Ultrastructure of initial nasal process cell fusion in spontaneous and 6-aminonicotinamide-induced mouse embryo cleft lip

A search was made for cell ultrastructure differences in the initial fusion process of the medial and lateral nasal processes in mouse embryos of the following types: A/J with 12% cleft lip (CL), CL/Fr with 23% CL--both cleft-lip-predisposed strains, CL/Fr 6-aminonicotinamide (6AN)-treated (94% CL) and controls from the C57BL/6 strain (0% CL) and dancer stock (0% CL). No detectable differences were found between the A/J and CL/Fr strains and the controls in the epithelial cells showing initial contact and fusion. Epithelial surfaces not in contact in controls and where clefts were developing were smooth. Cells approaching or in contact had cell projections, intercellular junctions, desmosomes, and microfilaments demonstrating firm contact between the apposed epithelia. It has been postulated that spontaneous cleft lip was due to a predisposing face shape bringing about a failure of contact in some embryos and in others where contact was achieved fusion was normal. These data support this view. The situation, however, in 6AN-treated embryos is different. A few 6AN-treated embryos showed abnormal contact that appeared malpositioned and tenuous. The teratogen also caused increased cell death and a denser epithelium and mesenchyme. Thus 6AN-induced cleft lip could be due to the epithelial cell changes and/or to the reduction in size of the nasal processes.     

Spontaneous cleft palate in CF#1/Ohu mice]

We found a spontaneous cleft palate in a mouse of CF#1/Ohu (Ohu University, Japan). Further, the frequency of the spontaneous cleft palate in strains of CF#1/Jms (Institute of Medical Science, University of Tokyo, Japan) and CF#1/Jah (National Institute of Animal Health, Japan) were about 3%, respectively. The frequency and the types of spontaneous cleft palate in CF#1 were clearly different from those in A/J and CL/Fr strains which were used as model animals of lip and cleft palate. We think that CF#1 is the new animal models to analyze a cleft palate genetically and biochemically.     

Increased susceptibility to 6-aminonicotinamide-induced cleft lip of heterozygote Dancer mice

Dancer heterozygotes (Dc/+) very rarely have cleft lip and show a dancing behaviour due to inner ear defects while homozygotes (Dc/Dc) have cleft lip. Males of the two genotypes Dc/+ and +/+ were mated to C3H strain and R stock females and Dc/+ males to Dc/+ females. On day 10/8 of gestation females were treated with 6-aminonicotinamide (6AN) at either 19 mg/kg or 28.5 mg/kg followed 3 h later by a protective dose of nicotinamide. Controls were untreated. Both 6AN treatments caused a significant increase in cleft lip to between 25% and 29% for crosses of Dc/+ males to C3H and R females whereas crosses with +/+ males gave 0% cleft lip. In the controls the cleft lip frequency was: for Dc/+ X Dc/+ 14%, Dc/+ X C3H 1.4%, and for the other three crosses 0%. The four crosses given the high dose of 6AN and the +/+ X C3H and Dc/+ X R cross at the low dose showed significantly increased resorption rates to between 23% and 47% over the control rates of from 5% to 11%. The presence of the Dc gene increased the susceptibility to cleft lip caused by 6AN.     

Epidemiological and genetic study of 200 cases of oral cleft in the Emilia Romagna region of northern Italy

Epidemiological and genetic variables in clefts were analyzed during the years 1978-1986 in a case-control study of congenital malformations in the Emilia Romagna region of northern Italy. Among 150,168 newborns, 200 cases of cleft were detected, yielding a prevalence of 1.33 per 1,000. These clefts consisted of 112 (0.075%) cases of cleft lip with or without cleft palate (CL +/- P) and 88 cases (0.058%) of cleft palate (CP). Coexisting abnormalities were found in 32% of cases. The heritability coefficient of CL +/- P was 0.84. No cluster in time or space could be demonstrated. Epilepsy was the only maternal risk factor found to be correlated with clefts. A predominance of males was found among CL +/- P cases.     

Association of cleft lip and atrial septal defect in mice: a preliminary report.

Newborn A/J and CL/Fr mice with congenital cleft lip usually have an atrial septal defect of the secundum type, often associated with cyanosis. Their littermates without cleft lip rarely have a septal defect. The atrial septal defect results from a delay in growth of the atrial septum primum.     

