Expanding the phenotype in Pitt-Hopkins syndrome; description of new oral finding and dental management considerations.

BACKGROUND: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder with physical, cognitive, and behavioral characteristics that is caused by heterozygous mutations in the TCF4 gene. Patients with PTHS might present a unique challenge for oral healthcare professionals because of the associated comorbidities. CASE REPORT: Here we describe a new case of PTHS in a 13-year-old girl with particular emphasis on oro-dental findings and oral healthcare management. Observed oro-dental findings in our case included shallow palate, absence of lingual frenum, gingival enlargement, thick lips and relative microdontia. The patient was unable to tolerate dental care under local anesthesia. Therefore, comprehensive dental treatment was performed under general anesthesia after a careful pre-anesthetic cardio-respiratory, neurological, and hematological evaluation. The patient was closely monitored intra-operatively for breathing rhythm, O2 saturation, and signs of respiratory distress. The patient was observed for 24 h post-op for respiratory distress and was discharged then uneventfully. CONCLUSION: Dental treatment under general anesthesia in these patients might be complicated by the abnormal breathing rhythm, and close monitoring and follow up for signs of respiratory distress after general anesthesia is necessary. Recognition of oral and dental findings might help to expand the phenotype and better characterize rare syndromes.

Cryptophthalmos, dental anomalies, oral vestibule defect, and a novel FREM2 mutation.

FREM2 is a member of the FREM2-FRAS1-FREM1 protein complex which contributes to epithelial-mesenchymal coupling. We report a Thai woman with cryptophthalmos, dental anomalies, and oral vestibule defect. A compound heterozygous mutation (c.6499C>T; p.Arg2167Trp and c.641_642del; p.Glu214GlyfsTer135) in the FREM2 gene was identified. The frameshift variant p.Glu214GlyfsTer135 is de novo and novel. It is predicted to result in the loss of most of the functional domains. The p.Arg2167Trp mutation was predicted to disrupt both Ca2+ binding and conformational change. The Arg2167Trp mutant protein has been shown to cause partial loss of function, decrease its interaction with FREM1 and result in impaired function of the FRAS1-FREM2-FREM1 complex. Frem2 was shown to be expressed in the developing tooth and vestibular lamina. It is hypothesized that these mutations resulted in aberration of the FRAS1-FREM2-FREM1 protein complex, resulting in loss of nephronectin, basement membrane disruption, and abnormal epithelial-mesenchymal interactions leading to dental and oral vestibule malformations.

Craniofacial phenotypes associated with Robinow syndrome.

Robinow syndrome is characterized by mesomelic limb shortening, hemivertebrae, and genital hypoplasia. Due to low prevalence and considerable phenotypic variability, it has been challenging to definitively characterize features of Robinow syndrome. While craniofacial abnormalities associated with Robinow syndrome have been broadly described, there is a lack of detailed descriptions of genotype-specific phenotypic craniofacial features. Patients with Robinow syndrome were invited for a multidisciplinary evaluation conducted by specialist physicians at our institution. A focused assessment of the craniofacial manifestations was performed by a single expert examiner using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnoses consistent with either dominant Robinow syndrome (DRS) or recessive Robinow syndrome (RRS) were evaluated. On craniofacial examination, gingival hyperplasia was nearly ubiquitous in all patients. Orbital hypertelorism, a short nose with anteverted and flared nares, a triangular mouth with a long philtrum, cleft palate, macrocephaly, and frontal bossing were not observed in all individuals but affected individuals with both DRS and RRS. Other anomalies were more selective in their distribution in this patient cohort. We present a comprehensive analysis of the craniofacial findings in patients with Robinow Syndrome, describing associated morphological features and correlating phenotypic manifestations to underlying genotype in a manner relevant for early recognition and focused evaluation of these patients.

Cleft Palate as Distinguishing Feature in a Patient with GABRB3 Epileptic Encephalopathy.

