Clinical Analysis of the Cleft Patterns of Lip and Palate

The patterns in the cleft lip and palate were classified in great detail, and the point of center of the clefts in this disease was speculated. The purpose of the present study was to establish the basic data for classifications of epidemiological surveys in the future. The subjects were 377 patients with cleft lips and palates who visited the Second Department of Oro-Maxillo-Facial Surgery, Aichi-Gakuin University Hospital. The models of cleft lip and palate divided into 17 segments prepared for an analysis of cleft patterns. And as consequence, the following results were obtained.     

Clinical Aspects of Cleft Lip and Cleft Palate Patients Treated at Kanazawa Medical University Hospital from 1974 to 1993*

ABSTRACT Currently, clefts of the lip, alveolus, and palate are thought to be the most common congenital malformations. In this study, we examined 1,565 cases of clefts we treated over the last 18 years, in order to summarize the clinical features and to evaluate the treatment outcomes. This study involved 589 cleft lip (CL) cases, 576 cleft lip and palate (CLP) cases, 286 cases of cleft palate (CP), 81 cases of submucous CP and 33 cases of CL and submucous CP. The familial incidence was 11.1% (174 cases). Overall, the average incidence of associated congenital abnormalities was 27.9%. Approximately half of the patients with CP alone or with submucous CP were found to have additional congenital malformations. Standeard surgical techniques for unilateral and bilateral CL cases were the Skoog's and Millard's methods, respecively, which resulted in satisfactory outcomes. As a primary operation for CP, pushback procedure was performed using a partial mucosal flap from the palate. Using this procedure 96.5% of 455 cases achieved satisfactory nasopharyngeal closure. The main objective in the treatment of CL patients is not only the repair of growing tissues but also appropriate morphological, functional and psychological reconstruction for the purpose of correcting growth inhibitory problems caused by anatomical malposition. Surgical procedures for CP patients are designed to meet several needs: correction of anatomical abnormalities of the palate and pharynx, achievement of proper nasopharyngeal closure necessary for normal phonation, prevention of growth disturbances of the maxilla, improvements in hearing and auditory tube function, and normalization of occlusion.     

A Study on the Growth and Development of the Cranial Base in the Japanese Unilateral Cleft Lip and Palate: Comparison with the Japanese Skeletal Class I Occlusion

Abstract The purpose of this study is to investigate the growth and the developmental dimension and the feature of cranial base transition in unilateral cleft lip and palate (UCLP). With regared to this proposition, we have already submitted a paper in which we compared our study with skeletal reversed occlusion on a scholary journal. The authors will present this proposition in comparison with skeletal class I. The subject group consisted of 15 males and 12 females with UCLP. The control group consisted of 11 males and 14 females with skeletal class I. Standared lateral cephalometric radiographs taken at first medical examination and three years later were used. The three linear dimensions (S-N, S-Ba, N-Ba) and craniobasal angle (N-S-Ba) were measured. The results were as follows: 1) Females showed no significant difference in S-N, S-Ba and N-Ba but males had smaller S-Ba and N-Ba in the UCLP as compared with the control at the first examination and 3 years later. 2) There were no significant difference in the three distance items, S-N, S-Ba, N-Ba, for females but significantly larger changes in N-Ba appeared in the UCLP as compared with the controls for males. 3) The cranial base angle (N-S-Ba) showed no significant difference between the UCLP and controls for both male and female subjects at any observation time. From the above evidences, it is estimated that the cranial base size and angle in the UCLP as compared with those of controls show no consistent trend owing to possible involvement of differential growth pattern between the anterior cranial base and posterior cranial base. The growth of cranial base itself per se seems to be influenced mutually at minimal level by the maxillofacial growth. This suggests growth patterns of cranial base and maxillofacial region are independent from each other.     