A digenic cause of cleft lip in A-strain mice and definition of candidate genes for the two loci

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate, CL(P), is a common human birth defect with a complex unknown genetic cause. The mouse model is the "A/-" strains. Our previous studies mapped two loci: clf1 on Chr11 and clf2 on Chr13--with a strong genetic maternal effect on the level of risk. Here we test the hypothesis that CL(P) is digenic and identify candidate genes for clf1 and clf2. METHODS: We observed E14 CL(P) frequencies in backcross (BC1) embryos from a new cross of A/WySn to AXB-4/Pgn and from test crosses of three new "congenic RI" lines. Using new polymorphic markers from genes and our mapping panels of segregants and RI strains, we identified the candidate genes for clf1 and clf2. We sequenced the coding region of Ptch in A/WySn cDNA. RESULTS: Seventy new BC1 CL(P) segregants (4%) were obtained, as predicted. All three new congenic RI lines homozygous for both clf1 and clf2 had A/WySn-level CL(P) frequencies (10-30%) in test crosses. The clf1 region contains 10 known genes (Arf2, Cdc27, Crhr1, Gosr2, Itgb3, Mapt, Myl4, Nsf, Wnt3, and Wnt9b). The clf2 region contains 17 known genes with human orthologs. Both regions contain additional potential genes. No causal mutation in Ptch coding sequence was found. CONCLUSIONS: In A-strain mice, nonsyndromic CL(P) is digenic, suggesting that nonsyndromic human CL(P) may also be digenic. The orthologous human genes are on 17q (clf1) and 9q, 8q and 5p (clf2), and good candidate genes are WNT3 or WNT9B (17q), and PTCH (9q) or MTRR (5p).     

Distinct functions for Bmp signaling in lip and palate fusion in mice

Previous work suggested that cleft lip with or without cleft palate (CL/P) is genetically distinct from isolated cleft secondary palate (CP). Mutations in the Bmp target gene Msx1 in families with both forms of orofacial clefting has implicated Bmp signaling in both pathways. To dissect the function of Bmp signaling in orofacial clefting, we conditionally inactivated the type 1 Bmp receptor Bmpr1a in the facial primordia, using the Nestin cre transgenic line. Nestin cre; Bmpr1a mutants had completely penetrant, bilateral CL/P with arrested tooth formation. The cleft secondary palate of Nestin cre; Bmpr1a mutant embryos was associated with diminished cell proliferation in maxillary process mesenchyme and defective anterior posterior patterning. By contrast, we observed elevated apoptosis in the fusing region of the Nestin cre; Bmpr1a mutant medial nasal process. Moreover, conditional inactivation of the Bmp4 gene using the Nestin cre transgenic line resulted in isolated cleft lip. Our data uncover a Bmp4-Bmpr1a genetic pathway that functions in lip fusion, and reveal that Bmp signaling has distinct roles in lip and palate fusion.     

Reduced epithelial surface activity is related to a higher incidence of facial clefting in A/WySn mice

The epithelial surfaces of the facial primordia were evaluated by scanning electron microscopy (SEM) during primary palatogenesis in two genetically related mouse strains, the A/J and the A/WySn strains. These two strains were selected because the reported frequency of spontaneous cleft lip with or without cleft palate [CL(P)] in the A/J strain approximates 0%, whereas the spontaneous frequency of CL(P) in the A/WySn strain is 20-30%. The embryos were examined prior to (two to six tail somites), during (seven to ten tail somites), and after (ten to 14 tail somites) primary palate fusion. During fusion, epithelial surface activity (characterized as cellular debris, dissociated cells, cellular projections, and epithelial bridging) was more pronounced in A/J embryos. A/WySn embryos with spontaneous cleft lip exhibited a marked deficiency in epithelial activity when compared to their normal littermates. No discernible differences were detected in the facial morphology, with the exception of the distal end of the medial nasal prominence, which appeared longer in the A/J strain. This study suggests that the degree of epithelial surface activity at the putative site of fusion and the relative length of the medial nasal prominence may account for the observed differences in facial clefting of the two strains. Face shape, related to prominence divergence, was similar in the two strains and could not explain the higher incidence of clefting observed in the A/WySn strain.     

