Uwe Baumert

Cleidocranial dysplasia : Molecular genetic analysis and phenotypic-based description of a middle European patient group

Cleidocranial dysplasia (CCD) (OMIM 119600) is a rare dysplasia of osseous and dental tissue. Characteristic features are typical facial and dental appearance plus morphologic anomalies. RUNX2 (OMIM 600211), the responsible gene for CCD, is considered to be a master gene for bone development and bone homeostasis. This study describes the genotype–phenotype correlation based on craniofacial features involving an interdisciplinary approach. Our patient cohort consisted of 31 CCD patients from 20 families; five patients from two families were unavailable for clinical examination. Since CCD mostly affects the craniofacial region, phenotypic characterization of each individual focused on craniofacial and dental aspects. After recording patient medical and family history, the phenotypic data was analyzed using homogeneity analysis (HOMALS), a statistical procedure for data reduction in categorical data analysis. The coding sequence of the RUNX2 gene was analyzed using PCR, direct sequencing, and restriction endonuclease digestion. Eight unpublished and four known heterozygous mutations in a total of 14/20 index patients (70%) were identified. In total, we detected 7 missense mutations, 5 frameshift mutations, and 2 nonsense mutations in 14 index patients (35%, 25%, 10%, respectively). The overall CCD phenotype varied from mild to fullblown expression. Using HOMALS, we were able to discriminate four groups of patients showing significant differences in phenotypic expressivity, thereby simplifying the grouping of our large patient cohort into clear distinguishable entities. Analysis of the mutation patterns revealed that mutational frequency and types of mutations found can be attributed to the genes structure and function.

Conventionally ligated versus self-ligating metal brackets—a comparative study

The purpose of this study was to compare the frictional properties of four self-ligating metal brackets, Speed, Damon 2, In-Ovation, and Time, with those of three conventionally ligated metal brackets, Time, Victory Twin, and Discovery. The self-ligating Time bracket can also be used as a conventionally ligated bracket. Friction was tested 20 times for each bracket/wire combination using a Zwick testing machine with stainless steel wires in three different wire dimensions (0.017 x 0.025, 0.018 x 0.025, and 0.019 x 0.025 inches). All brackets had a 0.022 inch slot and the prescription of an upper first premolar. The data were statistically analysed with unsigned comparisons of all bracket/wire combinations using the Mann-Whitney U-test and the Games-Howell post hoc test. The results showed almost all brackets to have the lowest frictional force with a wire dimension of 0.018 x 0.025 inch. Friction of the self-ligating brackets using wire with a dimension of 0.018 x 0.025 inches was 45-48 per cent lower than with 0.017 x 0.025 and 0.019 x 0.025 inch wires. Friction of the conventionally ligated brackets showed a 14 per cent or less reduced friction with 0.018 x 0.025 inch wire compared with 0.017 x 0.025 and 0.019 x 0.025 inch wires. The self-ligating metal brackets showed lower frictional forces with a 0.018 x 0.025 inch wire than conventionally ligated brackets, whereas conventionally ligated brackets showed lower friction with 0.017 x 0.025 and 0.019 x 0.025 inch wire. Friction values vary with different bracket/archwire combinations and, therefore, the choice of a bracket system for treatment should consider the correct wire dimension to produce the lowest possible frictional forces.

Comparison of maximum mouth-opening capacity and condylar path length in adults and children during the growth period.

A group of 80 children ranging in age from 6 to 10 years (subdivided into groups 1-5 according to chronological age) has been compared with an adult group on the basis of condylar path length and maximum mouth-opening capacity. The condylar path length and the mouth-opening capacity were measured using the ultrasonic JMA-System for registration. In the development of the temporomandibular joint (TMJ), condylar path length and mouth-opening capacity were found to increase with age in the juvenile group. In the oldest juvenile subgroup (subgroup 5; average age: 10.3 years) the condylar path length reached 17.6mm on the left and 17.3mm on the right. This is equivalent to 90.3% (left) and 91.1% (right) of the size in the adult group. The mean maximum mouth-opening capacity of the oldest juvenile subgroup was 56.3mm and reached 98.9% of the size in the adult group.

Variations in the inclination of the condylar path in children and adults.