Epidemiological Approaches to Identify Risk Factors for Human Congenital Malformations: Descriptive and Analytical Epidemiology of Cleft Lip and/or Palate in Japan*

Abstract This paper described three major epidemiological approaches to explore etiological clues to and risk factors for human congenital malformations, taking cleft lip and/or palate as an example. (1) An analysis of mortality statistics demonstrated an apparently downward trend of infant mortality from cleft lip and/or palate over the recent three decades in Japan. This particular finding was found to be plausibly ascribable to changing clinical assignment of causes of death from “cleft lip and/or palate” to “congenital heart diseases” or “multiple anomalies, syndromes or chromosome abnormalities”, when previous reports on incidence rate and autopsy series were examined. (2) A case-control study of 194 infants with cleft lip and/or palate (cases) and 194 normal infants (controls), who were matched to cases for sex, maternal age to within one year, birth order and residential area, yielded the following major findings, (a) A significantly increased risk was associated with parental highest educational attainment of less than 19 years, parental occupation of unskilled/service workers, positive family history of cleft lip and/or palate, positive past history of artificial abortion, maternal smoking habits at first trimester, and maternal episodes at first trimester of suffering from any diseases and of ingesting any drugs, (b) A significantly decreased risk was linked with frequent maternal intake at first trimester of such animal proteins as meats, fishes and shells, eggs and milk, (c) Maternal drinking habits and radiation exposures, and frequent maternal ingestion of Japanese/black tea were not associated. (d) Maternal coffee drinking at first trimester significantly elevated the risk, but turned to be unrelated when maternal smoking habits were statistically corrected. (3) A cohort study of approximately 10,000 pregnants, which is ongoing from April 1989 in Nagoya and aims to disclose the associations of parental life-style habits with general pregnancy outcomes including major congenital malformations, was briefly discussed.     

Spontaneous Intrauterine Repairment of Cleft Palate Induced by Amniocentesis in Rats

On day 15 of gestation, 180 fetal sacs in 43 pregnant Charles Foster rats were subjected to amniocentesis producing a series of total or partial clefts in the hard and soft palate regions. Fetuses recovered on days 19, 20 or 21 showed a gradual decline in the incidence of total clefts with increasing gestational age, i.e. 34% on day 19, 29% on day 20 and 13% on day 21, suggesting spontaneous ‘repairment’ of the clefts induced by amniotic sac puncture. Prenatal ‘repairment’ at times leaving residual partial clefts in the hard palate, suggested delayed rotation of the palatine shelves following reaccumulation of lost quantity of amniotic fluid and withdrawal of tongue obstruction. The experiment suggested that the palatine shelves retain intrinsic ‘shelf force’ for a much longer period than thought earlier. However, a gradual increase in the incidence of residual partial cleft with increasing gestational age, i.e. 45% on day 19; 50% on day 20 and 67% on day 21, respectively, suggests only incomplete (partial) repair in most of the cases probably due to paucity of time.     

Effect of Maternal Treatment with Methylmercury on the Manifestation of Cleft Lip in CL/Fr Mice

Abstract The interaction between methylmercury teratogenesis and manifestation of cleft lip and palate (CL(P)) of genetic origin was experimentally investigated in CL/Fr mice. Pregnant mice were given methylmercuric chloride orally on day 10 of pregnancy at doses of 5, 10, 15 and 20 mg/kg. Animals were put to death on day 18 of pregnancy and the fetuses were examined for malformations, especially facial anomalies. About 23% of fetuses manifested CL(P) in the control group. After maternal treatment with methylmercuric chloride, the incidence of fetuses with CL(P) did not remarkably change in groups of 5 mg/kg (about 30%) and 10 mg/kg (about 24%), but decreased significantly (p<0.01) in groups of 15 mg/kg (about 12%) and 20 mg/kg (about 12%). The average numbers of both early and late fetal deaths in the mercury-treated groups were not significantly different from those in the control group (p > 0.05): This suggested that the decreased incidence of fetuses with CL(P) was not attributable to the preferential mortality of embryos with CL(P). The incidence of isolated cleft palate (CP) was about 1, 5,40 and 80% after maternal treatments of 5,10,15 and 20 mg/kg methylmercuric chloride, respectively, showing the distinct threshold. No significant difference in mercury concentration was observed among normal fetuses, fetuses with CL(P) and with CP within any dose group.     

