Search

Popliteal pterygium syndrome (PPS) and Van der Woude syndrome (VWS) are caused by mutations in the gene interferon regulatory factor 6 (IRF6). Skeletal, genital malformations and involvement of the skin occur in PPS and orofacial clefting and lip pits occur in both. We report on a patient with unilateral cleft lip and palate, ankyloblepharon, paramedian lip pits, unilateral renal aplasia, and a coronal hypospadias. By sequencing IRF6, we detected a novel missense mutation (Arg339Ile). The other family members were unaffected and had no IRF6 mutations, including the patient's brother who was also born with hypospadias. The patient and his brother were both conceived by in vitro fertilization (IVF). It is discussed whether the renal malformation in the patient is related to the IVF procedure or to the IRF6 mutation. © 2008 Wiley-Liss, Inc.

Background: The Pierre Robin sequence (PRS), consisting of cleft palate, micrognathia and glossoptosis, can be seen as part of the phenotype in other Mendelian syndromes—for instance, campomelic dysplasia (CD) which is caused by SOX9 mutations—but the aetiology of non-syndromic PRS has not yet been unravelled. Objective: To gain more insight into the aetiology of PRS by studying patients with PRS using genetic and cytogenetic methods. Methods: 10 unrelated patients with PRS were investigated by chromosome analyses and bacterial artificial chromosome arrays. A balanced translocation was found in one patient, and the breakpoints were mapped with fluorescence in situ hybridisation and Southern blot analysis. All patients were screened for SOX9 and KCNJ2 mutations, and in five of the patients expression analysis of SOX9 and KCNJ2 was carried out by quantitative real-time PCR. Results: An abnormal balanced karyotype 46,XX, t(2;17)(q23.3;q24.3) was identified in one patient with PRS and the 17q breakpoint was mapped to 1.13 Mb upstream of the transcription factor SOX9 and 800 kb downstream of the gene KCNJ2 . Furthermore, a significantly reduced SOX9 and KCNJ2 mRNA expression was observed in patients with PRS. Conclusion: Our findings suggest that non-syndromic PRS may be caused by both SOX9 and KCNJ2 dysregulation.

Cervical spondylodiscitis was diagnosed in a 31-year-old man 2 months after palatopharyngeal flap surgery. Symptoms included pain in the neck and tingling and numbness in the left arm. The diagnosis was confirmed by magnetic resonance imaging, and the patient recovered on antibiotic treatment. We propose that the spondylodiscitis may have occurred as a result of a local infection in and around the surgical wound in the posterior pharyngeal wall.

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway.

Background Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, β 4 ( PLCB4 ) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 ( GNAI3 ) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. Results We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. Conclusions These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

Congenital anterior midline cervical cleft (CAMCC) is a rare anomaly, with less than 100 cases reported. The cause of CAMCC is unknown, but genetic factors must be considered as part of the etiology. Three cases of CAMCC are presented. This is the first genetic study of isolated CAMCC. Conventional cytogenetics, array-comparative genomic hybridization (CGH) and whole exome sequencing were performed, including a search of relevant syndromes in the Online Mendelian Inheritance in Man (OMIM) database. Array CGH indicated a loss of the PAPPA gene in one of the patients, while exome sequencing showed a mutation in SIX5 in another patient. Both aberrations were inherited from unaffected parents. These results most likely imply that the identified mutations are not disease-causing, although they may be contributing factors if CAMCC has a polygenic inheritance. © 2012 Wiley Periodicals, Inc.

Cleft lip and/or palate (CL/P) is a common congenital malformation with a complex etiology which is not fully elucidated yet. Epidemiological studies point to different etiologies in the cleft lip and palate subgroups, isolated cleft lip (CL), isolated cleft palate (CP) and combined cleft lip and palate (CLP). In order to understand the biological basis in these cleft lip and palate subgroups better we studied the expression profiles in human tissue from patients with CL/P. In each of the CL/P subgroups, samples were obtained from three patients and gene expression analysis was performed. Moreover, selected differentially expressed genes were analyzed by quantitative RT-PCR, and by immunohistochemical staining of craniofacial tissue from human embryos. Osteopontin (SPP1) and other immune related genes were significantly higher expressed in palate tissue from patients with CLP compared to CP and immunostaining in palatal shelves against SPP1, chemokine receptor 4 (CXCR4) and serglycin (PRG1) in human embryonic craniofacial tissue were positive, supporting a role for these genes in palatal development. However, gene expression profiles are subject to variations during growth and therefore we recommend that future gene expression in CL/P studies should use tissue from the correct embryonic time and place if possible, to overcome the biases in the presented study.