Mutations in GABAA-receptor subunit genes are associated with a heterogeneous spectrum of epilepsies. Patients with epilepsy caused by mutations in a specific GABAA-receptor (GABRA3) occasionally present with orofacial dysmorphism (e.g., cleft palates). While cleft palates have been described in Gabrb3 knockout mice and in humans with GABRB3 variants without epilepsy, the specific combination of epilepsy and cleft palate in humans with GABRB3 mutations has not yet been reported.We describe a patient with epileptic encephalopathy (EE) who presented with therapy-refractory neonatal-onset myoclonic seizures and severe developmental delay. Electroencephalogram showed burst suppression pattern at neonatal age and hypsarrhythmia at infantile age. Initial magnetic resonance imaging was unremarkable. As he additionally presented with a cleft palate, we were curious whether cleft palate and EE had the same genetic origin. Whole exome sequencing of the index patient revealed a novel pathogenic heterozygous de novo mutation in GABRB3 (c.899T > C; p.I300T). In consistency with Gabrb3 knockout mice data, this is the first report of cleft palate in a patient with GABRB3 associated EE.We suggest to add cleft palate to the phenotypic GABRB3 spectrum and to screen for mutations in GABAA-receptors in patients with EE and orofacial dysmorphism.

A novel PITX2 mutation in non-syndromic orodental anomalies.

OBJECTIVE: To identify orodental characteristics and genetic aetiology of a family affected with non-syndromic orodental anomalies. SUBJECTS AND METHODS: Physical and oral features were characterised. DNA was collected from an affected Thai family. Whole-exome sequencing was employed to identify the pathogenic variants associated with inherited orodental anomalies. The presence of the identified mutation was confirmed by Sanger sequencing. RESULTS: We observed unique orodental manifestations including oligodontia, retained primary teeth, taurodont molars, peg-shaped maxillary central incisors, high attached frenum with nodule and midline diastema in the proband and her mother. Mutation analyses revealed a novel heterozygous frameshift deletion, c.573_574delCA, p.L193QfsX5, in exon 5 of PITX2A in affected family members. The amino acid alterations, localised in the transcriptional activation domain 2 in the C-terminus of PITX2, were evolutionarily conserved. Mutations in PITX2 have been associated with autosomal-dominant Axenfeld-Rieger syndrome and non-syndromic eye abnormalities, but never been found to cause isolated oral anomalies. CONCLUSIONS: This study for the first time demonstrates that the PITX2 mutation could lead to non-syndromic orodental anomalies in humans. We propose that the specific location in the C-terminal domain of PITX2 is exclusively necessary for tooth development.

Zebrafish models of orofacial clefts.

Zebrafish is a model organism that affords experimental advantages toward investigating the normal function of genes associated with congenital birth defects. Here we summarize zebrafish studies of genes implicated in orofacial cleft (OFC). The most common use of zebrafish in this context has been to explore the normal function an OFC-associated gene product in craniofacial morphogenesis by inhibiting expression of its zebrafish ortholog. The most frequently deployed method has been to inject embryos with antisense morpholino oligonucleotides targeting the desired transcript. However, improvements in targeted mutagenesis strategies have led to widespread adoption of CRISPR/Cas9 technology. A second application of zebrafish has been for functional assays of gene variants found in OFC patients; such in vivo assays are valuable because the success of in silico methods for testing allele severity has been mixed. Finally, zebrafish have been used to test the tissue specificity of enhancers that harbor single nucleotide polymorphisms associated with risk for OFC. We review examples of each of these approaches in the context of genes that are implicated in syndromic and non-syndromic OFC. Developmental Dynamics 246:897-914, 2017. © 2017 Wiley Periodicals, Inc.

Nance-Horan syndrome-The oral perspective on a rare disease.

