Am J Hum Genet.
1991;
48
1012-1013
- 7
Shiang R, Lidral A C, Ardinger H H, Buetow K H, Romitti P A, Munger R G, Murray J C.
.
Am J Hum Genet.
1993;
53
836-843
- 8
Dixon M J, Garner J, Ferguson M WJ.
Immunolocalisation of epidermal growth factor (EGF), EGF receptor and transforming
growth factor alpha (TGFa) during murine palatogenesis in vivo and in vitro.
Anat Embryol.
1991;
184
83-91
- 9
Machida J, Yoshiura K, Funkhauser C D, Natsume N, Kawai T, Murray J C.
Transforming growth factor-α (TGFA): genomic structure, boundary sequences, and mutation
analysis in nonsyndromic cleft lip/palate and cleft palate only.
Genomics.
1999;
61
237-242
- 10
Luetteke N C, Qiu T H, Pfeiffer R L, Oliver P, Smithies O, Lee D C.
TGF alpha deficiency results in hair follicle and eye abnormalities in targeted and
waved-1 mice.
Cell.
1993;
73
263-278
- 11
Campbell K, Flavin N, Ivens A, Robert B, Buckingham M, Williamson R.
The human homeobox gene HOX7 maps to 4p16.1 and is deleted in Wolf-Hirschhorn syndrome
patients.
Am J Hum Genet.
1989;
45 (suppl)
179
- 12
Satokata I, Maas R.
Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth
development.
Nat Genet.
1994;
6
348-356
- 13
Van den Boogaard M JH, Dorland M, Beemer F A, Ploos van Amstel H K.
MSX1 mutation is associated with orofacial clefting and tooth aganesis in humans.
Nature Genet.
2000;
24
342-343
- 14
Lidral A C, Romitti P A, Basart A M, Doetschman T, Leysens N J, Daack-Hirsch S, Semina E V,
Johnson L R, Machida J, Burds A, Parnell T J, Rubenstein J L, Murray J C.
Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.
Am J Hum Genet.
1998;
63
557-568
- 15
Stein J, Mulliken J B, Stal S, Gasser D L, Malcolm S, Winter R, Blanton S H, Amos C,
Seemanova E, Hecht J T.
Nonsyndromic cleft lip with or without cleft plate: evidence of linkage to BCL3 in
17 multigenerational families.
Am J Hum Genet.
1995;
57
257-272
- 16
Shaw D, Ray A, Marazita M, Field L.
Further evidence of a relationship between the retinoid acid receptor alpha locus
and nonsyndromic cleft lip with or without cleft palate (CL+/-P).
Am J Hum Genet.
1993;
35
1156-1157
- 17
Vintiner G M, Holder S E, Winter R M, Malcolm S.
No evidence of linkage between the transforming growth factor-alpha gene in families
with apparently autosomal dominant inheritance of cleft lip and palate.
J Med Genet.
1993;
29
393-397
- 18
Lidral A C, Murray J C, Buetow K H, Basart A M, Schaerer H, Shiang R, Naval A, Layda E,
Magee K, Magee W.
Studies of the candidate genes TGFB2, MSX1, TGFA, and TGFB3 in the etiology of cleft
lip and palate in the Philippines.
Cleft Palate Craniofac J.
1997;
34
1-6
- 19
Wong F K, Hagberg C, Karsten A, Larson O, Gustavsson M, Huggare J, Larsson C, Teh B T,
Linder-Aronson S.
Linkage analysis of candidate regions in Swedish nonsyndromic cleft lip with or without
cleft palate families.
Cleft Palate Craniofac J.
2000;
37
357-362
- 20
Tolarova M, Harris J.
Reduced recurrence of orofacial clefts after periconceptional supplementation with
high-dose folic acid and multivitamins.
Teratology.
1995;
51
71-78
- 21
Shaw G, Lammer E J, Wasserman C R, O'Malley C D, Tolarova M.
Risks of orofacial clefts in children born to woman using multivitamins containing
folic acid periconceptionally.
Lancet.
1995;
346
393-396
- 22
Ou C, Stevenson R, Brown V, Schwartz C, Allen W, Khoury M, Rozen R, Oakley G J, Adams M J.
5,10-Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for
neutral tube defects.
Am J Med Genet.
1996;
63
610-614
- 23
Mills J L, Kirke P N, Molloy A M, Burke H, Conley M R, Lee Y J, Mayne P D, Weir D G,
Scott J M.
Methylenetetrahydrofolate reductase thermolabile variant and oral clefts.
Am J Med Genet.
1999;
86
71-74
- 24
Shaw G M, Rozen R, Finnell R H, Todoroff K, Lammer E J.
Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip.
Am J Med Genet.
1998;
80
196-198
- 25
Romitti P A, Lidral A C, Munger R G, Daack-Hirsch S, Burns T L, Murray J C.
Candidate Genes for nonsyndromic cleft lip and palate and maternal cigarette smolking
and alcohol consumption: evaluation of genotype-environment interactions from a population-based
case-control study of orofacial clefts.
Teratology.
1999;
59
39-50
- 26
Milerad J, Larson O, PhD D, Hagberg C, Ideberg M.
Associated malformations in infants with cleft lip and palate: a prospective, populationbased
study.
Pediatrcs.
1997;
100
180-186
- 27
Stoll C, Alembik Y, Dott B, Roth M P.
Associated malformations in cases with oral clefts.
Cleft Palate Craniofac J.
2000;
37
41-47
- 28
Clementi M, Tenconi R, Bianchi F, Stoll C.
Evaluation of prenatal diagnosis of cleft lip with or without cleft and cleft palate
by ultrasound: experience from 20 European registries.
Euroscan study group. Prenat Diagn.
2000;
20
870-875
Dr. med. Mine Arslan-Kirchner
Institut für Humangenetik
Medizinische Hochschule Hannover
Carl-Neuberg-Straße 1
30625 Hannover
