Lian Ma

A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635–0.778, P = 1.44 × 10−11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292–1.587, P = 5.01 × 10−12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

Association of AXIN2 with Non-syndromic Oral Clefts in Multiple Populations

We have previously shown the association of AXIN2 with oral clefts in a US population. Here, we expanded our study to explore the association of 11 AXIN2 markers in 682 cleft families from multiple populations. Alleles for each AXIN2 marker were tested for transmission distortion with clefts by means of the Family-based Association Test. We observed an association with SNP rs7224837 and all clefts in the combined populations (p = 0.001), and with SNP rs3923086 and cleft lip and palate in Asian populations (p = 0.004). We confirmed our association findings in an additional 528 cleft families from the United States (p < 0.009). We tested for gene-gene interaction between AXIN2 and additional cleft susceptibility loci. We assessed and detected Axin2 mRNA and protein expression during murine palatogenesis. In addition, we also observed co-localization of Axin2 with Irf6 proteins, particularly in the epithelium. Our results continue to support a role for AXIN2 in the etiology of human clefting. Additional studies should be performed to improve our understanding of the biological mechanisms linking AXIN2 to oral clefts.

CRISPLD2 Variants Including a C471T Silent Mutation May Contribute to Nonsyndromic Cleft Lip With or Without Cleft Palate

Objective To assess the association between nonsyndromic (NS) cleft lip with or without cleft palate (CL(P)) and single-nucleotide polymorphisms (SNPs) within the CRISPLD2 gene (cysteine-rich secretory protein LCCL domain containing 2). Design Four SNPs within the CRISPLD2 gene domain (rs1546124, rs8061351, rs2326398, rs4783099) were genotyped to test for association via family-based association methods. Participants A total of 5826 individuals from 1331 families in which one or more family member is affected with CL(P). Results Evidence of association was seen for SNP rs1546124 in U.S. (p = .02) and Brazilian (p = .04) Caucasian cohorts. We also found association of SNP rs1546124 with cleft palate alone (CP) in South Americans (Guatemala and ECLAMC) and combined Hispanics (Guatemala, ECLAMC, and Texas Hispanics; p = .03 for both comparisons) and with both cleft lip with cleft palate (CLP; p = .04) and CL(P) (p = .02) in North Americans. Strong evidence of association was found for SNP rs2326398 with CP in Asian populations (p = .003) and with CL(P) in Hispanics (p = .03) and also with bilateral CL(P) in Brazilians (p = .004). In Brazilians, SNP rs8061351 showed association with cleft subgroups incomplete CL(P) (p = .004) and unilateral incomplete CL(P) (p = .003). Prediction of SNP functionality revealed that the C allele in the C471T silent mutation (overrepresented in cases with CL(P) presents two putative exonic splicing enhancer motifs and creates a binding site AP-2 alpha, a transcription factor involved in craniofacial development. Conclusions Our results support the hypothesis that variants in the CRISPLD2 gene may be involved in the etiology of NS CL(P).

IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families

Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non‐syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non‐syndromic OFCs. Screening for IRF6 mutations in apparently non‐syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non‐syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non‐syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24–0.44% of apparently non‐syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.

The effects of unrepaired cleft palate on early language development in Chinese infants.

Objective To investigate the effects of unrepaired cleft palate on the development of vocabulary comprehension and expression of Chinese children aged 8 to 15 months. Methods The parents or caregivers of 40 infants with unrepaired cleft palate were recruited from the Cleft Lip and Palate Center at the Stomatology School of Peking University. Vocabulary development was assessed using a parent report protocol, the Chinese Communicative Development Inventory: Infant, for Putonghua (PCDI: Infant). The scores for vocabulary comprehension and expression of infants with clefts were compared with typically developing infants in the same age group. Results All infants with unrepaired cleft palate performed below the typically developing infants in vocabulary comprehension, but there were no significant differences from 8 to 15 months of age. No significant differences were found from 8 to 13 months of age on the expressive vocabulary portion of the Chinese Communicative Development Inventory: Infant, for Putonghua. However, a significant difference appeared at 14 and 15 months, with infants with cleft palate performing at a significantly lower level than the typically developing infants. Conclusion The development of vocabulary comprehension in Chinese infants younger than 14 months with unrepaired cleft palate is not significantly delayed. At 14 and 15 months, however, the development of vocabulary expression is delayed. The reasons may be found in the specific phonetic characteristics of Putonghua.