The present study describes seven patients with Nance-Horan syndrome, all referred to a specialized oral care unit in the Central Denmark Region. A literature search on "Nance Horan Syndrome" resulted in 53 publications among which 29 reported on dental findings. Findings reported in these papers have been systematized to obtain an overview of the reported findings and the terminology on dental morphology. All seven patients included in the present study showed deviations of crown morphology on incisors and/or molars. The only consistent and very clear dental aberration was alterations in the tooth morphology that is screwdriver-shaped incisors and bud molars being most pronounced in the permanent dentition, but were also present in the primary dentition. In addition, three patients had supernumerary teeth, and three had dental agenesis. In conclusion, a dental examination as a part of the diagnostic process may reveal distinct characteristics of the dental morphology, which could be of diagnostic value and facilitate an early diagnosis. In the description of molar morphology in NHS patients, it is recommended to use the term "bud molar." The combination of congenital cataract, screwdriwer-shaped incisors and bud-shaped molars is a strong clinical indication of Nance-Horan syndrome. © 2016 Wiley Periodicals, Inc.

Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel-Manzke syndrome in a fetus.

Pierre-Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel-Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel-Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G>T; p.(Ala100Ser) and the so far undescribed variant c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel-Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel-Manzke syndrome.

The role of cathepsin K in oral and maxillofacial disorders.

Cathepsin K (CTSK) was thought to be a collagenase, specifically expressed by osteoclasts, and played an important role in bone resorption. However, more and more research found that CTSK was expressed in more extensive cells, tissues, and organs. It may not only participate in regulating human physiological activity, but also be closely related to a variety of disease. In this review, we highlight the relationship between CTSK and oral and maxillofacial disorders on the following three aspects: oral and maxillofacial abnormities in patients with pycnodysostosis caused by CTSK mutations, oral and maxillofacial abnormities in Ctsk(-/-) mice, and the role of CTSK in oral and maxillofacial diseases, including periodontitis, peri-implantitis, tooth movement, oral and maxillofacial tumor, root resorption, and periapical disease.

[Trisomy 18 syndrome: A case report]. / Síndrome de trisomía 18. Reporte de un caso clínico.

INTRODUCTION: The trisomy 18 syndrome occurs due to the presence of an extra chromosome 18 in most cases. The prevalence in infants is estimated at 1:6000 to 1:8000. Those affected have a high mortality rate, only 4% may survive their first year of life. There are few reported cases exceeding five years of age. OBJECTIVE: The aim of this paper is to report a case of trisomy 18 of long survival with oral cavity features not described in the literature, and to provide information to physicians and paediatricians about aetiology, phenotype, survival and genetic counselling. CASE REPORT: A 7 year-old female patient with 2 karyotypes performed by lymphocyte culture showing 47XX+18 in all metaphases. She presented with growth deficiency, dysmorphic facies, severe psychomotor retardation and cognitive disability, inability to feed, lack of verbal language, sensorineural hearing loss, ataxia, cerebellar hypoplasia, and genitals with hypoplastic labia majora and minora. In the oral cavity: dome shaped palate, macroglossia, absence of upper central incisors and first upper and lower molars in mouth. X-ray findings showed formation of missing teeth, with late eruption being concluded. CONCLUSIONS: In cases of trisomy 18 syndrome there is an increased risk of neonatal and infant mortality. The clinical characteristics in utero and in neonates have been well described. Since few cases exceeding five years of age have been reported, the phenotype is yet to be established. In the case being reported we describe oral cavity findings not documented in the literature.

A rare variant in human fibroblast activation protein associated with ER stress, loss of enzymatic function and loss of cell surface localisation.