OBJECTIVE To test the null hypothesis that there are no differences between children and adults in the condylar path inclination angle on the right and left sides. MATERIALS AND METHODS A group of 80 children aged 6 to 10 years (subgroups I through V, according to chronologic age) was compared with an adult group with regard to the condylar path inclination angle (CPIA) on the right and left sides. The CPIA was measured using the ultrasonic JMA-System for registration. RESULTS During development of the temporomandibular joint the condylar path inclination angle increased with age in the subgroups of children. A significant difference was found in the CPIA between the groups of adults and children. In the group with the oldest children (mean age: 10.3 years) the condylar path inclination angle had reached 81.87% on the right side and 78.85% on the left side compared with the adult group at a 5 mm protrusive path. In the pooled group of children the CPIA amounted to 73.08% on the right side and 72.13% on the left side compared with the values for the adults. No significant difference was found between the right and left CPIA in any group. CONCLUSION The hypothesis is rejected. The CPIA on the right and left sides increased with age in the group of children and was significantly smaller in the group of children compared with the group of adults.

Growth-related differences in maximum laterotrusion and retrusion between children and adults.

OBJECTIVE To test the null hypothesis that there are no differences between children and adults in maximum laterotrusion and maximum retrusion on the right and left sides. MATERIALS AND METHODS This population-based study included 81 randomly selected children between the ages of 6 and 10 years and 67 adults. Kinematic variables were measured with the ultrasonic JMA-System for registration. RESULTS The mean maximum laterotrusion of the childrens group (10.6 +/- 1.5 mm on the left, 11.0 +/- 1.7 mm on the right) was significantly smaller than that of the adult group (11.7 +/- 2.0 mm on the left, 12.2 +/- 1.7 mm on the right). The maximum laterotrusion of the childrens group corresponded to about 90% on the left and right sides of that of the adult group. The mean maximum retrusion of the childrens group was significantly bigger than that of the adult group. There, the adult values corresponded to 66.7% on the left and 50% on the right side of the childrens values. No significant difference in maximum laterotrusion and retrusion was noted on the right and left sides, and no significant differences according to gender specificities were observed in either group. CONCLUSIONS The hypothesis is rejected. In development of the temporomandibular joint, maximum laterotrusion on the right and left sides increases significantly with age, and maximum retrusion decreases significantly with age.

Evidence of intrafamilial variability of CBFA1/RUNX2 expression in cleidocranial dysplasia--a family study.

AbstractAim: To investigate the phenotypical expression of an identical mutation of the CBFA1/RUNX2 gene within a family with cleidocranial dysplasia. Patients and Method: A five-member family underwent clinical examination.Two members, father and son, showed dissimilar symptoms of cleidocranial dysplasia. The two affected patients were examined for syndrome-typical symptoms, and the genotype was determined by molecular-genetic analysis. Results: In both patients an identical missense mutation (G146R) in exon 2 of the CBFA1/RUNX2 gene was identified. In father and son the dental disturbances were similarly clearly expressed. However, the craniofacial skeleton of the son exhibited fewer dysostotic ossification features than that of the father. In the three clinically healthy family-members no mutation of the CBFA1/RUNX2 gene was found. Conclusion: In two patients with cleidocranial dysplasia an identical missense mutation in the CBFA1/RUNX2 gene leading to a divergent craniofacial phenotype was determined. The results indicate marked variability in the phenotypical expression of CBFA1/RUNX2 mutations.ZusammenfassungZiel: Das Ziel dieser Untersuchung bestand darin, die phänotypische Expression einer identischen Mutation des CBFA1/RUNX2-Gens innerhalb einer Familie mit Dysostosis cleidocranialis zu analysieren. Patienten und Methode: Eine fünfköpfige Familie mit zwei Betroffenen wurde klinisch untersucht. Zwei Familienmitglieder, Vater und Sohn, wiesen in unterschiedlichem Umfang Symptome der Dysostosis cleidocranialis auf. Die beiden betroffenen Patienten wurden hinsichtlich der syndromtypischen Symptomatik befundet und er Genotyp molekulargenetisch bestimmt. Ergebnisse: Bei beiden Betroffenen gelang der Nachweis einer Punktmutation (G146R) in Exon 2 des CBFA1/RUNX2-Gens. Bei Vater und Sohn waren die Störung des Zahnsystems gleichermaßen deutlich ausgeprägt. Das kraniofaziale Skelett des Sohnes war jedoch in geringerem Umfang mit dysostostotischen Ossifikationsmerkmalen behaftet als das des Vaters. Bei den drei klinisch unauffälligen, direkt mit dem Vater verwandten Familenmitgliedern konnte keine Mutation des CBFA1/RUNX2-Gens festgestellt werden. Schlussfolgerung: Bei zwei Patienten mit Dysostosis cleidocranialis konnte eine identische Missensemutation im CBFA1/RUNX2-Gen nachgewiesen werden. Diese führte zu einem unterschiedlichen kraniofazialen Phänotyp. Die Ergebnisse weisen auf eine hohe Variabilität in der phänotypischen Expression von CBFA1/RUNX2-Mutationen hin.

