Cleft Lip Palate in a Patient with 5q14.3 Deletion Syndrome: A Possible Unreported Feature?

5q14.3 deletion syndrome (MIM#613443) is an uncommon but well-known syndrome characterized by intellectual disability, epilepsy, hypotonia, brain malformations, and facial dysmorphism. Most patients with this syndrome have lost one copy of the <i>MEF2C</i> gene (MIM*600662), whose haploinsufficiency is considered to be responsible for the distinctive phenotype. To date, nearly 40 cases have been reported; the deletion size and clinical spectrum are variable, and at least 6 cases without <i>MEF2C</i> involvement have been documented. We herein report the clinical and cytogenomic findings of an 11-year-old girl who has a 5q14.3q21.1 de novo deletion that does not involve <i>MEF2C</i> but shares the clinical features described in other reported patients. Moreover, she additionally presents with bilateral cleft-lip palate (CLP), which has not been previously reported as a feature of the syndrome. The most frequent syndromic forms of CLP were ruled out in our patient mainly by clinical examination, and Sanger sequencing was performed to discard the presence of a <i>TBX22</i> gene (MIM*300307) defect. Our report suggests CLP as a possible unreported feature and redefines the critical phenotypic regions of 5q14.3 deletion syndrome.

Psychosocial Experiences That Support Positive Self-Concept in Children with Cleft Lip and Palate Adopted From China

Objective Existing psychosocial research offers little information on the unique challenges and strengths of children adopted from China with cleft lip and/or palate (CL/P). The present study aimed to understand biopsychosocial factors that support positive self-concept in this population. Design Qualitative, semistructured interviews were conducted with children and their parents. Interpretive phenomenological analysis of transcribed interviews was utilized for data analysis. Setting Participants were recruited in an outpatient, pediatric multidisciplinary cleft clinic during a standard team visit. Patients, Participants Participants were ages 8 to 12 years with a diagnosis of isolated cleft lip-palate who were internationally adopted from China before the age of 2 years and English-speaking. Participants also included English-speaking parents. Results Themes reflecting data from the child and parent subsamples include: (1) child's characteristics, (2) family strengths, (3) adoption identity, (4) cultural identity, (5) coping with a cleft, and (6) social factors. Additional 2 to 3 subthemes were identified for the parent and child subsamples within each broader theme. Conclusions Findings from this sample suggested factors supporting positive self-concept included pride and self-efficacy in activities, family support, instilment of family values, strategies for coping with a cleft, family belonging, cultural exposure, and normalization of differences. Medical providers can support patients and families by providing education on surgeries, CL/P sequelae and outcomes, and pediatric medical stress. Mental health providers can screen for social and emotional challenges and provide psychoeducation on racial/ethnic socialization, identity development, and coping.

MEIS2 (15q14) gene deletions in siblings with mild developmental phenotypes and bifid uvula: documentation of mosaicism in an unaffected parent

MEIS2 (Meis homeobox 2) encodes a homeobox protein in the three amino acid loop extension (TALE) family of highly conserved homeodomain-containing transcription regulators important for development. MEIS2 deletions/mutations have been associated with cleft lip/palate, dysmorphic facial features, cardiac defects, as well as intellectual disability at a variable severity. Here we report on one familial case that two affected siblings carry the same non-mosaic ~ 423 kb genomic deletion at 15q14 encompassing the entirety of CDIN1 and the last three exons (ex. 10, 11, 12) of the MEIS2 gene, while their unaffected father is mosaic for the same deletion in about 10% lymphocytes. Both siblings presented with mild developmental delay and bifid uvula, while no congenital cardiac abnormalities were identified. The elder sister also showed syncopal episodes and mild speech delay and the father had atrial septal defects. This is the first report showing multiple family members inherit a genomic deletion resulting in a MEIS2 partial truncation from a mosaic parent. Taken all together, this study has important implications for genetic counseling regarding recurrence risk and also points to the importance of offering MEIS2 gene tests covering both point mutations and microdeletions to individuals with milder bifid uvula and developmental delay.

Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate

The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.

Isolation, Uncertainty and Treatment Delays: Parents’ Experiences of Having a Baby with Cleft Lip/Palate During the Covid-19 Pandemic

Objectives Previous literature finds that having a child with a cleft lip and/or palate (CL/P) may pose social and emotional challenges for parents. For parents of children born during the Covid-19 pandemic, such challenges may be heightened. Further, novel demands brought about by the pandemic could have caused additional hardships. The aim of this study was to describe the impact of the pandemic on new parents through qualitative exploration of their experiences. Design Semi-structured interviews were conducted with 14 parents of children born in the United Kingdom with CL/P between January and June 2020, around the start of the pandemic. Data were analysed using inductive thematic analysis. Results Three themes, with sub-themes, were identified. The first theme, “ Changes to Healthcare: The Impact of Restrictions and Reduced Contact”, discussed the impact of the pandemic on perinatal care, the care received from the specialist CL/P teams, and parents’ experiences of virtual consultations. The second theme, “Family Functioning During the Pandemic”, covered parental anxiety, fathers’ experiences, and social support. The third theme, “ Surgical Prioritisation: Delays and Uncertainty”, addressed changes to surgical protocols, coping with uncertainty, complications associated with delayed surgery, and how parents created positive meaning from this period. Conclusions A range of increased and additional psychosocial impacts for parents were identified, along with several coping strategies, utilization of social support, and the positive aspects of their experiences. As the pandemic continues, close monitoring of families affected by CL/P remains imperative, particularly for those at risk of emotional distress.

