Nasal expansion in the fetal lamb: a first step toward management of cleft nasal deformity in utero

The cleft nasal deformity, a combination of malpositioned cartilage and tissue and postrepair scarring, is a difficult problem to correct. To harness the potential of scarless fetal wound healing, in utero repair of cleft lip and palate deformities has been studied but the fetal cleft nose deformity has not been addressed. The purpose of this study was to manipulate the fetal nasal shape in utero as a first step toward restoration of normal nasal form in cleft nasal deformities. To do this, preformed hypertonic sponges were placed into the right nostril of eight fetal lambs during the second trimester (when scarless cutaneous wound repair is known to occur). Then, the size and shape of fetal nasal structures were analyzed after selected time periods (1, 2, and 6 weeks) with measurements, routine histologic examination, and three-dimensional computed tomographic scans of the experimentally expanded noses compared with the control nonexpanded noses of the birth twins or age-matched specimens. Results showed that experimentally expanded nasal structures had markedly increased in septal length measurement, in nostril area (doubled), and in intranasal volume (more than doubled). Histology showed normal cellular elements without scarring in the tissue sections from the expanded nasal areas. In conclusion, the shape of nasal tissue can be manipulated without scarring in second-trimester fetal lambs after placement of a nasal expansion device. This study is an experimental first step toward restoring normal nasal form by repositioning alar cartilages and soft tissue during fetal cleft repair.     

Three dimensional assessment of the pharyngeal airway in individuals with non-syndromic cleft lip and palate

Introduction

Children with cleft lip and palate (CLP) are known to have airway problems. Previous studies have shown that individuals with CLP have a 30% reduction in nasal airway size compared to non-cleft controls. No reports have been found on cross-sectional area and volume of the pharyngeal airway in clefts. Introduction of Cone-Beam CT (CBCT) and imaging software has facilitated generation of 3D images for assessment of the cross-sectional area and volume of the airway.

Objective

To assess the pharyngeal airway in individuals with CLP using CBCT by measuring volume and smallest cross-sectional areas and compare with 19 age- and sex-matched non-cleft controls.

Methods

Retrospective study of CBCT data of pre-adolescent individuals (N = 19, Mean age = 10.6, 7 females, 12 males, UCLP = 6, BCLP = 3) from the Center for Craniofacial Anomalies. Volumetric analysis was performed using image segmentation features in CB Works 3.0. Volume and smallest cross-sectional were studied in both groups. Seven measurements were repeated to verify reliability using Pearson correlation coefficient. Volume and cross-sectional area differences were analyzed using paired t-tests.

Results

The method was found to be reliable. Individuals with CLP did not exhibit smaller total airway volume and cross sectional area than non-CLP controls.

Conclusion

3D imaging using CBCT and CB Works is reliable for assessing airway volume. Previous studies have shown that the nasal airway is restricted in individuals with CLP. In our study, we found that the pharyngeal airway is not compromised in these individuals.     

Early palatal changes in complete and incomplete cleft lip and/or palate.

Early palatal development in various complete and incomplete forms of cleft lip and/or palate (CLP) was studied from birth to 3 months of age by means of dental casts. Palatal morphology (shape) and dimensions--based on reproducible reference points--were determined in a group of 128 CLP children and 68 normal children who served as controls. Substantial normal palatal growth during the first 3 months of life was observed. Round arch forms changed into oval arch forms. Growth mainly takes place in the sagittal direction (+4 mm) (transverse: +1 mm). Palates of CLP children differed significantly dependent on the type of cleft and whether the cleft was complete or incomplete. Cleft lip and alveolus children and bilateral cleft lip and palate children had more elongated palatal arches, whereas unilateral cleft lip and palate children and cleft palate children had wider palatal arches than the control group. Incomplete clefts differed from the control group in the same direction as their complete cleft forms, though less distinctly. Preoperative orthopedics used in CLP patients does not stimulate growth. On the contrary, it even restricts growth.     