Anomalies of the skull in cleidocranial dysplasia

ZusammenfassungHintergrundDarstellung der Verteilung charakteristischer HNO-ärztlicher und kraniofazialer Anomalien in einer Patientengruppe mit Dysostosis cleidocranialis.Material und MethodeIn dieser Studie wurden 26 Patienten mit Dysostosis cleidocranialis nach umfassender Familienanamnese HNO-ärztlich und kieferorthopädisch untersucht.ErgebnisseDer Anteil von Spontanmutationen lag bei 46,1%. Alle Patienten zeigten HNO-ärztliche sowie kraniofaziale Anomalien. Während einzelne HNO-ärztliche Anomalien bei 76,9–92,3% der Patienten zu diagnostizieren waren, verteilten sich einzelne kraniofazialen Befunde auf 84,6–92,3% der Patienten.SchlussfolgerungDie Expression dieser seltenen Erkrankung mit hoher Spontanmutationsrate ist variabel und ihre Symptomatik nicht immer augenscheinlich. Die adäquate Behandlung der Anomalien kann deutlich zur Verbesserung der Lebensqualität Betroffener beitragen. Bei unklarer Diagnose empfehlen wir die Vorstellung bei einem erfahrenen Behandler sowie eine genetische Familienberatung.AbstractBackgroundThe description of the otorhinolaryngeal and craniofacial anomalies in patients with cleidocranial dysplasia.MethodsFor this study, 26 patients with cleidocranial dysplasia were examined after their medical history had been recorded. The main focus was placed on otorhinolaryngological and orthodontic findings.ResultsThe portion of spontaneous mutations in our patient population was 46.1%. All patients exhibited otorhinolaryngological and craniofacial anomalies. While single ENT-anomalies were expressed in 76.9%–92.3% of the patients, the craniofacial findings were distributed over 84.6%–92.3%.ConclusionThe expression of this rare disorder is variable and its symptomatology not always distinct. Otorhinolaryngological and craniofacial anomalies are often apparent. Appropriate treatment can significantly contribute to an improvement in the patient’s quality of life. In cases of ambiguous findings, we recommend consultation with an experienced clinician as well as genetic counselling.