Relationship Between Palate-Vomer Development and Maxillary Growth in Submucous Cleft Palate Patients

Objective Experimental and clinical findings suggest that the vomer is involved in facial development and might contribute to the short and retrusive maxilla in cleft patients. The aim of this study was to investigate the relationship between vomer development and maxillary growth in unoperated submucous cleft palate (SMCP) patients. Design Retrospective cohort study. Participants Thirty unoperated SMCP patients were included. The criteria for clinical diagnosis were: bifid uvula, a translucent zone in the midline of the soft palate, and a touchable “V” notch on the posterior border of the bony palate. There were 19 female and 11 male patients, with an age range from 3 to 25 years. Interventions All patients were imaged using spiral computed tomography (CT) while in centric occlusion before the surgeries. Main Outcome Measures Three-dimensional (3D) reconstruction models were created, and dentoalveolar relationships were rated by three experienced doctors according to the GOSLON score principles. The patients then were divided into three groups: 1 - normal occlusion, 2 - edge-to-edge bite, and 3 - crossbite. The vomer-palate fusion rate was calculated on 3D CT images and represented the vomer development. Results The sagittal extent of the palatal cleft and the malformation of vomer in SMCP were greatly varied. The vomer-palate fusion rate in the crossbite group (occlusal score = 3) was significantly lower than that in the normal occlusion group (P .027). Conclusions Our findings suggest that correlation exists between vomer development and sagittal maxillary growth in unoperated SMCP patients.

Chinese speech audiometry material: Past, present, future

Abstract Speech audiometry plays an important role in the assessment of hearing abilities, as it may more accurately reflect auditory function in the daily communication environment of listeners than other auditory assessment measures. Speech perception tests have been developed for over a century in Western countries, and they are commonly used procedures in North America and Europe, as well as Australia. The course of history and scientific progress has influenced speech audiometry in both its clinical and research aspects. Test materials developed from syllables and words to phases and sentences, and test protocols have evolved from using only simple speech stimuli in quiet to hearing-in-noise tests. In the early years, the purpose of speech audiometry was primarily to evaluate telecommunication systems. Today, speech tests are more often applied to assess speech perception abilities for individuals with hearing impairment. In addition to aiding diagnosis of the location of peripheral auditory pathology and measuring (central) auditory processing abilities, with the development of auditory amplification devices speech tests are also utilized to assess the outcomes of hearing aid and cochlear implant rehabilitation. Compared to the well documented speech test materials of Western countries, development in this field in China has been relatively delayed. A lack of material standardization, few test versions for the numerous Chinese dialect groups or for non-Chinese language minority populations, and insufficient test materials for children, have obstructed the development of speech audiometry in China. This review highlights key research milestones in the development of Chinese speech audiometry material, including work conducted in mainland China, Hong Kong, and Taiwan, and suggests priorities for future research in this field in China.

Assessing the Interdental Septal Thickness in Alveolar Bone Grafting Using Cone Beam Computed Tomography