Bilateral Cleft Lip Repairs: The Manchester Method and Presurgical Orthodontic Treatment*

ABSTRACT From 1974 to 1984 we have performed operations on 142 patients with bilateral cleft lip using the Manchester method. Presurgical oral orthodontics were given to 84 patients out of 142. We used a head cap with elastic band and oral appliance which was devised by Dr. J. H. Peat. Experience proves that the earlier presurgical oral orthodontics was begun, the more more satisfactory were the results. Treatment of our cases was started as early as at approximately 4-6 weeks of age. The average length of treatment was 8 weeks, and the patients were opearated on at the age of 3-5 months. Post operative results in almost all of our cases were satisfactory. The advantages were 1) lip with satisfactory lenght, 2) acceptable scar pattern, 3) free prolabium and deep gingiva-labial sulcus. However, several problems to be overcome in our cases were remained. These problems appeared severely depending on the degree of congenital deformity. Secondary repair to the extremely depressed nose and short columella was performed at the age of 4-6 years. In these cases we made a forked flap on the upper lip and elongated a short columella while at the same time repairing the wide cupid's bow.     

Intrauterine Repair of Cleft Lip in Mouse Fetuses

Since most fetuses with drug-induced cleft lip have concurrent cleft palate, they die shortly after birth as a result of difficulty in suckling. We devised an experimental model, in which cleft lip unaccompanied by cleft palate was produced artificially, in order to permit long-term follow-up of intrauterine cleft lip repair surgery. Fifteen Jcl:ICR mice each on days 15, 16, 17 and 18 of gestation (the day when a vaginal plug was found = day 0 of gestation) were used. Each mouse was laparotomized by midline incision of the lower abdomen, and the fetus at the distal end or the fetus adjacent to the fetus at the distal end of the uterine horn was subjected to surgery. Using a surgical microscope, the uterine wall was incised, and the amnion and chorion were pierced to expose the snout of the fetus. After unilateral complete cleft lip was created, the wound was repaired with 10–0 nylon sutures. The snout was then replaced within the uterus, and the surgical wound in the uterine wall was closed. The uterine horn was then placed back into the peritoneal cavity, and the abdominal wound was closed. The dams were then returned to their individual cages, and the fetuses were delivered spontaneously. The live birth rate for surgically treated fetuses was 60% in animals treated on day 15 of gestation, 73% among those treated on day 16, 80% among those treated on day 17, and 60% among those treated on day 18. The offspring underwent the normal course of postnatal growth, with good jaw development and no cicatrization at the site of upper lip surgery either grossly or histologically.     

Cleft lip and palate in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin: a morphological in vivo study

It is well-known that TCDD (2,3,7,8, tetrachloridedibenzo-p-dioxin) induces cleft palates (CPs) in pregnant C57BL mice. However, it is unclear if TCDD is a possible teratogen for cleft lip. We examined maxillofacial malformations including cleft lip in three animal strains: A/J mice, C57BL/6J mice and ICR mice. The A/J mouse develops cleft lip and palate spontaneously at a 5-10% rate. TCDD was administered in olive oil on gestation day (GD) 12.5 with gastric tubes at 10 microg/kg, 20 microg/kg, or 40 microg/kg to examine the dose-response, and on a single day from GD 8.5-14.5 to examine the timing effects of TCDD administration on lip and palate formation. Furthermore, the palatal shelf movements during GD 8.5-14.5 were observed with a stereoscopic microscope. All embryos had cleft palates when the TCDD was administered just before palatogenesis (GD11.5-GD12.5). With respect to the TCDD effects, there were large differences among the strains. In the A/J mice, the difference between a lethal dose and a dose that could induce a cleft palate was close. Cleft lips were not induced, even when the TCDD was given just before labiogenesis. Morphologically, both palatal shelves contacted perfectly along their lengths, but separated and formed cleft palates. In conclusion, TCDD is a strong inducer of cleft palates, and interferes with the fusion phase of the secondary palate, but has no effect on the lip.     

