Lacrimo-auriculo-dento-digital syndrome with AIRE mutation: A case report.

Congenital absence or hypoplasia of the major salivary glands is rarely observed and easily overlooked in the clinic. Lacrimo-auriculo-dento-digital syndrome (LADD) is a congenital anomaly disorder that is characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary glands and caused by FGFR2, FGFR3, or FGF10 gene mutation. Autoimmune polyendocrine syndrome type 1 (APS-I) caused by an AIRE gene mutation is a rare inherited autoimmune disease characterized by chronic mucocutaneous candidiasis, Addison disease, and hypoparathyroidism. However, simultaneous mutations in pathogenic genes of the two syndromes (LADD and APS-I) in one patient is rarely observed. Herein, we have presented a patient with main complaints of xerostomia and xerophthalmia that was diagnosed with LADD syndrome with AIRE mutation.

Fine Breakpoint Mapping by Genome Sequencing Reveals the First Large X Inversion Disrupting the NHS Gene in a Patient with Syndromic Cataracts.

Inversions are structural variants that are generally balanced. However, they could lead to gene disruptions or have positional effects leading to diseases. Mutations in the NHS gene cause Nance-Horan syndrome, an X-linked disorder characterised by congenital cataracts and dental anomalies. Here, we aimed to characterise a balanced pericentric inversion X(p22q27), maternally inherited, in a child with syndromic bilateral cataracts by breakpoint mapping using whole-genome sequencing (WGS). 30× Illumina paired-end WGS was performed in the proband, and breakpoints were confirmed by Sanger sequencing. EdU assays and FISH analysis were used to assess skewed X-inactivation patterns. RNA expression of involved genes in the breakpoint boundaries was evaluated by droplet-digital PCR. We defined the breakpoint position of the inversion at Xp22.13, with a 15 bp deletion, disrupting the unusually large intron 1 of the canonical NHS isoform, and also perturbing topologically-associated domains (TADs). Moreover, a microhomology region of 5 bp was found on both sides. RNA analysis confirmed null and reduced NHS expression in the proband and his unaffected mother, respectively. In conclusion, we report the first chromosomal inversion disrupting NHS, fine-mapped by WGS. Our data expand the clinical spectrum and the pathogenic mechanisms underlying the NHS defects.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Microdont Developing Outside the Alveolar Process and Within Oral Diffuse and Plexiform Neurofibroma in Neurofibromatosis Type 1.

BACKGROUND/AIM: Numerical aberrations of permanent dentition and dystopic tooth eruption are part of the phenotype of the tumor predisposition syndrome neurofibromatosis type 1 (NF1). In these cases, surplus tooth germs usually develop in the alveolar processes of the jaw. This report attests to the dystopic development of a dysplastic supernumerary tooth in NF1 arising outside the jaw. CASE REPORT: The 8-year-old male patient developed a microdont outside the bone and above the occlusal plane of the retained maxillary right second molar. The supernumerary tooth was completely embedded in oral soft tissue. Hyperplastic oral soft tissue in the molar region and microdont were excised. Specimen of the mucosa surrounding the teeth was interspersed with diffuse and plexiform neurofibroma. The retained upper right first molar emerged spontaneously within a few months after surgery. The upper right second molar did not change position. CONCLUSION: Odontogenesis can take place within tumorous oral mucosa in NF1. Surgical removal of the tumorous mucous membrane facilitates tooth eruption in some cases.

Odontogenic and Developmental Oral Lesions in Pediatric Patients.

This article reviews odontogenic and developmental oral lesions encountered in the gnathic region of pediatric patients. The process of odontogenesis is discussed as it is essential to understanding the pathogenesis of odontogenic tumors. The clinical presentation, microscopic features, and prognosis are addressed for odontogenic lesions in the neonate (dental lamina cysts/gingival cysts of the newborn, congenital (granular cell) epulis of the newborn, melanotic neuroectodermal tumor, choristoma/heterotopia, cysts of foregut origin), lesions associated with unerupted/erupting teeth (hyperplastic dental follicle, eruption cyst, dentigerous cyst, odontogenic keratocyst/keratocystic odonogenic tumor, buccal bifurcation cyst/inflammatory collateral cyst) and pediatric odontogenic hamartomas and tumors (odontoma, ameloblastic fibroma, ameloblastoma, adenomatoid odontogenic tumor, primordial odontogenic tumor). Pediatric odontogenic and developmental oral lesions range from common to rare, but familiarity with these entities is essential due to the varying management implications of these diagnoses.

Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities.

COL27A1 encodes a collagen type XXVII alpha 1 chain. It is the product of this gene that provides the structural support of connective tissue and is reported to be the causative gene of Steel syndrome (OMIM #615155). The primary symptoms of patients with this defect are consistent with systemic bone disease; however, recent reports note findings of intellectual disability and hearing loss. In this study, we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome. This variant, of maternal origin, caused an amino acid substitution of arginine for glycine, c.2026G>C or p.G676R, in the collagen helix domain, which is assumed to damage the structure of the helix. The paternally transmitted variant, c.2367G>A, is located at the 3' end of exon 12, and cDNA analysis revealed a splicing alteration. These novel, compound heterozygous COL27A1 variants might indicate an association of the gene with tooth and genital abnormalities.

Two loss-of-function ANKRD11 variants in Chinese patients with short stature and a possible molecular pathway.

