Journal of craniofacial genetics and developmental biology. Supplement最新文献

By three pedigree and statistical criteria van der Woude syndrome (VWS) appears to have been underreported and frequently not diagnosed. Eight percent of gene carriers are not diagnosed because they are nonpenetrant. But among penetrant gene carriers as many as 80% may not have been recognized in the past. A direct estimate of incidence of VWS is 3.6/100,000 births; indirect estimates are more than double that. The relative risk of inheriting a cleft from an affected parent is 22.43%; the risk of inheriting lip pits only, or being nonpenetrant is 27.57%. (This corrects a similar statement in the abstract of Burdick et al [J Craniofacial Genet Dev Biol 5:181-208, 1985], which was incorrectly calculated). The idea of unitary control of the action of the VWS gene in the three target tissues appears not to be supported. Rather, we tend to support the idea that the gene is controlled independently in the three tissues. Indications of a family at risk are listed and discussed.

Chronokinetic synergism, a holistic and extremely sensitive experimental design, has shown in the mouse embryo that site-specific epigenetic forces differentially regulate genesis of the palate (cleft palate) and limb bud organogenesis (shortened stature). Acute exposures of 11-day pregnant mice to minimally effective doses of thymidine or ethanol followed 5 or 8 hr later by minimal exposure to retinoic acid have enabled quantitative and qualitative assay for genomic-epigenetic interactions. These site-specific morphogenetic regulations occurred during palatal genesis from the maxillary prominence of the first pharyngeal arch and during limb bud prechondrogenesis. Thymidine is presumed to induce its response by inhibition of DNA polymerase and hence by transitory cytostatic block. (Embryo size was not detectably changed). Ethanol is interpreted, guilt by associated response, indirectly to interfere with histone regulation of transcription. Two central findings have demonstrated the coordinated regulation of genomic and epigenetic positional information. First, thymidine or ethanol as epigenetic probes for limb prechondrogenesis and palatal precursor cells have activated distinctive site-specific responses. Second, responses to chronokinetic synergisms have indicated that epigenetic regulators for limb and palate dysmorphogenesis may affect distinctly different phases of the cell division cycle and hence induce differential DNA expressions. Although each of palate and limb is concurrently susceptible to epigenetic regulation, their differential intrinsic genomic capabilities appear to have been uncoupled. The putative homeostatic balance of genomic expressions in the palate precursor and the prechondrogenic limb bud cells of the 11-day mouse embryo has been characterized as epigenetically regulated, alternatively expressed, and positionally restricted. We propose that the chronokinetic synergisms have disclosed the existence of distinctive palate-determining genes and stature-determining genes.

An estimated 85-day-old human fetus exhibited a malformation complex consisting of holoprosencephaly, absent calvaria, exophthalmic hypertelorism, and severe bilateral midfacial orofacial clefting involving the maxillary/frontonasal prominences (oblique facial clefts), upper lip (bilateral clefts), and palate (complete cleft). This combination of dysplasias precludes assignment to previously described syndrome complexes. The presence of an olfactory nerve/ethmoidal bone complex does not conform with "classic holoprosencephaly," nor does acalvaria without cerebral dysraphism fit into the cranioschisis and exencephaly syndromes. It is postulated that this combination of anomalies is due to faulty embryogenesis of the prechordal cephalic mesenchyme, leading to failure of telencephalic cleavage and of neural crest-mediated development of the calvaria and facial prominences.

The effects of excess retinol (vitamin A alcohol) on facial process formation were examined in cultured rat embryos. The embryos were explanted at day 11 of gestation (plug day = 0) and cultured for up to the 50-somite stage in rat serum containing added 1 microgram/ml or 10 micrograms/ml retinol. The reduction in outgrowth of facial processes was observed in 1-microgram/ml-retinol-treated embryos and this type of malformation was found to be more severe in 10-micrograms/ml-retinol-treated embryos. Histological findings of 10-micrograms/ml-retinol-treated embryos at the 50-somite stage showed that the nasal epithelium was developed but folded. In the mesenchyme, there were necrotic cells. Thymidine incorporation by mesenchymal cells of facial processes was determined. At the 50-somite stage, the uptake was decreased to 66.4% of control value at 1 microgram/ml retinol, whereas the addition of the same dose of retinol did not cause the inhibition at the 36-, 40-, and 42-somite stages. The uptake at the 50-somite stage was decreased to 23.0% as a result of the 10 micrograms/ml retinol treatment. Furthermore, the effects of cartilage-derived factor (CDF) on the facial mesenchyme were examined; 20 micrograms/ml of CDF stimulated the 3H-thymidine incorporation in facial mesenchyme, especially after the 42-somite stage. By the addition of 10 micrograms/ml retinol, the incorporation decreased to 45.7% at the 38-somite stage, but it did not decline with concomitant use of CDF after the 38-somite stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Two genetic analyses suggested that the spontaneous and low frequency trait of cleft lip (primary palate) in the mouse is determined either by a recessive gene at one autosomal locus or by two loci with duplicate epistasis. The low frequency trait of open eyelids, which is characteristic of the A/J strain and sometimes reported to be associated with cleft lip as part of a "syndrome," has not been analyzed genetically. A backcross and test-mating study between A/J and C57BL/6J, done originally to define the genetic control of embryonic tolerance to cortisone-induced cleft palate (secondary palate), was reanalyzed for the cleft lip and open eyelids traits. Cleft lip frequencies in A/J did not change in dose-response studies of either cortisone- or 6-aminonicotinamide-induced cleft palate; for both teratogens the frequencies of open eyelids differed between doses but did not exhibit any obvious dose response. It appeared that the frequency of 7.6% cleft lip and 17.6% open eyelids in A/J in the genetic study, in which all pregnant A/J test-females were treated with a single dose of cortisone (100 mg/kg, day 12), did reflect the occurrence of the spontaneous traits. Within the A/J strain, the traits were not associated and, as expected on outcrossing to C57BL/6J (A.B6 F1 fetuses), both traits are recessive. Significant bimodality of the cleft lip scores of the BC1 sires (BC2 fetuses), test-mated with A/J, suggested that liability to cleft lip is determined by a single autosomal recessive gene. The distribution of open eyelids scores of the BC1 sires did not differ from one normal distribution, and this trait is, therefore, controlled by more than one genetic locus with additivity between loci. Cleft lip and open eyelids segregated independently and do not form a syndrome, in A/J, with one underlying genetic cause. There was no association between cleft lip and three autosomal marker genes, brown (b, chromosome 4), albinism (c, chromosome 7) and H-2 (chromosome 17), or the genetically independent tolerance traits of cortisone- and 6-aminonicotinamide-induced cleft palate. There was significant association between open eyelids and albinism (c) that is in a direction suggesting linkage or pleiotropy. Whether liability of the embryo to cleft lip is determined by one or two genes may be solved by a concerted effort to map the trait; a marker gene will be the key to further analysis of its cause.

