Journal of craniofacial genetics and developmental biology最新文献

The formation of an enamel-free area (EFA), a region of the dentin without an enamel cap at the cusp tip of rodent molar, is thought to depend on the specific differentiation and function of inner enamel epithelium of EFAs (EFA cells). The authors attempted to clarify both the ultrastructure and alkaline phosphatase (ALPase) activity of EFA cells up until tooth eruption by using rat mandibular first molars. Apoptosis was also examined. The EFA cells differentiated into secretory cells resembling differentiating ameloblasts but without Tomes' processes (postnatal day 1-3). No reactivity for ALPase was observed in the EFA cells. Enamel-like crystals were detected in close vicinity to dentin crystals at this stage. Thereafter, EFA cells became maturative ameloblast-like with ruffled border-like structures (postnatal day 5-8) and exhibited a strong reactivity for ALPase. These findings suggest that EFA cells change from secretory to absorptive cells within a short period and become reduced enamel epithelium at the early stage of tooth development. Apoptosis occurs in EFA cells, as it does in ameloblasts, but its significance seems to differ between the two cell types.

The craniofacial growth of 17 children born small for gestational age (SGA), who had received high-dose growth hormone (GH) treatment, was studied during the post-treatment phase. The preceding GH treatment consisted of a daily s.c. dose of either 0.2 or 0.3 IU/kg for 2 years. The group consisted of 9 girls and 8 boys with a mean (range) age of 6.9 yr (4-10 years) at the start of the post-treatment period, a mean (SD) bone age of 6.3 (2.1) years, and a mean (SD) height for chronological age of -1.0 (0.6) SDS. During the post-treatment period of 2 years, a catch-down effect was found for all linear craniofacial measurements in both treatment groups, even for the components that had not presented accelerated growth during GH treatment. Major growth vectors, such as the posterior total face height (S-Go) and the overall length of the mandible (Art-Pog), showed a low growth velocity, while minor growth parameters remained almost unchanged during this period. The angular measurements showed no significant changes during this period. It can be concluded that craniofacial growth in short SGA children showed, after a period of GH-induced acceleration, a catch-down period when GH administration is stopped. Despite this low post-treatment growth velocity, the craniofacial linear measurements in lateral aspect, remained larger than in untreated children.

Dentin dysplasia, type II (MIM*125420) is an autosomal dominant disorder of dentin development. Clinically the primary dentition appears opalescent, and radiographically the pulp chambers are obliterated, resembling dentinogenesis imperfecta. However, unlike dentinogenesis imperfecta, the permanent teeth in dentin dysplasia, type II are normal in color and, on radiographs, have a thistle-tube pulp chamber configuration with pulp stones. The similarity of the primary dentition phenotype suggested that the gene for dentin dysplasia, type II is allelic with the gene for dentinogenesis imperfecta, Shields type II (DGII; MIM*125490), which has been localized to chromosome 4q13-q21. Twenty-four members of a three generation family in which ten members are affected with dentin dysplasia, type II were genotyped for microsatellite alleles specific for the area of chromosome 4q linked to DGII. Linkage was assessed by using the LINKAGE computer program, assuming autosomal dominant inheritance, a disease allele frequency of 0.0001, and complete penetrance. The maximum two-point LOD score (Zmax = 4.2 at theta = 0.0) was obtained with SPPI and D4S2691. Multipoint analysis gave a maximum LOD score of 4.33. The candidate region for dentin dysplasia, type II is approximately 14.1 cM, includes SPPI, D4S2691, D4S2690, D4S451, and D4S2456, and overlaps the most likely location of the DGII locus. A candidate gene for DGII should also be considered a candidate gene for dentin dysplasia, type II.