Genetic differences in the frequency of acetazolamide-induced ectrodactyly in the mouse exhibit directional dominance of relative embryonic resistance

Eleven of the common inbred strains of the mouse were surveyed for their teratogenic response to acetazolamide that was administered three times per os at 1,000 mg/kg (9 A.M. and 4 P.M. on day 9 and 9 A.M. on day 10). The products of conception were examined for gross malformations on day 15. One strain, SJL/J, exhibited maternal toxicity to the dosage regime and was excluded from the survey. Five strains exhibited significantly increased resorption rates after treatment. All strains responded with the expected malformation of postaxial forelimb ectrodactyly with a right-sided predominance. Nine of the strains could be assigned to one of four mutually exclusive classes of frequency of ectrodactyly and the tenth strain (BALB/cByJ) showed overlap between the two intermediate classes. The data suggest major genes determine the difference in sensitivity to ectrodactyly rather than a polygenic mode of inheritance. Induced cleft lip was found in four strains and one of these strains, SWR/J, exhibited a significantly higher frequency. The strain differences in sensitivity to induced resorption, forelimb ectrodactyly, and cleft lip were genetically independent. A reciprocal cross study was conducted with five of the strains from the four classes of frequency of ectrodactyly response in order to determine gene action. A significant maternal effect on the ectrodactyly response was found only with one of the strain pairs in the ten sets of reciprocal crosses with the five strains. When there was a significant difference between two strains, the F1 embryos exhibited dominance of relative resistance to ectrodactyly. The directional dominance of relative resistance to acetazolamide-induced ectrodactyly suggests that regulatory genes control the embryonic differences in frequency of ectrodactyly response to acetazolamide. By analogy with other metric traits of development that exhibit directional dominance, the genetic variation in ectrodactyly response that has been observed so far in the mouse embryo may not be involved with the primary target of acetazolamide teratogenesis.     

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.     

Genetics of cleft lip and cleft palate in China.

During the past 10 years, 60 cases of cleft lip with or without cleft palate [CL(P)] were recorded among 45,072 newborns at Shanghai International Peace Maternity and Infant Hospital, China. The incidence was 1.33 per 1,000 births. The family histories of 163 CL(P) patients were analyzed. The incidences of CL(P) in the first-, second-, and third-degree relatives of CL(P) patients were 11/246 (4.47%), 10/1,032 (0.97%), and 6/1,727 (0.35%), respectively. Of the 163 probands, three had a history of consanguinity of the parents (1.8%), in contrast to 0.77% in the general population. These data are suggestive of multifactorial inheritance. The heritability of CL(P) in our study calculated by Falconer's formula was 77.6%.     

Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate.

Complex segregation analysis of pedigrees having nonsyndromic cleft lip with or without cleft palate (CL/P) (Chung et al. 1986; Marazita et al. 1986) has shown that a major-locus model best explains the observed recurrence of CL/P in Caucasian families. To identify this major gene, we compared the frequencies of 12 RFLPs at five loci-epidermal growth factor, transforming growth factor-alpha, epidermal growth factor receptor, glucocorticoid receptor, and estrogen receptor-in both a group of 80 subjects with nonsyndromic CL/P and 102 controls. These candidate genes were selected because studies in rodents had suggested their possible involvement in palatogenesis. A significant association was observed between two RFLPs at the transforming-growth-factor-alpha (TGFA) locus and the occurrence of clefting (P = .0047 and P = .0052). This suggests that either the TGFA gene itself or DNA sequences in an adjacent region contribute to the development of a portion of cases of CL/P in humans and provides an opportunity to begin to examine the molecular events underlying lip and palate formation.     

Unravelling the complex genetics of cleft lip in the mouse model

Nonsyndromic cleft lip in ``A' strain mice and humans is genetically complex and is distinct from isolated cleft palate. Cleft lip embryos recovered in 2.4% of 1485 first backcross (BC₁) segregants from a cross of A/WySnJ (24% cleft lip) and C57BL/6J (no cleft lip) in A/WySnJ mothers, and in testcrosses of 10 recombinant inbred (RI) strains (AXB/Pgn or BXA/Pgn), were used for gene mapping and for inference of genetic architecture. The A/WySnJ maternal genotype increased cleft lip risk in reciprocal crosses; the relevant genetic difference between AXB-6/Pgn (8%) and A/WySnJ (24%) is entirely maternal. A combination of new mapping panels (325 meioses), new markers, and a recombinant cleft lip embryo redefined the location of a recessive factor essential to cleft lip risk, clf1, and candidate genes Itgb3 and Crhr, to between D11Mit146/360 and D11Mit166/147. A screen of 54 YACs for 46 genes and SSLP loci located Wnt15, Wnt3, Crhr, Mtapt, Itgb3, Dlx3, and Dlx7 within the clf1 candidate region. The clf2 locus was newly mapped to Chromosome (Chr) 13 by a genome screen of BC₁ segregants, and further defined to a 4-cM region between D13Mit13/54 and D13Mit231 by strain distribution patterns of cleft lip liability and markers in testcrossed RI strains. Specific combinations of marker genotypes associated with cleft lip risk indicated that high risk in A/WySnJ mice is caused by epistatic interaction between clf1 and clf2 in the context of a genetic maternal effect. Human homologs of clf1 and clf2 are expected to be on 17q and 5q/9q. Received: 17 May 2000 / Accepted: 30 November 2000     

