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European collaboration on craniofacial anomalies

Livrables

A EUROCRAN Biobank to underpin future research into gene-gene and gene-environment interaction in cleft lip and/or cleft palate (CL/P). This Biobank contains nuclear triad DNA underpinned by maternal exposure data and will be a unique resource for future research into genetic and environmental factors that are implicated in the aetiology of clefts. Through this, there exists a potential for identification of risk factors, thereby enabling targeted intervention to reduce a risk of clefts in future generations.
The SATB2 gene encodes a protein of 733 amino acids that has a homeodomain showing a high degree of evolutionary conservation, but the function of which remains unclear. This gene was discovered by means of an innovative research methodology whereby probands with balanced chromosomal rearrangements were found to have a disturbance of the SATB2 locus at the chromosomal break point at 2q33. This "Proof of Concept" discovery represents an innovation which has implications for craniofacial development and dysmorphology research. In situ hybridization to mouse embryos shows site and stage specific expression of SATB2 in the developing palate, and therefore it may well play a role in the pathogenesis of isolated cleft palate in humans.
MSX1 (muscle specific homeobox gene 1) is a key factor in craniofacial morphogenesis, and has been implicated in the pathogenesis of cleft palate in a number of recent scientific reports. The EUROCRAN study provides further evidence, by means of association of a genetic risk factor for the occurrence of either Cleft Lip and Palate or isolated Cleft Palate in the offspring. Such information may be used in maternal public health risk assessment and should be the subject of ongoing research, and used in conjunction with other evidence in this field. Mutations in this gene may prove to be one of the universal genetic factors that contributes to orofacial clefting, and in the future this raises the possibility of developing targeted preventive strategies.
EUROCRAN Clinical Outcomes Library: this web-based tool to facilitate online assessment of clinical outcomes is an innovative first and has been made available to support surgical teams and affected familes. Access to the Clinical Outcomes Library is password protected.
Improved pre- and post-natal molecular diagnosis and genetic counselling for Treacher Collins Syndrome. This is the first time that diagnostic screening in the field has been placed on a service footing. End users are patients who request molecular diagnosis for TCS.
Relative safety of four surgical operations for the treatment of babies with cleft lip and / or palate established via a randomised controlled trial. The established trial is a global first in the field and the results will provide the first firm evidence base for the selection of surgery for affected babies. End users will be surgical teams and families in Europe and further afield.
Distraction Osteogenesis Registry and Recommendations: a web-based prospective registry of European patients with craniofacial anomalies treated with distraction osteogenesis and associated recommendations. The registry is the first collaboration of its kind where treatment of a large number of patients (161) with rare conditions is being monitored as a means of developing guidelines for future practice. End users are surgical teams and affected patients.
Identification of mutations in the IRF6 gene as the cause of both Van der Woude and popliteal pterygium syndrome leading to improved molecular diagnosis and genetic counselling for these conditions. End users are affected patients and their families.
In humans, SOX9 heterozygous mutations cause campomelic dysplasia, a syndrome with severe skeletal dysmorphology. The available evidence suggests that Sox 9 has a role in the regulation of cartilage growth and mice with the heterozygous Sox 9 mutation die perenataly with cleft palate a small lower jaw and poor formation of skeletal structure is derived from cartilage precursors. The same chromosomal breakpoint methodology identified a mutation in the region of the Sox 9 gene to be also implicated in cleft palate and a significant proportion of cleft palate patients also have mandibular hypoplasia, and this phenotype is characteristic of Pierre Robin sequence. SOX9 misregulation is therefore implicated in Pierre Robin sequence. This finding has broader implications for the pathogenesis of craniofacial deformity and also for chromatin biology and craniofacial development.
The EUROCRAN Speech Project is a web-based interactive tool for cleft lip and palate speech and language assessment. This is the first tool of its kind and incorporates speech examples from 6 European languages. End users are speech and language therapists and affected patients.
Low maternal folate or vitamin B 12 status has been implicated in numerous pregnancy complications including spontaneous abortion. MTHFD1 (5,10-methylene-tetrahydrofolate dehydrogenase 1) is another enzyme involved in the folic acid metabolic pathway with potential implications for susceptibility to orofacial clefts. Like MTHFR, this polymorphism is widely reported in the literature as a factor which reduces the bio availability of folic acid with reciprocal implications for homocysteine metabolism, and excess homocysteine may be teratogenic. The results of the EUROCRAN study raises the interesting possibility that the MTHFD1 1958AA genotype may be an important maternal risk factor for cleft lip and palate to consider during pregnancy. As a result further research in this area is required.
The first external evaluation of the standards of care for cleft lip and / or palate in eight countries of the Newly Associated States has already influenced surgery within participating groups and serves as a model for clinical governance across the EU. End users will be surgical teams and families in Europe and further afield.
EUROCRAN Project website (www.eurocran.org) incorporating the European Directory of Resources for Craniofacial Anomalies and links to Genetic Databases which is the first such web-based resource to support researchers and affected individuals and their families.
Methylene tertrahydro folate reductase (MTHFR) is a key enzyme in the folic acid metabolic pathway, and the 677 C - T polymorphism in the 5-10 MTHFR gene has been implicated in a number of congenital birth defects, including cleft lip with or without cleft palate (CL/P) in some populations, but not others. In the EUROCRAN study, it was interesting to find that the mutation giving the rare variant of the enzyme is in the affected infants genome. Therefore, our results reinforce the idea that the maternal MTHFR genotype plays a significant role in susceptibility to CL/P, but its teratogenic effect depends on the genotype of the offspring. This finding has potential implications for the aetiology and pathogenesis of cleft lip and palate.