Fibroblast activation protein (FAP) is a focus of interest as a potential cancer therapy target. This membrane bound protease possesses the unique catalytic activity of hydrolysis of the post-proline bond two or more residues from the N-terminus of substrates. FAP is highly expressed in activated fibroblastic cells in tumours, arthritis and fibrosis. A rare, novel, human polymorphism, C1088T, encoding Ser363 to Leu, occurring in the sixth blade of the ß propeller domain, was identified in a family. Both in primary human fibroblasts and in Ser363LeuFAP transfected cells, we showed that this single substitution ablates FAP dimerisation and causes loss of enzyme activity. Ser363LeuFAP was detectable only in endoplasmic reticulum (ER), in contrast to the distribution of wild-type FAP on the cell surface. The variant FAP showed decreased conformational antibody binding, consistent with an altered tertiary structure. Ser363LeuFAP expression was associated with upregulation of the ER chaperone BiP/GRP78, ER stress sensor ATF6, and the ER stress response target phospho-eIF2α, all indicators of ER stress. Proteasomal inhibition resulted in accumulation of Ser363LeuFAP, indicating the involvement of ER associated degradation (ERAD). Neither CHOP expression nor apoptosis was elevated, so ERAD is probably important for protecting Ser363LeuFAP expressing cells. These data on the first loss of function human FAP gene variant indicates that although the protein is vulnerable to an amino acid substitution in the ß-propeller domain, inactive, unfolded FAP can be tolerated by cells.

Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch.

The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism. Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population; however, the signals controlling the proliferation-differentiation switch in vivo remain elusive. Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 (Irf6), the homolog of the gene mutated in the human congenital disorders Van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3sigma) show similar defects of keratinizing epithelia. Our results indicate that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process.

Single gene disorders with craniofacial and oral manifestations.

Gene and environmental factors are instrumental in genesis of complex and wide range of disorders and syndromes. The newer gene sequencing and other advanced technologies have made our previous knowledge of genetic etiopathogenesis of various disorders more transparent. Single gene disorders refer to the disorders caused due to mutations in a single gene and a fair number of these manifest as craniofacial defects and anomalies. This review is an attempt to give a detailed insight into the varied single gene disorders and syndromes with an emphasis on dental implications.

Precocious puberty in a patient with Oculo-Auriculo-Verebral spectrum (OAVS).

The authors report on the first case of OAVS (Oculo-Auriculo- Vertebral-Spectrum), with hemifacial microsomy, hydrocephalus, pubertas precox, thelarche at 4 years of age, vaginal bleeding at 5 years, and left ovary of adult type on echography (right ovary initially not visualized). FISH and CGH-ARRAYS methods were negative. By GnRH therapy the delay of onset puberty was obtained. The authors ascribe facial and ovary asymmetry to a derangement of blastogenesis, during which axial right-left structures begin the develop with consequent migration or interation with surrounding tissues of neural crest cells and alteration of diencephalic pituitary systems.

Family-based association tests using genotype data with uncertainty.

Family-based association studies have been widely used to identify association between diseases and genetic markers. It is known that genotyping uncertainty is inherent in both directly genotyped or sequenced DNA variations and imputed data in silico. The uncertainty can lead to genotyping errors and missingness and can negatively impact the power and Type I error rates of family-based association studies even if the uncertainty is independent of disease status. Compared with studies using unrelated subjects, there are very few methods that address the issue of genotyping uncertainty for family-based designs. The limited attempts have mostly been made to correct the bias caused by genotyping errors. Without properly addressing the issue, the conventional testing strategy, i.e. family-based association tests using called genotypes, can yield invalid statistical inferences. Here, we propose a new test to address the challenges in analyzing case-parents data by using calls with high accuracy and modeling genotype-specific call rates. Our simulations show that compared with the conventional strategy and an alternative test, our new test has an improved performance in the presence of substantial uncertainty and has a similar performance when the uncertainty level is low. We also demonstrate the advantages of our new method by applying it to imputed markers from a genome-wide case-parents association study.

Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome.