Medical sequencing of candidate genes for nonsyndromic cleft lip and palate

Nonsyndromic or isolated cleft lip with or without cleft palate (CL/P) occurs in wide geographic distribution with an average birth prevalence of 1/700. We used direct sequencing as an approach to study candidate genes for CL/P. We report here the results of sequencing on 20 candidate genes for clefts in 184 cases with CL/P selected with an emphasis on severity and positive family history. Genes were selected based on expression patterns, animal models, and/or role in known human clefting syndromes. For seven genes with identified coding mutations that are potentially etiologic, we performed linkage disequilibrium studies as well in 501 family triads (affected child/mother/father). The recently reported MSX1 P147Q mutation was also studied in an additional 1,098 cleft cases. Selected missense mutations were screened in 1,064 controls from unrelated individuals on the Centre d'Étude du Polymorphisme Humain (CEPH) diversity cell line panel. Our aggregate data suggest that point mutations in these candidate genes are likely to contribute to 6% of isolated clefts, particularly those with more severe phenotypes (bilateral cleft of the lip with cleft palate). Additional cases, possibly due to microdeletions or isodisomy, were also detected and may contribute to clefts as well. Sequence analysis alone suggests that point mutations in FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of isolated cleft lip with or without cleft palate, and the linkage disequilibrium data support a larger, as yet unspecified, role for variants in or near MSX2, JAG2, and SKI. This study also illustrates the need to test large numbers of controls to distinguish rare polymorphic variants and prioritize functional studies for rare point mutations.     

A comparative study of development during primary palate formation in A/WySn, C57BL/6, and their F1 crosses

Preliminary to a study comparing the morphological differences in facial growth of A/WySn (25% cleft lip) and C57BL/6 (0% cleft lip) mice, the growth and development of these strains and their reciprocal F1 hybrids was examined. Litters of these four populations were observed at D 10/8, D 10/20, D 11/8, and D 11/20 and scored for crown-rump length (CRL), somite number, and stage of facial development. Analysis of the data showed that, at any given gestational age, a hierarchy exists in which A/WySn is the smallest (based on CRL), has the fewest somites, and has the least-developed face. It is followed by the A/WySn-C57BL/6 (AC) cross, C57BL/6, and the C57BL/6-A/WySn (CA) cross, in order of increasing growth and development. The significant differences occurring between AC and CA indicate that maternal effects exist in A/WySn that retard the growth and development of its progeny. When the four populations were compared at similar facial stages, there was no significant difference between A/WySn and C57BL/6 in CRL or somite number. However, the hybrid populations tended to have significantly fewer somites and to be significantly larger than the parental populations at comparable stages of facial development. This suggests that, although somatic growth and development are coordinated with facial development in both cleft lip-susceptible and resistant strains, the association can be influenced by hybrid vigor. Thus, maternal effects do not appear to produce cleft lip through selective retardation of facial development in the purebred A/WySn. Nonetheless, these effects may still potentiate the expression of cleft lip.     

Association between MTHFR polymorphisms and orofacial clefts risk: a meta-analysis

BACKGROUND The roles of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in orofacial clefts (OFCs) risk have been substantially explored, but the results remain conflicting. To address this gap, we conducted a meta-analysis involving all eligible studies. METHODS: Electronic literature searches of the PubMed, EmBase, and Medline databases were performed up to October 31, 2011. Fixed-effects or random-effects models were used to calculate the pooled odds ratios (ORs) for two genetic comparisons (heterozygous mutation vs. wild type, homozygous mutation vs. wild type). RESULTS A total of 18 studies were ultimately identified. The pooled results revealed no statistical association between infant and maternal C677T and A1298C variants and risk of cleft lip with or without palate (CL/P) or cleft palate only (CPO), except for the maternal 677TT genotype for CL/P, the OR was 1.32 (95% confidence interval [CI], 1.06-1.63) as compared to the normal 677CC genotype. In the subgroup analyses on CL/P data based on ethnicity and source of control subjects, almost all of the results were replicated as nonsignificant associations in both examined polymorphisms, whereas the pooled risk estimate calculated for maternal 677TT genotype in the white population remained statistically significant, with an OR of 1.36 (95% CI, 1.05-1.76). CONCLUSIONS This meta-analysis suggests that maternal MTHFR 677TT genotype might increase the risk of having a CL/P offspring in the white population. However, these findings remain to be confirmed by additional investigations.     

