Jorma Rautio

Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.

Afghan war wounded : Experience with 200 cases

The injuries seen in 200 Afghan war wounded in the International Committee of the Red Cross (ICRC) hospital in Quetta are reported. Evacuation took several days and no proper initial first aid was available. Therefore few of those reaching us had serious multiple injuries. The anatomic distribution of wounds was remarkably similar to that seen in other conflicts: 38% of the injuries were caused by bullets, 50% by fragmentation weapons, and 10% by mines. Two thirds of the patients had limb injuries. Of all wounded, patients with fractures of long bones needed the greatest number of repeated operations and the longest hospitalization time. Twenty-five patients had abdominal or perineal wounds and 12 needed laparotomy. Of 25 with head injuries 14 had penetrating brain trauma. Thoracic, vascular, and burn injuries were rare. The eight patients with spinal cord injury could fortunately be referred to the ICRC rehabilitation center in Peshawar within a week. Wound sepsis was the major problem due to the extraordinarly long delay in the initiation of treatment. In spite of the often grossly infected wounds, radical debridement usually led to good recovery for most patients, with a hospital mortality rate of only 2.5%.

Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia

Cleft palate is a common birth defect, but its etiopathogenesis is mostly unknown. Several studies have shown that cleft palate has a strong genetic component. Robin sequence consists of three of the following four findings: micrognathia, glossoptosis, obstructive apnea, and cleft palate. While cleft palate is mainly nonsyndromic, about 80 percent of Robin sequence cases are associated with syndromes. Mutations in genes coding for cartilage collagens II and XI, COL2A1, COL11A1 and COL11A2, have been shown to cause chondrodysplasias that are commonly associated with Robin sequence, micrognathia or cleft palate. We therefore analyzed a cohort of 24 patients with nonsyndromic Robin sequence, 17 with nonsyndromic cleft palate and 21 with nonsyndromic micrognathia for mutations in COL11A2. A total of 23 Robin sequence patients were also analyzed for mutations in COL2A1 and COL11A1. We detected two disease-associated mutations in patients with Robin sequence, an Arg to stop codon mutation in COL11A2 and a splicing mutation in COL11A1. Two putatively disease-associated sequence variations were found in COL11A1 in Robin sequence patients, one in COL11A2 in a patient with micrognathia and one in COL2A1 in two patients with Robin sequence. The results showed that sequence variations in these genes can play a role in the etiology of Robin sequence, cleft palate and micrognathia but are not common causes of these phenotypes.

Mapping of the second locus for the Van der Woude syndrome to chromosome 1p34

The Van der Woude syndrome (VWS) is a dominantly inherited developmental disorder characterized by pits and/or sinuses of the lower lip, cleft lip and/or cleft palate. It is the most common cleft syndrome. VWS has shown remarkable genetic homogeneity in all populations, and so far, all families reported have been linked to 1q32-q41. A large Finnish pedigree with VWS was recently found to be unlinked to 1q32-q41. In order to map the disease locus in this family, a genome wide linkage scan was performed. A maximum lod score of 3.18 was obtained with the marker D1S2797, thus assigning the disease locus to chromosomal region 1p34. By analyses of meiotic recombinants an ∼30 cM region of shared haplotypes was identified. The results confirm the heterogeneity of the VWS syndrome, and they place the second disease locus in 1p34. This finding has a special interest because the phenotype in VWS closely resembles the phenotype in non-syndromic forms of cleft lip and palate.

Mechanical sensibility of the sole of the foot determined with vibratory stimuli of varying frequency

SummaryThe mechanoreceptive properties of the sole of the foot were determined by measuring the detection thresholds to vibratory stimuli of 20, 80, and 240 Hz frequency and 300 ms duration. The thresholds were measured at six different sites on the left sole and at toes 1 and 3 with probes of 2 and 8 mm diameter connected to the moving coil of an electromechanical vibrator. The subject sat in an armchair during the experiments, with the left leg supported horizontally by a vacuum cast positioned on a table. Six subjects participated in the experiments. A simple method of limits was used to make the measurements. Lower average thresholds were obtained with higher vibration frequencies, the average thresholds varying between 40–90 μm at 20 Hz and well below 10 μm at 240 Hz. The major decrease in thresholds occurred between 20 and 80 Hz. Interindividual variability in thresholds was large, but the threshold curves obtained from different subjects and from different stimulation points were of the same general shape. The highest thresholds were measured from the toes, but this regional difference in sensibility was obtained only at the higher vibration frequencies. Comparison of the threshold values at the sole with those found with similar stimuli at the thenar eminence and middle fingertip indicates that the mechanoreceptor mechanisms transmitting information about low-frequency vibration in the sole are similar to those in the palmar skin of the hand.

Dental abnormalities in permanent dentition in children with submucous cleft palate.

Seventy‐three children with submucous cleft palate (38 girls and 35 boys), mean age 8.2 years (range 7.7–9.5), were studied retrospectively from orthopantomograms. Dental abnormalities in permanent dentition were found in 26 patients (36%). Missing teeth, mainly lower 2nd premolars, upper lateral incisors, and upper 2nd premolars, were found in 12 patients (16%). Most of the patients had 1 or 2 missing teeth, 2 had 3 missing teeth. In 5 patients hypodontia was associated with another dental abnormality. Other dental abnormalities included peg‐shaped lateral incisors in 7 patients (10%), ectopic eruption of upper 1st molars in 6 patients (8%), transposition of upper canines and 1st premolars in 3 patients (4%), supernumerary teeth in 2 patients (3%), and palatally displaced upper canines in 1 patient (1%). As children with submucous cleft palate have a tendency towards increased frequency of missing teeth and other dental abnormalities, the need for thorough clinical and radiological dental examination is emphasized.