The p53 tumor suppressor gene encodes a transcriptional activator whose targets include genes that regulate cell cycle progression and apoptosis. Since we have shown that a critical event in the life history of the chondrocyte is programmed cell death, we asked the question: does loss of the p53 gene influence skeletogenesis? Female p53(+/-) mice were mated with p53(+/-) male mice and 17-day-old fetal mice were studied. Exencephaly was the most profound skeletal defect of the p53 null mutation. This defect was due to failure of formation of the bones that comprise the mouse calvarium. There was also loss of the hyoid bone, and defective mineralization of the manubrium sternum and the terminal phalanges. In the homozygous state (-/-), in the absence of exencephaly, the number of skeletal deformities was markedly reduced. Aside from the gross changes associated with null status, the mutants exhibited alterations in bone length and width. Small differences in the size and orientation of the mineral crystals in embryonic bone, as evaluated by small-angle X-ray scattering, were found to disappear after birth. To explain these observations, we evaluated the extent of apoptosis in the tibial growth plates using the TUNEL stain. In the growth plate of the p53(-/-) homozygote, there was minimal labeling of the hypertrophic layer. Since the p53(-/-) TUNEL stain pattern at 17 days was very similar to the pattern of labeling of the p53(+/+) at 15 days, we concluded that the growth defect reflected a delay in cartilage maturation rather than a change in chondrocyte phenotype. On this basis, we predict that after birth, in mice that survive, differences in bone length would become minimal, and at maturity, the length of the long bones of (+/+) and (-/-) mice would be similar.

The defective bone resorption in the osteopetrotic op/op mouse brings about cranio-facial deformation and failure of tooth eruption. This study was conducted to elucidate the morphological changes of the condylar head and mandibular ramus in growing op/op mice. In normal mice, the condylar head is much broader than the ramus beneath it, enlargement and ossification of the condylar head begin after weaning, and the ramus becomes compact bone tissue. None of these changes were found in the op/op mice in the present observation. The condylar head was small, and its inner side was occupied by hypertrophic cartilage cells. In spite of the lack of bone resorption in op/op mice, the compaction of the mandibular ramus, which was composed of bone trabeculae, occurred later than that in normal mice. In view of recently studies reported evidence that local mechanical stress regulates the bone formation, we consider that undergrowth of the condylar head and the ramus in the op/op mouse results from not only a deficiency of osteoclasts but also insufficient mechanical stress from mastication.

Epidemiological studies revealed population differences in the frequency of cleft lip and palate, with wide faced, rapid growing populations having the highest incidence: Mongoloids > Caucasoids > Blacks. Laboratory studies have also demonstrated higher incidence of vitamin A-induced cleft palate in both rats and mice with rapid somatic growth rates compared to those with slower rates. The present study was designed to test the hypothesis that palatal width growth rates are significantly correlated with frequencies of cleft palate induced by hypervitaminosis A in seven strains of mice. Palatal width growth rates were calculated using 158 fetuses from 26 timed pregnant mice. Anterior and posterior palatal width growth rates during secondary palatogenesis were calculated between day 15 (n = 88) and day 18 (n = 70) gestational age. Anterior palatal width rates ranged from 0.106 mm/day (BALB/cByJ) to 0.219 mm/day (C57BL/6J), and rates for the posterior measure ranged from 0.111 mm/day (BALB/cByJ) to 0.179 mm/day (CBA/J). Vitamin A (10,000 IU/kg) was administered to an additional 26 timed pregnant mice on day 10 of gestation. The frequency of clefting, calculated from 181 fetuses at day 18 of gestation, was found to range from 52.4% +/- 9.7 (C3H/HeJ) to 96.3 +/- 6.4 (CBA/J). No significant correlation (P > 0.05) was found between palatal width growth rates and the frequencies of vitamin A induced cleft palate. It is concluded that if the rate of growth in the width of the palate is causative in clefting, it must be a pre-clefting (i.e., pre-shelf elevation) event and may only be detectable earlier than day 15 of gestation in the mouse.

Seventeen patients (twelve males and five females) with craniopharyngioma were studied by retrospective review (stature, bone age, and hormone therapy) and by follow-up assessment in all seventeen survivors (stature and craniofacial development). Roentgencephalometric films in the lateral and frontal projections were analyzed. Individual and mean facial diagrams were produced based on 221 reference points in the individual patients and compared to normative data. The posterior cranial base was significantly reduced in length and the cranial base angle was significantly increased. In the facial regions great variations in size and prognathy of the jaws were recorded; on average the patients' maxilla and especially the mandible were short and retrognathic in relation to the anterior cranial base when compared to average adults. Average size and shape of the calvaria, cranial base, and facial regions in the adult male craniopharyngioma group corresponded closely to the average male at the stage of maximum growth in body height, i.e., around 14 years of age. It was concluded that size and morphology of the sphenoid and basioccipital bones were severely affected, possibly as a result of the interfering growth of a craniopharyngioma in childhood. The retrusion of the facial regions might be present as a result of the flattening of the posterior cranial base, but the relatively short and retruded mandible could also be caused by growth hormone deficiency before diagnosis/operation and in periods of sub-optimal therapy. The close resemblance of craniofacial morphology between adult males with craniopharyngioma and normal boys at the time of peak height velocity might reflect the fact that imitation of the natural, optimal balance between growth hormone and sex steroid in puberty is difficult to obtain in therapy.