Rotation advancement of the midface by distraction osteogenesis

A wide variety of disease processes produce alteration of midfacial skeletal growth, resulting in moderate-to-severe midface deficiency presenting as retrusion associated with Angle's class III malocclusion. Le Fort III osteotomies with advancement can provide an excellent tool for correction of this deformity. Recently, the corrective procedure of choice for advancement of midfacial segments has been distraction osteogenesis after osteotomy. Straight linear advancement is the most common choice for corrective movement of the midfacial segment, whether accomplished through acute surgical advancement or through the progressive distraction technique. Unfortunately, linear advancement can produce abnormal configurations, both at the nasal root and lateral orbits, regardless of the technique used. Enophthalmos, caused by orbital enlargement, may limit the advancement necessary to achieve class I occlusion.The authors have extended the utility of the Le Fort III procedure and have improved the final outcome by creating a controlled rotation advancement of the midfacial segment using distraction. The application of an existing internal distraction device is modified to control the movement of the midfacial segment in a rotation advancement path. Included in the series were 10 patients with severe midface retrusion secondary to multiple congenital syndromes, along with cleft lip and palate. The ages of the patients ranged from 6 to 14 years. An internal distraction system was used in all cases. Application of the distractor was substantially modified to simplify both fixation and removal and to produce controlled rotation advancement. The team orthodontist determined the final occlusal relationship. Percutaneous distractor drive rods were removed 4 to 6 weeks after active distraction to increase patient comfort. The distractors and all associated hardware were removed after 12 to 16 weeks of consolidation; follow-up periods ranged from 1 to 3 years.By using the modified distractor application to produce rotation advancement, the contour abnormalities at the nasal root and lateral orbit and the enophthalmos produced by linear advancement were eliminated. Significant improvement in facial contour and class I occlusion was obtained in all cases. Complications consisted of near exposure of the device in one patient. Stability has been excellent, with no relapse reported by the orthodontist.Rotational advancement of facial segments by distraction allows successful early intervention in patients with significant midface retrusion. The abnormal nasal root and lateral orbital configurations produced by direct linear advancement are avoided, and a stable and normalized facial configuration is produced.     

Development of the orbicularis oris muscle in normal and cleft lip and palate human fetuses using three-dimensional computer reconstruction

As part of an ongoing study of cleft lip and palate fetal morphology, normal and dysmorphic development of the human fetal orbicularis oris muscle was studied in a cross-sectional sample of 29 human fetuses (20 "normal" and 9 cleft lip and palate) ranging in age from 8 to 21 postmenstrual weeks. The specimens were embedded in celloidin and sectioned at 20 microns, and every tenth section was stained with hematoxylin and eosin. A computer reconstruction technique was applied to produce three-dimensional representations of the orbicularis oris muscle. The orbicularis oris muscle in the normal fetal sample with discernible lip fibers (N = 15) increased symmetrically in both fiber density and complexity from 12 to 21 weeks. Metrically, muscle volume and thickness growth curves were consistent with qualitative observations. In contrast, the unilateral cleft lip and palate fetal specimens with discernible lip fibers (N = 3) exhibited a 3.5-week delay in overall muscle development, asymmetrical fiber distribution, and abnormal fiber insertions. However, quantitatively, no significant (p greater than 0.05) differences were noted in orbicularis oris muscle thickness or volume between the normal and cleft lip and palate fetal specimens through 21 weeks. Findings suggest that orbicularis muscle deficiency, noted clinically in cleft lip and palate neonates, may be a result of perinatal functional dysmorphogenesis rather than congenital mesenchymal reduction or deficiency.     

Bmp4 gene is expressed at the putative site of fusion in the midfacial region

The molecular mechanisms by which the primordia of the midface grow and fuse to form the primary palate portion of the craniofacial region are not well characterized. This is in spite of the fact that failure of growth and/or fusion of these primordia leads to the most common craniofacial birth defect in humans (i.e. clefts of the lip and/or palate). Bmp4 plays a critical role during early embryonic development and has previously been shown to play a role in epithelial-mesenchymal interactions in the craniofacial region of chicks. We analyze the expression of bmp4 in mouse as the midfacial processes undergo fusion to form the primary palate. We show that bmp4 is expressed in a very distinct manner in the three midfacial processes (lateral nasal, LNP, medial nasal, MNP, and maxillary processes, MxP) that ultimately fuse to form the midface. Prior to fusion of the midfacial processes, bmp4 is expressed in the ectoderm of the LNP, MNP, and MxP in a distinct spatial and temporal manner near and at the site of fusion of the midface. Bmp4 appears to demarcate the cells in the LNP and MNP that will eventually contact and fuse with each other. As fusion of the three prominences proceeds, some bmp4 expressing cells are trapped in the fusion line. Later, the expression of bmp4 switches to the mesenchyme of the midface underlying its initial expression in the ectoderm. The switch occurs soon after fusion of the three processes. The pattern of expression in the midfacial region implicates the important role of bmp4 in mediating the fusion process, possibly through apoptosis of cells in the putative site of fusion, during midfacial morphogenesis.     