Prevalence of cleft lip and/or palate in children from Lodz between years 1981–2010

Congenital malformations constitute a serious problem of both medical and social nature. Cleft lip and/or palate represent the most common congenital anomaly of the face that is why it is essential to know the real frequency of the described phenomenon. The aim of this paper is to determine the frequency of cleft lip and/or palate and the types of malformations that occurred in Lodz city between the years 1981–2010. Our clinic has been carrying on the studies concerning the incidence of cleft lip and/or palate since 1981. The Polish Registry of Congenital Malformations has been operating in Poland since 1 April 1997. The team has managed to obtain data, from the Registry, concerning the total number of all live born infants and the number of children with cleft lip and/or palate, who were born in Lodz, between 1998 and 2010. In years 1981–2010, 319 children, in 210 952 live born infants, were born with cleft lip and/or palate in Lodz. The isolated cleft palate was observed more frequently in girls and the unilateral cleft of lip and palate in boys. In all three decades palate clefts are more common whereas bilateral lip, alveolus and palate clefts are more infrequent. A small tendency to decrease in actual cleft lip and/or palate frequency among children, in the period of 30 years, is observed in Lodz. Over the years it has still been observed that the isolated cleft palate is the most common type of defect.     

Effects of the Ay Gene on the Sensitive Periods of Hydrocortisone-Induced Cleft Palate and Palatal Slit in Mice

The effects of the A^y gene on the sensitive periods of hydrocortisone-induced cleft palate and palatal slit were investigated in C57BL/6 (a/a) and its congenic strain of C57BL/6-A^y (A^y/a) mice by using the single-dose administration method. Matings were conducted as follows (femalex male): Group I, a/a × a/a; Group n, a/a ×A^y/a; and Group III, A^y/a × a/a. Pregnant females were subcutaneously given a single dose of 200 or 400 mg/kg of hydrocortisone on day 11, 12, 13 or 14 of pregnancy and killed on day 18 for examination of palatal defects of live fetuses. Cleft palate was produced in all groups by treatment on days 11–13 of pregnancy at a dose of 200 mg/kg without any increase in fetal mortality. In Group I, the maximum incidence was observed on day 11 and followed by a rapid decrease thereafter. In Group U, in which half of the fetuses were expected to carry the A^y gene, the incidence still remained high on day 12, although it was decreased to the level of Group I by day 13. In Group HI, in which maternal mice as well as half of their fetuses carried the A^y gene, significantly higher incidences were observed on days 12 and 13 with the maximum value on day 12 when compared with those in Groups I and/or II. Palatal slit was also induced in all groups on each of treatment days at a dose of 200 mg/kg. Although the incidences in both Groups I and II were high on days 11 and 12 and gradually decreased thereafter, the value on day 13 was significantly higher in Group II than in Group I. In Group IE, the maximum incidence was found on day 12 and the values on days 13 and 14 were still significantly higher than those in Groups I and/or II. These results indicate that the sensitive periods of hydrocortisone-induced cleft palate and palatal slit are prolonged into the later stage of embryonic development as a result of the A^y-gene effects.     

Palatal Slit and Cleft Palate in Rats Treated with Glucocorticoids II. Comparative Teratogenicity of Prednisolone, Triamcinolone Acetonide and Hydrocortisone

The induction of abnormal palatal development by three glucocorticoids; prednisolone, triamcinolone acetonide and hydrocortisone was evaluated in rat fetuses. Pregnant rats were injected subcutaneously with either prednisolone (12.5-100 mg/kg/day), triamcinolone acetonide (0.25-2 mg/kg/day) or hydrocortisone (100 mg/kg/day) on days 14 and 15 of gestation. These females were humanely killed on day 20 of gestation and viable fetuses were inspected for their palatal abnormalities. The frequencies of cleft palate were significantly higher in the group treated with 100 mg/kg/day prednisolone (10.6%), and in the groups treated with 0.5, 1 and 2 mg/kg/day triamcinolone acetonide (8.6%, 26.1% and 58.3%, respectively) than the control frequency of 0%. Triamcinolone acetonide was 70 times as potent as prednisolone in inducing palatal slit, with ED₅₀ value of 1.0 mg/kg/day and 70 mg/kg/day, respectively. Hydrocortisone showed no potentiality for the induction of cleft palate and palatal slit. Other developmental abnormalities including omphalocele and general edema, late resorption, and growth retardation were induced by triamcinolone acetonide and prednisolone. These findings indicate that triamcinolone acetonide has a significantly higher potentiality for the induction of palatal slit in rats, as well as in mice, compared to prednisolone and hydrocortisone.     