Diastrophic dysplasia (DTD) is a well-characterized, recessively inherited osteochondrodysplasia. Thirty-seven patients were studied for transverse craniofacial characteristics. Of these patients, 10 had cleft palate and 11 had submucous cleft palate. A cephalometric analysis based on posteroanterior (PA) cephalograms was performed: 16 landmarks were identified and digitized into a computer. Seven linear and four angular variables were calculated and the values compared with those of a matched control population. DTD patients differed from controls only in cases with cleft palate where the mesio-orbital, bigonial, and antegonial widths were large compared with controls. The present findings indicate that although the development and growth of cartilaginous structures are disturbed in DTD, the intramembranously developing bones and the appositional growth pattern do not seem to be primarily affected.

The etiology of non-syndromic cleft lip with or without cleft palate (CL +/- P) is unclear, although both familial and environmental factors are implicated. Because CL +/- P occurs at approximately the time of brain lateralization and is most often unilateral, developmental asymmetry effects have been postulated in CL +/- P etiology. Handedness is frequently used as an indicator of brain lateralization; therefore, several studies have examined the relationship between cleft laterality and handedness. However, these studies have had conflicting results. The present study investigated handedness in a Chinese sample of 211 non-syndromic CL +/- P surgical probands (ascertained in Shanghai for family studies of CL +/- P), 221 population-based but unmatched controls, and 272 first-degree relatives of the probands. Handedness was assessed by means of laterality quotients (LQ) calculated from questionnaire data. Mean LQ's were compared, as were various arbitrary definitions of handedness based on the LQ, for cases versus controls, males versus females, right-sided versus left-sided clefts, and cleft lip alone versus cleft lip plus cleft palate. CL +/- P cases had a significantly higher proportion of non-right-handedness (NRH) than controls, regardless of the definition of NRH (P values < or = .001). There were no statistically significant differences for any of the other comparisons. Familiarity of NRH was tested by comparing first-degree relatives of cases to controls; first-degree relatives were found to have a significantly higher proportion of NRH than controls, supporting familial effects in NRH. These results support the concept of a common etiology and/or developmental pathway for CL +/- P and handedness.

A cross-nursing experiment was conducted to examine the nursing dam strain effect on the postnatal growth of a newborn mouse offspring by simultaneously using larger DDD strain mice and smaller C57BL strain ones. A periodical cephalometric observation of the postnatal craniofacial growth of the offspring was longitudinally made from birth up to the 100th day of life in addition to measuring the offspring weight. According to multivariate statistical analyses, the following results were obtained: 1) The mean body weight of the DDD offspring cross-nursed by the C57BL dam was significantly lighter than that of the DDD offspring self-nursed by the DDD dam throughout the whole experimental period except at birth and on the 100th day. 2) The mean body weight of the C57BL offspring cross-nursed by the DDD dam was significantly heavier than that of the C57BL offspring self-nursed by the C57BL dam from the 10th day up to the 30th day. 3) There was a significant positive relationship between the offspring weight and the offspring craniofacial size throughout the entire experimental period in the C57BL offspring and from the 10th day up to the 40th day in the DDD offspring. 4) The nursing dam strain effect on the craniofacial size of the DDD offspring was also significant on the 30th, 60th, 80th, and 100th days. The adjusted craniofacial size of the DDD offspring cross-nursed by the C57BL dam was significantly smaller than that of the DDD offspring self-nursed by the DDD dam on the 30th, 60th, 80th, and 100th days. 5) The nursing dam strain effect on the craniofacial size of the C57BL offspring was not significant throughout the whole experimental period. The adjusted craniofacial size of the C57BL offspring cross-nursed by the DDD dam was almost the same as that of the C57BL offspring self-nursed by the C57BL dam throughout the whole experimental period. 6) The fat content of the DDD dam tended to be higher than that of the C57BL dam and the interstrain difference was closed to a significant level (P = 0.06) on the 20th day. The moisture content of the DDD dam tended to be lower than that of the C57BL dam and the interstrain difference was also significant on the 7th day (P < 0.001). Based on these findings, it can thus be concluded that the nursing dam strain effect played an important role in the postnatal somatic growth of the DDD and the C57BL offspring and the craniofacial growth and the DDD offspring.