Prenatal epidemiology of spontaneous cleft lip and palate, open eyelid, and embryonic death in A/J mice.

Nongenetic bases of variability in the frequencies of spontaneous cleft lip and palate (CLP), open eyelid (OL), and fetal resorption were searched for in A/J mouse litters of prenatal ages 17-21 days post-VP and parities 1-7. The malformation rates did not decrease with advancing fetal age, and hence prenatal elimination does not account for the lower rates seen in newborns. Multivariate analysis indicated that the frequencies of CLP and resorption were inversely related to maternal age and directly related to litter size, and that the frequency of OL was related, directly, only to litter size; but that none were associated with maternal weight, parity, and several other variables. Regarding uterine location, the frequency of CLP was higher at the ovarian and cervical sites, OL higher at the cervical site, and resorption lower at the ovarian site, than elesewhere. CLP was significantly commoner in females, and OL commoner in males; also, since the percentage of males increased with parity, the frequency of CLP in males relative to that in females decreased with parity, and that of OL increased. Malformed offspring weighed less than normal ones; and the sex with the lower frequency of CLP or OL had the greater weight reduction. The results are discussed in relation to the frequency of malformations in human fetuses and newborns.     

Palatal growth in baboons (Papio cynocephalus anubis)

In this study the structure and development of the palate as observed in a cross-sectional collection of olive baboons (Papio cynocephalus anubis) skulls are described and analyzed using craniometric techniques. Considered are structural functional relationships among different parts of the palate, and between the palate and other parts of the craniofacial skeleton. Several inferences are drawn and speculated upon. These inferences are as follows: odontogenesis affects premaxillary growth the most during late fetal and early postnatal development; maxillary length is significantly affected by development and eruption of the maxillary dentition, whereas maxillary breadth is less affected by dental development. Growth of the palatine bones and nasopharyngeal airway is correlated with dentomasticatory changes; the developmental and functional significance of these correlations is unclear. Further inferences are that growth rates for each palatal component differ for each sex even though lengths of the components relative to total palatal dimensions show no sexual dimorphism. Also, it is determined that maxillary length remains constant, premaxillary length reduces and palatine length increases relative to total palatal length with growth.     

Maxillary reconstruction: functional and aesthetic considerations

Maxillary reconstruction is a challenging endeavor in functional and aesthetic restoration. Given its central location in the midface and its contributions to the key midfacial elements--the orbits, the zygomaticomaxillary complex, the nasal unit, and the stomatognathic complex--the maxilla functions as the keystone of the midface and unifies these elements into a functional and aesthetic unit. Maxillary defects are inherently complex because they generally involve more than one midfacial component. In addition, most maxillary defects are composite in nature, and they often require skin coverage, bony support, and mucosal lining for reconstruction. In the reconstruction of maxillary defects secondary to trauma, ablative tumor surgery, or congenital deformities, the following goals must be met: (1) obliteration of the defect; (2) restoration of essential functions of the midface, such as mastication and speech; (3) provision for adequate structural support to each of the midfacial units; and (4) aesthetic reconstruction of the external features. This review will discuss the pertinent anatomic considerations, the historical approaches to maxillary reconstruction, and the merits of the techniques in use today, with an emphasis on state-of-the-art reconstruction and dental rehabilitation of extensive maxillary defects.     

Radiographic analysis of the midface of a stillborn infant with a unilateral cleft lip and palate

The midface of a full-term stillborn infant with a right complete unilateral cleft lip and palate was studied with plain-film radiography and tomography, xeroradiography, and computerized axial tomography. Gross skeletal and soft-tissue deficiencies on the cleft side were evident as compared to the noncleft side and involved the entire bony maxillary complex and antrum, the orbit, and the nasal pyramid and intranasal structures. The area on the cleft side was 19 percent less than the noncleft side, and the maximal anteroposterior dimension was 16 percent less. The cleft bony palatal shelf was 12.5 mm wide compared to 20 mm on the noncleft side. The findings demonstrate the deficient and abnormal functional matrix inherent in the cleft condition.     