Embryology and epidemiology of microtia.

The auricle derives from six hillocks arising from the first and second branchial arches. Different hillocks give rise to different parts of the pinna. In the course of embryonic development, the auricle migrates postero-cranially as the mandible enlarges. Auricular malformations, such as microtia, are thought to be related to cell death of the first and second arch derivatives. The prevalence and characteristics of microtia vary in different populations. The prevalence ranges from 0.83 to 17.4 per 10,000. Microtia is more common in males, and right-sided dominance varies from 57 to 67%. The prevalence of aural atresia or stenosis varies from 55 to 93%. Microtia has been associated with numerous risk factors including race and gender. Genetic factors are likely to have an effect at least in some patients with microtia.

Early placement of ventilation tubes in cleft lip and palate patients: does palatal closure affect tube occlusion and short-term outcome?

OBJECTIVES Otitis media with effusion is almost universal in children with cleft palate due to the poor function of the Eustachian tube. Our study investigates the functioning of ventilation tubes placed at the time of primary cleft surgery (4 months of age) and at the time of secondary surgery (12 months of age). We compared two different surgical protocols: (Leg A) closure of the lip and soft palate at the age of 3-4 months (primary surgery) and closure of the hard palate at the age of 12 months (secondary surgery), and (Leg C) closure of the lip at the age of 3-4 months (primary surgery) and closure of the hard and soft palate at the age of 12 months (secondary surgery). METHODS A retrospective review of the medical records of 97 Finnish children with unilateral cleft lip and palate (UCLP) included in the Scandcleft study and randomized into two groups. RESULTS The majority (63%) of cleft (lip and) palate children benefit from early placement of ventilation tubes, and this group is even larger with early closure of the soft palate (86%; p=0.02). Closure of the soft palate at four months of age also reduces the frequency of OME in ears with the tube extruded or occluded, thus indicating better function of the Eustachian tube (p=0.02). CONCLUSIONS Early tympanostomy tube placement should be considered in children with cleft lip and palate, even prior to palatal closure.

A genome-wide scan of non-syndromic cleft palate only (CPO) in Finnish multiplex families

Oral clefts are the most common congenital malformations worldwide. Cleft palate can be non-syndromic (MIM 119540) or it can appear as a part of a syndrome or recurrence pattern. Non-syndromic cleft palate and non-syndromic cleft lip with or without cleft palate (CL/P) are considered to be separate entities, on the basis of different embryonic timing and epidemiology. However, in some syndromes, both of these cleft types segregate in the same pedigree, suggesting that they might share a common genetic background. Oral clefts manifest in over 300 different syndromes, and in some of these syndromes the gene defect is already known (Online Mendelian Inheritance in Man database 2004, http://www.ncbi.nlm.nih.gov/Omim/). Identified mutations in cleft syndromes have shown that functionally and structurally very distinct types of genes have an effect on palatogenesis. Recently, a mutation in interferon regulatory factor 6 (IFR6) was found to cause van der Woude syndrome (VWS) (MIM 119300),1 which is one of the most common cleft syndromes. Mutations in very different type of genes can lead to cleft palate in mice. These genes encode growth factors, receptors, transcription regulators, and enzymes for signalling molecule synthesis. Cleft palate, in addition to other congenital malformations, is found in ∼70 knock out mice strains (The Transgenic/Targeted Mutation Database, http://tbase.jax.org/). Other anomalies occur frequently, and therefore no exact model for non-syndromic cleft palate exists. Usually the penetrance is not complete, but Msx-1 knock outs result in 100% cleft palate.2 It has been suggested that, in humans, ∼50% of cases of cleft palate are non-syndromic.3 The etiology and pathogenesis of non-syndromic cleft palate—and also of all other clefts—are poorly understood. Extrinsic factors, such as maternal smoking4 with a particular allele in TGFα locus,5–7 maternal alcohol consumption,8,9 maternal intake of drugs during the first trimester,10 and …

Cone beam computed tomography in the assessment of alveolar bone grafting in children with unilateral cleft lip and palate

OBJECTIVES To quantify the treatment outcome of secondary alveolar bone grafting (SABG) in individuals with unilateral cleft lip and palate using cone beam computed tomography (CBCT) and to reveal needs for improvement in surgical technique. MATERIAL AND METHODS CBCT images taken 6 months after SABG of 35 patients were analysed. Vertical and horizontal bone supports of the grafted bone at three levels of the roots of the adjacent teeth were classified, the height of the nasal floor was compared with the unaffected side, and the inter- and intraexaminer reproducibility of these evaluations was assessed. RESULTS The grafted bone filled the defect in all three vertical measurement levels in 34 per cent. The labiopalatal thickness of the grafted bone was good in at least one-third of the root length in 66 per cent and fair in 34 per cent. Typically, the bone graft was deficient in the apical and palatal direction. Clear asymmetry in the nasal floor was found in 72 per cent. Kappa values indicated excellent agreement for all but one measured parameter. LIMITATIONS This is a preliminary study involving only a limited number of study subjects. CONCLUSIONS Our results showed mainly a good or fair treatment outcome. Deficiency of the bone graft was observed mostly in the apical and palatal areas of the defect. Asymmetry of the nasal floor was observed frequently. Careful insertion of the bone graft towards the palatal and apical direction of the cleft is recommended.