Objective To assess the interdental septal thickness of grafted bone bridges using cone beam computed tomography (CBCT). Patients Of 71 patients with cleft lip and/or palate having undergone alveolar bone grafting for the first time at least 6 months previously, 52 patients with 57 grafted sites rated type I or II based on the Bergland scale using occlusal radiographs were selected. Interventions CBCT was performed for each bone-grafted alveolar cleft within 1 week after the occlusal radiographs were taken. Main Outcome Measures The thickness of the grafted bone bridge was evaluated using CBCT according to the relationship between crest thickness and the root width of cleft-adjacent teeth, and the results were classified into four categories, with scores of 1 to 4 indicating that the thickness of the bony bridge was ≥100%, ≥75%, ≥50%, and <50% of the root width of the cleft-adjacent teeth, respectively. Results Of the 34 grafted sites rated type I on the Bergland scale, 15 (44.12%), 10 (29.41%), 4 (11.76%), and 5 (14.71%) clefts were scored 1 to 4 on interdental septal thickness using CBCT, respectively. Of the 23 cases of type II, 3 (13.04%), 9 (39.13%), 1 (3.45%), and 10 (43.48%) clefts were scored 1 to 4, respectively. Conclusions The interdental septal thickness of grafted bone bridges with clinically successful heights based on the Bergland scale (type I or II) using occlusal radiographs varied significantly in the evaluation using CBCT.

Chinese children with nonsyndromic cleft lip/palate: Factors associated with hearing disorder

OBJECTIVES This study examined the auditory status of Chinese children with nonsyndromic cleft lip/palate (NSCL/P), investigated factors associated with peripheral hearing loss and compared results with earlier studies in western countries. METHODS Case history profiles and audiological data from 148 Chinese children with NSCL/P, aged between 6 and 15 years, who attended the Cleft Lip and Palate Clinic Center in a major Chinese urban hospital from July 2012 to September 2013 were acquired. The audiological status of the participants was reviewed, based on the results of their pure tone audiometry, tympanometry and acoustic reflex thresholds assessments. Factors including age, gender, cleft type, residential locality and school achievement were examined in relation to auditory status. RESULTS Findings revealed that 17% of the Chinese children with NSCL/P had hearing impairment at the time of assessment. Unilateral hearing loss was noted in 12% of children and in 5% of cases bilateral hearing loss was noted. In the majority of cases the hearing loss was slight and conductive in nature. Age, gender, residential locality and school achievement were found to have no relationship with severity of hearing loss. Children with cleft lip showed a lower degree of hearing impairment than children with cleft palate or cleft lip and palate. CONCLUSION Similar to studies for western children, Chinese children with CL/P associated with no known syndrome are at risk of peripheral hearing loss, generally of conductive type. However, the prevalence of peripheral hearing loss appears to be less than in western children with NSCL/P. Ethnic/racial factors may be a major contributing factor accounting for the discrepancies between the current results and western studies.

Electrophysiological assessment of auditory processing disorder in children with non-syndromic cleft lip and/or palate

Objectives Cleft lip and/or palate is a common congenital craniofacial malformation found worldwide. A frequently associated disorder is conductive hearing loss, and this disorder has been thoroughly investigated in children with non-syndromic cleft lip and/or palate (NSCL/P). However, analysis of auditory processing function is rarely reported for this population, although this issue should not be ignored since abnormal auditory cortical structures have been found in populations with cleft disorders. The present study utilized electrophysiological tests to assess the auditory status of a large group of children with NSCL/P, and investigated whether this group had less robust central auditory processing abilities compared to craniofacially normal children. Methods 146 children with NSCL/P who had normal peripheral hearing thresholds, and 60 craniofacially normal children aged from 6 to 15 years, were recruited. Electrophysiological tests, including auditory brainstem response (ABR), P1-N1-P2 complex, and P300 component recording, were conducted. Results ABR and N1 wave latencies were significantly prolonged in children with NSCL/P. An atypical developmental trend was found for long latency potentials in children with cleft compared to control group children. Children with unilateral cleft lip and palate showed a greater level of abnormal results compared with other cleft subgroups, whereas the cleft lip subgroup had the most robust responses for all tests. Conclusion Children with NSCL/P may have slower than normal neural transmission times between the peripheral auditory nerve and brainstem. Possible delayed development of myelination and synaptogenesis may also influence auditory processing function in this population. Present research outcomes were consistent with previous, smaller sample size, electrophysiological studies on infants and children with cleft lip/palate disorders. In view of the these findings, and reports of educational disadvantage associated with cleft disorders, further research that focuses on the auditory processing abilities of children with cleft lip/palate disorder is warranted.