Binderoid complete cleft lip/palate

A small subset of infants with complete cleft lip/palate look different because they have nasolabiomaxillary hypoplasia and orbital hypotelorism. The authors' purpose was to define the clinical and radiographic features of these patients and to comment on operative management, classification, and terminology. The authors reviewed 695 patients with all forms of incomplete and complete cleft lip/palate and identified 15 patients with nasolabiomaxillary hypoplasia and orbital hypotelorism. All 15 patients had complete labial clefting (5 percent of 320 patients with complete cleft lip/palate), equally divided between bilateral and unilateral forms. The female-to-male ratio was 2:1. Of the seven infants with unilateral complete cleft lip/palate, one had an intact secondary palate and all had a hypoplastic septum, small alar cartilages, narrow basilar columella, underdeveloped contralateral philtral ridge, ill-defined Cupid's bow, thin vermilion-mucosa on both sides of the cleft, and a diminutive premaxilla. Of the eight infants with bilateral complete cleft lip, one had an intact secondary palate. The features were the same as in patients with unilateral cleft, but with a more severely hypoplastic nasal tip, conical columella, tiny prolabium, underdeveloped lateral labial elements, and small/mobile premaxilla. Central midfacial hypoplasia and hypotelorism did not change during childhood and adolescence. Intermedial canthal measurements remained 1.5 SD below normal age-matched controls. Skeletal analysis (mean age, 10 years; range, 4 months to 19 years) documented maxillary retrusion (mean sagittal maxillomandibular discrepancy, 13.7 mm; range, 3 to 17 mm), absent anterior nasal spine, and a class III relationship. The mean sella nasion A point (S-N-A) angle of 74 degrees (range, 65 to 79 degrees) and sella nasion B point (S-N-B) angle of 81 degrees (range, 71 to 90 degrees) were significantly different from age-matched norms ( = 0.0007 and = 0.004, respectively). The ipsilateral central and lateral incisors were absent in all children with unilateral cleft, whereas a single-toothed premaxilla was typically found in the bilateral patients. Several modifications were necessary during primary nasolabial repair because of the diminutive bony and soft-tissue elements. All adolescent patients had Le Fort I maxillary advancement and construction of an adult nasal framework with costochondral or cranial graft. Other often-used procedures were bony augmentation of the anterior maxilla; cartilage grafts to the nasal tip and columella; and dermal grafting to the median tubercle, philtral ridge, and basal columella. Infants with complete unilateral or bilateral cleft lip/palate in association with nasolabiomaxillary hypoplasia and orbital hypotelorism do not belong on the holoprosencephalic spectrum because they have normal head circumference, stature, and intelligence, nor should they be referred to as having Binder anomaly. The authors propose the term cleft lip/palate for these children. Early recognition of this entity is important for counseling parents and because alterations in standard operative methods and orthodontic protocols are necessary.     

Premaxillary-maxillary suture fusion and anterior nasal tubercle morphology in the chimpanzee

The anterior nasal spine (ANS) is considered by some to be a unique characteristic of modern humans; however, it has been reported to occur in chimpanzees. Among human populations, ANS size correlates with facial prognathism and timing of premaxillary-maxillary sutural fusion, which may have implications for models of midfacial growth. To investigate these questions, skulls from 55 chimpanzees (Pan troglodytes) (29 male, 26 female), ranging in age from infants to adults, were examined. None of the 55 specimens examined had a true ANS, but a number of specimens exhibited raised anterior nasal prominences or tubercles (ANT) on the nasal surface of the premaxilla. Female specimens had significantly (P less than .05) more ANTs and more extensive fusion of both the palatal and facial components of the suture than did the male specimens. Results from the present study document the presence of an ANT in a sample of chimpanzee crania and are consonant with associations predicted by a septal-traction model of midfacial growth.     

Cephalometric and anthropomorphic observations of Binder's syndrome: a study of 19 patients

Binder's syndrome (maxillonasal dysplasia) is a disorder characterized by nasomaxillary hypoplasia. To ascertain the extent of underdevelopment of the midfacial skeleton and soft tissues, 19 of 29 patients with Binder's syndrome were retrospectively evaluated, both with cephalometry and anthropometry. Ten females and nine males were placed collectively into three age groups: 6 years, 10 years, and 16 to 17 years. Cephalometric measurements disclosed a short anterior cranial base (S-N), a normal length of the vertical maxilla (SE-PNS), a decreased horizontal maxilla (PNS-A, Co-A), a recessed orbitale (SNO), and a high-normal mandibular length (Co-Gn). Anthropometry revealed a large nasofrontal angle, acute nasal inclination and nasolabial angle, decreased nasal prominence (Sn-Prn), a decreased columellar length (C-Sn), and a normal vertical nose (N-Sn) and upper lip (Sn-Sto) length.     