Signaling through Tgf-beta type I receptor Alk5 is required for upper lip fusion

Cleft lip with or without cleft palate is one of the most common congenital malformations in newborns. While numerous studies on secondary palatogenesis exist, data regarding normal upper lip formation and cleft lip is limited. We previously showed that conditional inactivation of Tgf-beta type I receptor Alk5 in the ectomesenchyme resulted in total facial clefting. While the role of Tgf-beta signaling in palatal fusion is relatively well understood, its role in upper lip fusion remains unknown. In order to investigate a role for Tgf-beta signaling in upper lip formation, we used the Nes-Cre transgenic mouse line to delete the Alk5 gene in developing facial prominences. We show that Alk5/Nes-Cre mutants display incompletely penetrant unilateral or bilateral cleft lip. Increased cell death seen in the medial nasal process and the maxillary process may explain the hypoplastic maxillary process observed in mutants. The resultant reduced contact is insufficient for normal lip fusion leading to cleft lip. These mice also display retarded development of palatal shelves and die at E15. Our findings support a role for Alk5 in normal upper lip formation not previously reported.     

Population-Based Study of Birth Prevalence and Factors Associated with Cleft Lip and/or Palate in Taiwan 2002–2009

Background

Facial cleft deformities, including cleft lip with or without cleft palate (CL/P) and cleft palate (CP), are common congenital birth anomalies, especially in Asia. This study aimed to analyze the prevalence of CL/P and CP and to identify associated factors in Taiwan.

Methods

This population-based epidemiological study retrospectively analyzed birth data obtained from the Department of Health in Taiwan for years 2002–2009. Frequency distribution, percentages and related predictors were investigated, and findings were presented by types of cleft deformities. Logistic regression analysis was performed to identify factors associated with cleft deformities.

Results

Overall prevalence of cleft deformities among 1,705,192 births was 0.1% for CL/P and 0.04% for CP over the 8-year study period. Higher prevalence of CL/P or CP was observed with multiple pregnancies, being male for CL/P, being female for CP, gestational age ≤37 weeks and lower birth weight (<1.5 kg). Both CL/P and CP were significantly associated with gestational age <37 weeks and birth weight<1.5 kg (all P <0.0001). CL/P was significantly associated with multiple parities (P = 0.0004–0.002). Male newborns and female newborns were significantly associated with CL/P and CP, respectively (both P<0.0001).

Conclusions

Overall prevalence for congenital cleft deformities in study subjects was 0.1%, in keeping with high rates in Asia. Results suggest the need for awareness and early identification of those at high risk for cleft deformities, including newborns with gestational age <37 weeks, weighing <1.5 kg at birth and women with multiple parities, as a potential strategy to counter long-term adverse effects on speech and language in this population.     

Periconceptional health and lifestyle factors of both parents affect the risk of live-born children with orofacial clefts

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO) are orofacial clefts and have a multifactorial etiology. The identification of amendable parental risk factors may contribute to a reduced occurrence of these malformations in the future. METHODS: Standardized demographic and periconceptional exposure data from 284 parents of a child with CL/P, 66 parents of a child with a CPO and 222 parents of a child without congenital malformations were collected at approximately 24 months after the periconceptional period of the index child. Univariate and multivariate logistic regression analyses were used to estimate relative risks by odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Univariate results suggest that low parental education, periconceptional maternal medication use and illnesses, paternal smoking, and first-trimester maternal common cold increased CL/P risk. Pregnancy planning and periconceptional folic acid supplementation, however, reduced CL/P risk by approximately 50% (OR, 0.5; 95% CI, 0.3-0.8) and 40% (OR, 0.6; 95% CI, 0.4-0.9), respectively. Mostly comparable results were obtained for CPO. Being a boy (OR, 2.0; 95% CI, 1.4-3.0), folic acid supplementation (OR, 0.6; 95% CI, 0.4-0.9), and low paternal education (OR, 1.6; 95% CI, 1.0-2.3) mainly determined CL/P in the multivariate analyses, compared to low paternal (OR, 4.5; 95% CI, 2.1-9.4) and maternal medication use (OR, 2.0; 95% CI, 1.0-4.0) for CPO. CONCLUSIONS: Preconceptional counseling for orofacial cleft risk assessment should pay attention to maternal medication use, periconceptional folic acid supplementation, and exposures of the father. These determinants can be amended, thereby modifying orofacial cleft risk.     

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.