Oral Rehabilitation of Bilateral Cleft Lip and Palate Patient with Simultaneous LeFort I Osteotomy and Zygomatic Implants: A Case Report

The aim of this study is to evaluate Le Fort I Osteotomy and zygomatic implantation without any graft placement for management of a cleft lip and palate patient. This case report describes oral rehabilitation of a 33-year-old patient with bilateral cleft lip-palate and oronasal fistula and atrophic pre-maxilla. As treatment, the patient received simultaneous Le Fort I osteotomy, palatoplasty and two zygomatic implant insertions. The prosthetic superstructure included zygomatic implant-supported removable hybrid prosthesis on bar locator and metal-ceramic fixed bridges in the posterior region. As conclusion, this protocol can be promising for management of patients with cleft lip-palate and malocclusion.

An Evaluation of Muscle Repair Techniques: Implications in Musculoskeletal Healing and Corollaries in Oral-Facial Clefting

We performed an animal study to identify the techniques associated with the best muscle healing outcomes in cleft lip/palate surgery. The right triceps of thirty adult male Sprague–Dawley rats were cut and repaired by three different suture techniques: simple (n = 10), overlapping (n = 10), and splitting sutures (n = 10). Muscle tissues were isolated from 5 rats per group 1 and 8 weeks postoperation. The inflammatory response and muscle fiber healing were evaluated by hematoxylin and eosin (H&E) staining, Western blotting, immunohistochemistry for TNF-α and IL-1β, and immunofluorescence for laminin and MyoD. Grip strength (N/100 g) and spatial gait symmetry were evaluated before surgery and 1, 2, 4 and 8 weeks postoperation. Eight weeks postoperation, grip force per weight was significantly higher in the simple suture (median, 3.49; IQR, 3.28–3.66) and overlapping groups (median, 3.3; IQR, 3.17–3.47) than the splitting group (median, 2.91; IQR, 2.76–3.05). There was no significant difference in range of motion between groups. The simple group exhibited significant remission of inflammation by H&E staining and lower expression of TNF-α and IL-1β than the other groups by Western blotting and immunohistochemistry. Immunofluorescence revealed stronger expression of MyoD and weaker expression of laminin in the splitting group than in the other groups at week 8, indicating prolonged inflammation and healing followed by poor muscle fiber remodeling. Simple and overlapping sutures demonstrated similar functional healing, although greater inflammation and failure to maintain a thicker muscle belly were observed in the overlapping suture group compared with the simple suture group. Therefore, reconstruction of the philtral column with overlapping sutures alone may result in limited long-term fullness, and additional procedures may be needed.

Association of IRF6 rs2235371 Polymorphism with Non-Syndromic Cleft Lip/Palate: A Meta-analysis

Background: The previous published data on the association between interferon regulatory factor 6 (IRF6) polymorphisms and non-syndromic Cleft Lip/Palate (NSCL ± P) risk remained inconclusive. The aim of this study was to conduct a meta-analysis to further assess the associations. Methods: A comprehensive search in PubMed, EMBASE, Web of Science, and CNKI for all eligible studies up July 2021. Results: A total of 23 studies with 6,161 cases and 8,919 controls were selected for this meta-analysis. Overall pooled analysis suggest a significant association between IRF6 rs2235371 polymorphism and CL±P risk under all the five genetic models, i.e., allele (A vs. G: OR=0.754, 95% CI 0.628-0.905, P=0.002), homozygote (AA vs. GG: OR=0.621 95% 0.405-0.953, P=0.029), heterozygote (AC vs. GG: OR=0.619, 95% CI 0.485-0.791, P≤0.001), dominant (AA+AG vs. GG: OR=0.550, 95% CI 0.381-0.794, P=0.001) and recessive model (AA vs. AG+GG: OR=0.583, 95% CI 0.423-0.804, P=0.001). Subgroup analysis by ethnicity showed that rs2235371 was associated with NSCL±P risk in Asians. Conclusion: This meta-analysis provides strong evidences that IRF6 rs2235371 might be associated with risk of NSCL ± P.

Familial cleft tongue caused by a unique translation initiation codon variant in TP63

Variants in transcription factor p63 have been linked to several autosomal dominantly inherited malformation syndromes. These disorders show overlapping phenotypic characteristics with various combinations of the following features: ectodermal dysplasia, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypoplastic breasts and/or nipples, ankyloblepharon filiforme adnatum, hypospadias and cleft lip/palate. We describe a family with six individuals presenting with a striking novel phenotype characterized by a furrowed or cleft tongue, a narrow face, reddish hair, freckles and various foot deformities. Whole-exome sequencing (WES) identified a novel heterozygous variant, c.3G>T, in TP63 affecting the translation initiation codon (p.1Met?). Sanger sequencing confirmed dominant inheritance of this unique variant in all six affected family members. In summary, our findings indicate that heterozygous variants in TP63 affecting the first translation initiation codon result in a novel phenotype dominated by a cleft tongue, expanding the complex genotypic and phenotypic spectrum of TP63-associated disorders.

Study on the Effect of Socio-Demographic Factors on Different Congenital Disorders

Congenital disorders define the disease that occurs since the birth of a baby. Down syndrome, Turner syndrome, cleft lip, and congenital heart disease are the most common congenital disorders worldwide. A retrospective study was carried out, examining the effect of sociodemographic factors on congenital anomalies in the state of West Bengal, India, over a period of 6 years. A total of 595 cases with congenital disorders including Down syndrome, Turner syndrome, and other abnormalities (cleft lip/palate, syndactyly, ambiguous genitalia) were statistically analyzed along with the sociodemographic characteristics through Statistical Analysis System (SAS) 9.3.2. Down syndrome is seemed to be associated with age, ethnicity, parental addiction, especially smoking, while Turner syndrome is associated with ethnicity and gender. Other congenital disorders such as ambiguous genitalia are found to be associated with maternal addiction.