Schädelanomalien bei Dysostosis cleidocranialis

ZusammenfassungHintergrundDarstellung der Verteilung charakteristischer HNO-ärztlicher und kraniofazialer Anomalien in einer Patientengruppe mit Dysostosis cleidocranialis.Material und MethodeIn dieser Studie wurden 26 Patienten mit Dysostosis cleidocranialis nach umfassender Familienanamnese HNO-ärztlich und kieferorthopädisch untersucht.ErgebnisseDer Anteil von Spontanmutationen lag bei 46,1%. Alle Patienten zeigten HNO-ärztliche sowie kraniofaziale Anomalien. Während einzelne HNO-ärztliche Anomalien bei 76,9–92,3% der Patienten zu diagnostizieren waren, verteilten sich einzelne kraniofazialen Befunde auf 84,6–92,3% der Patienten.SchlussfolgerungDie Expression dieser seltenen Erkrankung mit hoher Spontanmutationsrate ist variabel und ihre Symptomatik nicht immer augenscheinlich. Die adäquate Behandlung der Anomalien kann deutlich zur Verbesserung der Lebensqualität Betroffener beitragen. Bei unklarer Diagnose empfehlen wir die Vorstellung bei einem erfahrenen Behandler sowie eine genetische Familienberatung.AbstractBackgroundThe description of the otorhinolaryngeal and craniofacial anomalies in patients with cleidocranial dysplasia.MethodsFor this study, 26 patients with cleidocranial dysplasia were examined after their medical history had been recorded. The main focus was placed on otorhinolaryngological and orthodontic findings.ResultsThe portion of spontaneous mutations in our patient population was 46.1%. All patients exhibited otorhinolaryngological and craniofacial anomalies. While single ENT-anomalies were expressed in 76.9%–92.3% of the patients, the craniofacial findings were distributed over 84.6%–92.3%.ConclusionThe expression of this rare disorder is variable and its symptomatology not always distinct. Otorhinolaryngological and craniofacial anomalies are often apparent. Appropriate treatment can significantly contribute to an improvement in the patient’s quality of life. In cases of ambiguous findings, we recommend consultation with an experienced clinician as well as genetic counselling.

Clarification of data reported in “Cleidocranial Dysplasia: Molecular Genetic Analysis and Phenotypic-Based Description of a Middle European Patient Group” (AJMG 139A:78–85)†

Uwe Baumert,* Ilan Golan, Meir Redlich, Jean-Jacques Aknin, and Dieter Muessig Department of Orthodontics, Center for Craniofacial Genetics, University of Regensburg, Regensburg, Germany Department of Orthodontics, Hebrew University, Hadassah Faculty of Dental Medicine, founded by the Alpha Omega Fraternity, Jerusalem, Israel Departement d’Orthopedie Dento-Faciale, Faculté d’Odontologie, Lyon, France Department of Orthodontics, University of Regensburg, Regensburg, Germany Danube University Krems, Krems, Austria

Schädelanomalien bei Dysostosis cleidocranialis@@@Anomalies of the skull in cleidocranial dysplasia: Eine HNO-ärztliche und kraniofaziale Röntgenstudie@@@An otorhinolaryngological and craniofacial radiological study

ZusammenfassungHintergrundDarstellung der Verteilung charakteristischer HNO-ärztlicher und kraniofazialer Anomalien in einer Patientengruppe mit Dysostosis cleidocranialis.Material und MethodeIn dieser Studie wurden 26 Patienten mit Dysostosis cleidocranialis nach umfassender Familienanamnese HNO-ärztlich und kieferorthopädisch untersucht.ErgebnisseDer Anteil von Spontanmutationen lag bei 46,1%. Alle Patienten zeigten HNO-ärztliche sowie kraniofaziale Anomalien. Während einzelne HNO-ärztliche Anomalien bei 76,9–92,3% der Patienten zu diagnostizieren waren, verteilten sich einzelne kraniofazialen Befunde auf 84,6–92,3% der Patienten.SchlussfolgerungDie Expression dieser seltenen Erkrankung mit hoher Spontanmutationsrate ist variabel und ihre Symptomatik nicht immer augenscheinlich. Die adäquate Behandlung der Anomalien kann deutlich zur Verbesserung der Lebensqualität Betroffener beitragen. Bei unklarer Diagnose empfehlen wir die Vorstellung bei einem erfahrenen Behandler sowie eine genetische Familienberatung.AbstractBackgroundThe description of the otorhinolaryngeal and craniofacial anomalies in patients with cleidocranial dysplasia.MethodsFor this study, 26 patients with cleidocranial dysplasia were examined after their medical history had been recorded. The main focus was placed on otorhinolaryngological and orthodontic findings.ResultsThe portion of spontaneous mutations in our patient population was 46.1%. All patients exhibited otorhinolaryngological and craniofacial anomalies. While single ENT-anomalies were expressed in 76.9%–92.3% of the patients, the craniofacial findings were distributed over 84.6%–92.3%.ConclusionThe expression of this rare disorder is variable and its symptomatology not always distinct. Otorhinolaryngological and craniofacial anomalies are often apparent. Appropriate treatment can significantly contribute to an improvement in the patient’s quality of life. In cases of ambiguous findings, we recommend consultation with an experienced clinician as well as genetic counselling.