A comparison of the craniofacial morphology in 2-month-old unoperated infants with unilateral complete cleft lip and palate, and unilateral incomplete cleft lip.

This paper reports a cephalometric analysis of the craniofacial morphology in infants with unoperated unilateral complete cleft lip and palate (UCCLP) and unoperated unilateral incomplete cleft lip (UICL). The purpose of the study was to determine the nature and extent of the craniofacial deviations in UCCLP as compared to the morphology in UICL, which has previously been shown to be close to normal. The samples comprised 82 infants with UCCLP (58 males and 24 females) and 75 with UICL (48 males and 27 females). The mean age was about 2 months in both groups. The cephalometric analysis of craniofacial morphology included the lateral, frontal, and axial projections. The data were presented as mean plots of the craniofacial region including the calvaria, cranial base, orbits, nasal bone, maxilla, mandible, cervical column, pharynx, and soft-tissue profile. The most pronounced deviations in the UCCLP group were observed in the maxillary complex and the mandible. The most striking findings were: markedly increased width of the maxilla, a short mandible, and bimaxillary retrognathia except for the premaxillary area, which was relatively protruding and asymmetric. The study did not support the hypothesis previously suggested in the literature that cleft lip and palate is a craniofacial anomaly as size and shape of the calvaria and cranial base were found to be normal. The etiology of cleft lip and palate is still incompletely understood. Based on the present study, we suggest that facial type may be a liability factor that could represent a developmental threshold increasing the probability of cleft lip and palate.     

6.5-mm human embryo with a single nasal placode: cyclopia or hypotelorism?

A macroscopic study on the missing elements in cyclopia (a single eye or closely approximated eyes with all intergrades in a single orbit) with or without proboscis and hypotelorism was performed on 12 human fetuses and 2 human fetal skulls. In addition, microscopic investigations were carried out on the orbital contents of the cyclops with a single eye without proboscis, crown-heel length (C-HL) 37 cm, and on the 6.5-mm-crown-rump length (C-RL) human embryo with a single nasal placode localized in front of two eye cups. In the embryo and in all 14 fetal cases the midfacial region was more-or-less deficient. In the two cyclopia cases without proboscis the nasal placode(s) had not developed at all during the embryonic period. In cases with proboscis, consisting of a single tube localized above both eyes, and in the hypotelorismic specimens, there could only have been a single nasal placode during development: a situation evident in the 6.5-mm-C-RL human embryo. In this holoprosencephalic embryo the single nasal placode was undulated, as if formed from two fused nasal placodes, and flanked by the prospective areas for the lateral nasal processes. Caudally, it was bordered by the maxillary processes. In view of the position of the single placode in this embryonic face, as described above, it is most likely that this is a preliminary stage of hypotelorism. Moreover, both medial nasal processes with the internasal groove in between, i.e., the interplacodal area, were missing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic analysis in families with van der Woude syndrome

We have brought together information on 864 affected individuals in 164 families (including three new pedigrees) reported in the 137 year period since 1845 when Demarquay first described a family with what was later called van der Woude syndrome (VWS). Both types of oral cleft, cleft palate (CP) and cleft lip with or without CP (CLP), segregate in these families together with lower lip pits or fistulae in an autosomal dominant mode with high penetrance estimated to be K = .89 and .99 by different methods. Cleft types (CLP and CP) occur in VWS in the same proportions as in the general non-VWS population, ie, about twice as many cleft-bearing individuals have CLP as have CP. On the other hand, we do not find the usually observed excess of females with CP and excess of males with CLP; in VWS the sex ratios are more nearly equal. Lip pits also are equally distributed between the sexes. Affected males and females are equally likely to transmit VWS. However, there is an excess of less severely affected individuals among transmitters and a deficiency of more severely affected, brought about by a proband bias and differential fecundity. The expression of VWS is significantly modified by the genetic background: More extreme phenotypes in parents tend to produce more extreme expression in their children. For a VWS gene carrier the relative risk of transmitting a cleft is 26.45%; that of transmitting lower lip pits is 23.55%. Three pedigrees of lip pits in the literature show no clefts among a significant number of affected individuals. Control of gene expression in VWS in the three target tissues appears to be independent and separately designated. Mutation rate of the VWS gene is calculated to be 1.8 X 10(-5).     