CHARGE (coloboma of the eye, heart defects, choanal atresia, retarded growth and development, genital hypoplasia and ear anomalies and/or hearing loss) syndrome is a rare genetic, multiple-malformation syndrome. About 80% of patients with a clinical diagnose, have a mutation or a deletion in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). Genotype-phenotype correlation is only partly known. In this nationwide study, phenotypic characteristics of 18 Danish CHD7 mutation positive CHARGE individuals (N = 18) are presented. We studied patient records, clinical photographs, computed tomography, and magnetic resonance imaging (MRI). Information was not available for all traits in all subjects. Therefore, the results are presented as fractions. The following prevalence of cardinal symptoms were found: coloboma, 16/17; heart defects, 14/18; choanal atresia, 7/17; retarded growth and development, 11/13; genital abnormalities, 5/18; ear anomalies, 15/17 and sensorineural hearing loss, 14/15. Vestibular dysfunction (10/13) and swallowing problems (12/15) were other frequent cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in >85%. CHARGE syndrome present a broad phenotypic spectrum, although some clinical features are more frequently occurring than others. Here, we suggest that genetic testing for CHD7 mutation should be considered in neonates with a specific combination of several clinical symptoms.

TBX22 and tongue-tie.

OBJECTIVE: To resolve if TBX22 mutations cause isolated tongue-tie in the Finnish population. DESIGN: Mutation analysis of the coding region of the TBX22 gene in 50 Finnish isolated tongue-tie patients and 61 control samples. RESULTS: One putative sequence variation was identified from two male patients, but whether this represents a polymorphism or causative mutation remains unknown. CONCLUSIONS: Mutations in the coding region of the TBX22 gene are not a major cause of ankyloglossia in the Finnish population and do not explain the sex difference or inheritance of tongue-tie.

TBX22 mutation associated with cleft lip/palate, hypodontia, and limb anomaly.

Mutations in TBX22 are known causes of cleft palate with/without ankyloglossia. We identified a hemizygous missense c.452G>T (p.Arg151Leu) mutation in a Thai boy who had unilateral complete cleft lip and palate, agenesis of a maxillary second premolar, ankyloglossia, hypoplastic carpal bones, and hypoplastic right thumb. Our study has demonstrated that TBX22 mutation is associated not only with cleft palate and ankyloglossia, but also cleft lip and palate and tooth agenesis. Phenotypic variability caused by a single nucleotide substitution is clearly demonstrated.

An/micr-ophthalmia, cleft lip/palate, and short limbs: a new syndrome simulating a short rib syndrome.

We report on a male infant born at 38 weeks of gestation with hydrocephalus, right anophthalmia, left microphthalmia, cleft palate, midline cleft of lip, and microphallus. Autopsy showed pulmonary bronchial lymphangiectasia, hepatic periportal fibrosis, adrenal agenesis, ventricular septal defect, aortic stenosis, and undescended testes. The radiographic findings include short limbs and mild shortness of ribs. Karyotype with high-resolution banding was normal (46,XY). The combination of anomalies in this case could suggest a ciliopathy and may represent a new entity similar to that described by Cideciyan et al. [1].

Craniofacial and intraoral phenotype of Robinow syndrome forms.

Robinow syndrome (RS) is a rare genetic condition with two inheritance forms, autosomal dominant RS (DRS) and autosomal recessive RS (RRS). The characteristic features of this syndrome overlap in both inheritance forms, which make the clinical differential diagnosis difficult, especially in isolated cases. The objective of this study was to identify differences in the craniofacial and intraoral phenotype of patients with DRS and RRS. The characteristics and frequency of 13 facial and 13 intraoral clinical features associated with both DRS and RRS were assessed by direct dysmorphology examination and using a digital photographic analysis in 12 affected subjects. Although the phenotypic presentation varied and overlapped in the two forms of the syndrome, there were differences in the severity of the craniofacial and intraoral features. The craniofacial dysmorphology of RS was more severe in RRS. Nasal anomalies were the most frequent craniofacial features in both DRS and RRS. In contrast, intraoral features such as wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding and hypodontia were more severe in patients with DRS. Overall, facial characteristics appeared less pronounced in adult subjects compared to younger subjects. Craniofacial and intraoral findings are highly variable in RS, with abnormalities of the intraoral structures being more prominent in the DRS form. We propose that the difference in the alveolar ridge deformation pattern and severity of other intraoral characteristics could enhance the differential diagnosis of the two forms of this syndrome.