Postoperative speech development based on cleft types in children with cleft palate

BACKGROUND: The purpose of this historical cohort study was to compare the speech development of children with three types of cleft palate while controlling for some confounding factors. METHODS: Subjects included 28 children with bilateral cleft lip and palate (BCLP), 74 with unilateral cleft lip and palate (UCLP), 33 with isolated cleft palate (ICP), and 168 normal control children. Children with cleft palate attended a speech clinic in Fukuoka, had attained adequate velopharyngeal function after palatoplasty carried out within 18 months after birth, and had no syndromic diseases, persistent hearing loss, mental retardation, or central nervous system problems. RESULTS: Children with BCLP began using two-word sentences later than other children (3 months, P<0.01). However, the difference based on sex was also statistically significant. Female patients started using two-word sentences earlier than male patients (2 months, P<0.01). Children with BCLP had lower verbal scores on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) than other children (12.4-14.9 points, P<0.01). There was no significant difference based on sex. CONCLUSIONS: The results of this research indicate the following: speech development of children with ICP and UCLP was similar to that of normal children; however, speech development of children with BCLP was delayed compared with other children with or without cleft palate.     

Prevalence of Congenital Heart Diseases in Oral Cleft Patients

To establish the prevalence of congenital heart diseases (CHDs) in cleft patients, the type of cleft and the presence of a syndrome were coded in 220 patients. A Doppler echocardiogram with color-flow mapping (DE) was obtained in all patients. Mean age was 112.0 ± 101.2 months (range, 1–576 months), and 56.8% (125) were males. Cleft lip and palate occurred in 144 patients (65.5%), cleft lip in 40 (18.2%), and cleft palate in 36 (16.4%). Cleft palates were more frequent among females. Twenty-four CHDs were diagnosed in 21 of 220 patients (9.5%): 7 mitral valve prolapses, 6 atrial septal defects, 4 patent ductus arteriosus, 3 ventricular septal defects, 2 cases of tetralogy of Fallot, 1 pulmonary stenosis, and 1 bicuspid aortic valve. The presence of CHD did not correlate with the type of clef. Syndromes occurred in 28 patients (12.7%), and this association was higher among patients with a cleft palate.     

A multiple malformations syndrome with cleft lip and palate and ankyloblepharon filiforme adnatum

A case of bilateral ankyloblepharon filiforma adnatum with cleft lip and palate, bilateral popliteal pterygia, bilateral complete syndactyly of 2nd and 3rd toes associated with hypoplastic nails, accessory nipple and partially descrended testes is presented. It is a rare case with unusual associations which are all potentially correctable surgically. Ankyloblepharon and cryptophthalmos must be distinguished from each other as syndromic diagnosis is different as also the prognosis for normal vision.     

COL2A1基因变异相关腭裂1例报告并文献复习

目的探讨腭裂患儿的临床特征及致病基因。方法回顾分析1例COL2A1基因变异腭裂患儿的临床资料,并复习c.2292 delA变异相关腭裂相关文献。结果患儿男,生后即发现上腭畸形,临床表现有双眼略凸出、哭声低哑、喉中痰鸣、呼吸阵发性急促有吐沫、下颌小、舌短、软腭及悬雍垂裂、硬腭部分裂开。全外显子组基因靶向捕获-高通量测序示患儿COL2A1基因存在c.2292 delA移码缺失变异。文献复习发现,COL2A1基因移码变异已在人类基因变异数据库(HGMD)和ClinVar中报道,但本例患儿的变异位点未有报道,在正常人群数据库gnomAD、千人数据库和ExAC数据库中也均未被收录,为罕见变异。结论COL2A1基因变异c.2292 delA相关腭裂较罕见,基因检测可协助诊断。