Cleft lip and/or palate (CL/P) is a common congenital malformation with a complex etiology, as many genes and environmental factors have been shown to play a role in craniofacial development. We used a genetic mapping approach to analyze a family with multiplex CL/P. A genome-wide scan with a 10 kb single nucleotide polymorphism (SNP) chip followed by fine mapping with microsatellite markers in a CL/P multiplex family suggested linkage (maximum multipoint LOD score of 2.41) to a 6.5 Mb interval at 1q32.1-q32.2. This interval was close to, but excluded IRF6. Mutations in the IRF6 (1q32.2) cause syndromic forms of CL/P, and several association studies have shown that polymorphisms in and around IRF6 are associated with non-syndromic CL/P (NSCLP). However, in the family described here, IRF6 was excluded from the linkage interval. Sequencing of selected genes in the interval and comparative genome hybridization (CGH) did not reveal any mutations or genomic aberrations. Our data suggest that an unidentified CL/P gene, or a non-coding IRF6 regulatory element in this linkage interval may have caused CL/P in this family.

Objective The Pierre Robin Sequence (PRS) is subgroup of the cleft palate population. As with the etiology of cleft lip or palate, the etiology of PRS is generally unknown. Some factors are suggestive of a genetic basis for PRS. The purpose of this study was to compare genetic information on PRS available in the literature and in a cytogenetic database to facilitate focused genetic studies of PRS. Design After searching Medline for “pierre robin and genetics,” the Mendelian Cytogenetics Network database for “robin” and “pierre robin,” and two reviews from the Human Cytogenetics Database for “cleft palate” and “micrognathia,” a comparison of the data and a search in Online Mendelian Inheritance in Man (OMIM) Gene Map was performed to identify relevant candidate genes. Results The findings revealed consistency to a certain degree to loci 2q24.1-33.3, 4q32-qter, 11q21-23.1, and 17q21-24.3. A search in the OMIM Gene Map provided many candidate genes for PRS in these regions. The GAD67 on 2q31, the PVRL1 on 11q23-q24, and the SOX9 gene on 17q24.3-q25.1 are suggested to be of particular importance. Conclusion Candidate loci and a few potential candidate genes for PRS are proposed from the present study. This may enable researchers to focus their effort in the studies of PRS.

Objective To describe the occurrence of cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP) in the Faroe Islands and Greenland over a 50-year time period that has included substantial changes in lifestyle. Design A prevalence study based on patient records obtained from the Institute of Speech and Hearing Disorders in Copenhagen, Denmark, at which the treatment of patients with CP and CL/P from Greenland, the Faroe Islands, and Denmark is coordinated. Participants All live-born children in the Faroe Islands, Greenland, and Denmark with CL/P or CP born in the period 1950 to 1999 (Faroe Islands and Greenland) and 1950 to 1987 (Denmark). Results and Conclusion The mean prevalence of CL/P in the Faroe Islands and Greenland during the period 1950 to 1999 was 1.0 and 0.6 per 1000 live births, respectively. This is significantly lower than the mean prevalence of 1.4 (p < .05 and p < .001) per 1000 live births found in Denmark. The mean prevalence of CP in the Faroe Islands and Greenland was 1.5 and 1.1 per 1000 live births, respectively, which is significantly higher than the Danish prevalence of 0.5 per 1000 live births (p < .001 in both tests). There was no clear time trend in the prevalence, indicating that genetic factors or timetable environmental factors play a dominating role in the etiology of CL/P and CP in the Faroe Islands and Greenland.