Facial skeletal growth in growing "toothless" osteopetrotic (op/op) mice: radiographic findings

The defective bone resorption in the osteopetrotic (op/op) mouse brings about failure of tooth eruption. Furthermore, the op/op mouse has been studied as a "toothless" mouse in recent morphological and physiological investigations of the relationship between mastication and masseter muscle development. The present study was conducted to examine in detail the nasal bone and the premaxillary bone in this mutant mouse and to assess the roles of incisor growth and the mechanical stress of mastication in nasal bone and premaxillary bone growth. The forms of the nasal bone and the premaxillary bone were observed using roentgenography in both toothless op/op and normal (control) mice. In the op/op mouse, the nasal bone and the premaxillary bone show remarkable deformity. In contrast, the normal mouse appears well developed. This suggests that growth of the incisor root is important to normal upper jaw growth in the mouse. Furthermore, it is proposed that the upper facial phenotype seen in the op/op mice results from not only decreased bone resorption, but also from absence of the mechanical stress provided by normal mastication.     

Morphological characteristics of monosomy X in spontaneous abortions

From a morphologic and cytogenetic study of 160 spontaneous abortion specimens with 45,X, as well as data from the literature, we conclude that monosomy X has characteristics which can suggest the diagnosis in prenatal life in the absence of a karyotype. Specimens in our study could be classified into four groups: (I) 49% consisted of a chorionic and amniotic sac, usually ruptured, containing a well-defined umbilical cord with a fragment of embryonic tissue at its end. (II) 25% consisted of small macerated embryos of 40-44 days developmental age, with pronounced retrognathia and lack of nasofrontal angle. Two specimens had a neural tube defect, one had cleft lip and palate, and two had an isolated cleft palate. The developmental age of the embryos was 5-6 weeks behind their gestational age. (III) 5% were very macerated second trimester fetuses with cystic hygromata, lymph-edema of the hands and feet, ascites, hydrothorax, and hypoplastic lungs. Four had coarctation of the aorta, three had single umbilical artery, and two had persistent left cardinal vein. Horseshoe kidney, ventricular septal defect, and anomalous subclavian artery were found once. (IV) The remaining 21% consisted only of fragments of ruptured sacs without an umbilical cord insertion site, pieces of fetal membranes or chorionic villi only. The spectrum of anomalies observed suggests that the pathogenetic mechanism for early death in 45,X embryos and fetuses may be related to vascular abnormalities or to abnormal fluid balance, leading to disturbed embryo-placental circulation, and excess fluid volume in the fetus. The 45,X karyotype is compatible with quite normal morphological development up to the fetal stage, and no specimens were found where development had ceased at a very early stage. The usual lethality of monosomy X may be explained by the presence of genes, essential for survival, on the pseudoautosomal segment of the X and Y. Lethality could result from recessive lethal mutations in this region, or from the necessity for two copies of this regions for normal development.     

Traction, prenatal development, and the labioseptopremaxillary region

Twenty-nine human fetuses ranging in age from 8 to 22 weeks were coronally sectioned for gross light microscope analysis of the labioseptopremaxillary region. In "normal" fetuses from 8 to 15 weeks, the septopremaxillary ligament was present. The horizontal and oblique fibers of the orbicularis oris muscle were poorly developed initially and increased in density with age. The anterior nasal spine and the alveolar process of the maxillae were present and in the same coronal plane. From 15 to 22 weeks, the horizontal and oblique fibers were well developed and inserted into the perichondrium of both alar and nasal cartilages. The septopremaxillary ligament was thus obliterated or more difficult to define, and the anterior nasal spine was located anterior to the alveolar process. In the cleft fetuses from 8 to 15 weeks, the nasal septum was absent or horizontally rotated. No septopremaxillary ligament or orbicularis oris fibers were noted, and the anterior nasal spine was not distinguishable. From weeks 15 to 20, the fibers of the orbicularis oris muscle were poorly differentiated, inserting asymmetrically into the perichondrium of the lateral alar cartilage on the noncleft side, the septopremaxillary ligament was absent, and the anterior nasal spine and the premaxillae were in the same coronal plane. These results suggest that the midfacial deficiencies seen in some cleft patients might have an origin in prenatal dysmorphology.