A review of the autopsy records of the Department of Pathology of Nagasaki University and the Department of Geneticopathology of Hiroshima University from 1944 through 1982 revealed that during this period there were 11,050 cases of fetuses and newborns, including 432 cases with craniofacial and oral malformations and 22 cases with amniogenous malformations. Among the cranial malformations, there were 202 (46.8%) anencephaly cases, 38 (8.8%) holoprosencephaly, 28 (6.48%) hydrocephaly, 27 (6.25%) meningoencephalocele, and 13 other cranial malformations (seven microcephaly and two each of macrocephaly, dolichocephaly, and iniencephaly). Among the oral malformations, there were 25 (5.78%) cleft lip cases, 23 (5.32%) cleft palate, and 76 (17.6%) cleft lip and palate. Among the facial malformations, there were 12 (2.78%) anomicrophthalmia cases, 37 (8.56%) ear malformations, 15 (3.47%) micrognathia, and 8 (1.85%) nose malformations. One cranial malformation was found that was complicated with anencephaly and holoprosencephaly. Of 307 cranial malformations, 38 (12.4%) were complicated with oral malformations and 4 (4.6%) with facial malformations. Among the 124 cases of oral malformations, 38 (30.6%) were complicated with cranial malformations. The complicating cranial malformations were anencephaly in 16 cases, holoprosencephaly in seven, hydrocephaly in six, meningoencephalocele in seven, other cranial malformations in two, and with facial malformations in 19 cases. Among the 72 cases of facial malformations, 14 were complicated with cranial malformations and 19 with oral malformations. Four cases showed three or more cranial, facial, and/or oral malformations at the same time. Recently, experimental embryological studies have shown that the neural crest cell-derived mesectoderm participates largely in the morphogenesis of the face and the cardiovascular system. It may be said that neural crest cells are deeply involved in the teratogenesis.

The facial processes, which consist of the medial nasal process (MNP), the lateral nasal process (LNP), and the maxillary process (MP), are basal components in facial morphogenesis, especially upper lip formation. To examine the relative role of each facial process in normal or abnormal facial development, rat embryos that had had a part of each facial process excised were cultured for 72 hr in vitro from gestational day 11.5 (plug day = day 0). At the termination of culture, although the epithelial wound was healed over, the defect was observed corresponding to excised region in form. Only in the MNP-excised group was cleft liplike malformation observed, but in other groups this malformation was absent or at a lower rate. This suggests that the medial nasal process in this stage plays a critical role in normal facial development as well as cleft lip formation.

Cleft lip with or without associated cleft palate [CL(P)], one of the most common human malformations, is in most cases, believed to be caused by a combination of genetic and environmental factors. Previous studies have shown that maternal respiratory hypoxia (10% O2) increases the incidence of CL(P) from the spontaneous level of 36% to 89% in CL/Fr mice. The current investigation was designed to study, morphologically, the developmental alterations of the primary palate primordia in CL/Fr embryos, following a reduction in maternal respiratory oxygen levels. Scanning electron microscopy was utilized to compare the development of 35-43 somite hypoxia and control (normoxia) embryos. Hypoxia increased the incidence of resorptions and increased the incidence of CL(P) in viable embryos, compared to normoxia. Debris, most of which was limited to the deeper aspects of the invaginating nasal placode, was present in hypoxia embryos at stages prior to primary palate fusion and was absent in comparably staged normoxia embryos. It is believed that this debris is cellular in nature and that associated retardation of placodal invagination is primarily responsible for the increased incidence of CL(P). Other effects on morphogenesis and/or growth retardation may also be contributing factors.

Responses of the epithelial and mesenchymal cells of the developing hamster secondary palate to hadacidin, 5-fluorouracil, and hydrocortisone were analysed. Correlation of data on cellular response with morphological and biochemical observations suggested that several aspects of differentiation of palatal cells needs to be analysed before pathogenesis of teratogen-induced cleft palate can be defined.

During the past three decades, Burmese cats have been selected for a shorter muzzle and a more rounded face. Recently there arose a line of these animals that consistently exhibit such a brachycephalic appearance; unfortunately, approximately 25% of these kittens are born with a neonatal lethal midfacial malformation. The abnormality is characterized by agenesis of all derivatives of the medial nasal prominence; lateral duplication of most derivatives of the maxillary process; including the canine teeth and whiskers fields; telencephalic meningoencephalocele; and secondary ocular degeneration. The anatomy, embryology, and pattern of inheritance of this unique midfacial malformation are described.