Expression analyses of human cleft palate tissue suggest a role for osteopontin and immune related factors in palatal development.

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.

A novel mutation in IRF6 resulting in VWS-PPS spectrum disorder with renal aplasia.

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.

Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2.

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.

Metastatic basal cell carcinoma caused by carcinoma misdiagnosed as acne - case report and literature review.

Basal cell carcinoma can be misdiagnosed as acne; thus, carcinoma should be considered in treatment-resistant acne. Although rare, neglected basal cell carcinoma increases the risk of metastasis.

Isolated malignant melanoma metastasis to the pancreas.

SUMMARY: Malignant melanomas rarely develop isolated pancreatic metastases. We describe a unique patient who is still alive 22 years following an isolated pancreatic melanoma metastasis, and we review the sparse literature in the field.

Cervical spondylodiscitis--a rare complication of palatopharyngeal flap surgery.

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.

Suggestive linkage to a neighboring region of IRF6 in a cleft lip and palate multiplex family.

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.

The genetic basis of the Pierre Robin Sequence.

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.

Occurrence of cleft lip and palate in the Faroe Islands and Greenland from 1950 to 1999.

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.