KBG syndrome is a rare genetic disease characterized mainly by skeletal abnormalities, distinctive facial features, and intellectual disability. Heterozygous mutations in ANKRD11 gene, or deletion of 16q24.3 that includes ANKRD11 gene are the cause of KBG syndrome. We describe two patients presenting with short stature and partial facial features, whereas no intellectual disability or hearing loss was observed in them. Two ANKRD11 variants, c.4039_4041del (p. Lys1347del) and c.6427C > G (p. Leu2143Val), were identified in this study. Both of them were classified as variants of uncertain significance (VOUS) by ACMG/AMP guidelines and were inherited from their mothers. ANKRD11 could enhance the transactivation of p21 gene, which was identified to participate in chondrogenic differentiation. In this study, we demonstrated that the knockdown of ANKRD11 could reduce the p21-promoter luciferase activities while re-introduction of wild type ANKRD11, but not ANKRD11 variants (p. Lys1347del or p. Leu2143Val), could restore the p21 levels. Thus, our study report two loss-of-function ANKRD11 variants which might provide new insight on pathogenic mechanism that correlates ANKRD11 variants with the short stature phenotype of KBG syndrome.

Calmodulin Directly Interacts with the Cx43 Carboxyl-Terminus and Cytoplasmic Loop Containing Three ODDD-Linked Mutants (M147T, R148Q, and T154A) that Retain α-Helical Structure, but Exhibit Loss-of-Function and Cellular Trafficking Defects.

The autosomal-dominant pleiotropic disorder called oculodentodigital dysplasia (ODDD) is caused by mutations in the gap junction protein Cx43. Of the 73 mutations identified to date, over one-third are localized in the cytoplasmic loop (Cx43CL) domain. Here, we determined the mechanism by which three ODDD mutations (M147T, R148Q, and T154A), all of which localize within the predicted 1-5-10 calmodulin-binding motif of the Cx43CL, manifest the disease. Nuclear magnetic resonance (NMR) and circular dichroism revealed that the three ODDD mutations had little-to-no effect on the ability of the Cx43CL to form α-helical structure as well as bind calmodulin. Combination of microscopy and a dye-transfer assay uncovered these mutations increased the intracellular level of Cx43 and those that trafficked to the plasma membrane did not form functional channels. NMR also identify that CaM can directly interact with the Cx43CT domain. The Cx43CT residues involved in the CaM interaction overlap with tyrosines phosphorylated by Pyk2 and Src. In vitro and in cyto data provide evidence that the importance of the CaM interaction with the Cx43CT may lie in restricting Pyk2 and Src phosphorylation, and their subsequent downstream effects.

Oral, dental, and craniofacial features in chronic acid sphingomyelinase deficiency.

The aim of this study was to evaluate the oral, dental, and craniofacial features of individuals affected by the chronic forms of acid sphingomyelinase deficiency (ASMD). This study comprised a sample of adult and pediatric patients (n = 8) with chronic ASMD. The individuals underwent oral examinations to evaluate the occurrence of caries, as well as full-mouth periodontal examinations, to assess the occurrence and severity of periodontal diseases. Panoramic and profile radiographs were obtained to analyze dental conditions and craniofacial parameters. Participants also answered questionnaires to identify systemic impairment, parafunctional habits, and bruxism. Dental anomalies of size, shape, and number were found, with agenesis and microdontia being the predominant findings. The average of caries experience was 11.75 (±8.1). Only one patient had periodontal health and all adult individuals had periodontitis at different stages and degrees. Bruxism was found in 87.5% of the sample. The convex profile and maxillary and mandibular retrusion were the most relevant findings in the cephalometric analysis. It is concluded that individuals with chronic ASMD, in addition to several systemic manifestations, present significant modifications in their oral health, from a greater occurrence of dental anomalies, caries, periodontal disease, in addition to skeletal changes.

Effects of Reduced Connexin43 Function on Mandibular Morphology and Osteogenesis in Mutant Mouse Models of Oculodentodigital Dysplasia.

Mutations in the gene encoding the gap-junctional protein connexin43 (Cx43) are the cause of the human disease oculodentodigital dysplasia (ODDD). The mandible is often affected in this disease, with clinical reports describing both mandibular overgrowth and conversely, retrognathia. These seemingly opposing observations underscore our relative lack of understanding of how ODDD affects mandibular morphology. Using two mutant mouse models that mimic the ODDD phenotype (I130T/+ and G60S/+), we sought to uncover how altered Cx43 function may affect mandibular development. Specifically, mandibles of newborn mice were imaged using micro-CT, to enable statistical comparisons of shape. Tissue-level comparisons of key regions of the mandible were conducted using histomorphology, and we quantified the mRNA expression of several cartilage and bone cell differentiation markers. Both G60S/+ and I130T/+ mutant mice had altered mandibular morphology compared to their wildtype counterparts, and the morphological effects were similarly localized for both mutants. Specifically, the biggest phenotypic differences in mutant mice were focused in regions exposed to mechanical forces, such as alveolar bone, muscular attachment sites, and articular surfaces. Histological analyses revealed differences in ossification of the intramembranous bone of the mandibles of both mutant mice compared to their wildtype littermates. However, chondrocyte organization within the secondary cartilages of the mandible was unaffected in the mutant mice. Overall, our results suggest that the morphological differences seen in G60S/+ and I130T/+ mouse mandibles are due to delayed ossification and suggest that mechanical forces may exacerbate the effects of ODDD on the skeleton.

Clinical Orodental Anomalies in Taiwanese Children under Age Six: a Study Based on the 1995-1997 National Dental Survey.

There are few published studies that report the prevalence of intraoral anomalies for young children. The purpose of this study was to investigate the prevalence and distribution of several congenital oral and paraoral anomalies in Taiwanese children under age six. Twenty-five cities and townships were randomly sampled in different areas of Taiwan using the stratified method. These cities and townships represent cross-sectional samples of geographic locations and socioeconomic levels. A total of 981 Taiwanese children under age six were examined with dental mirrors and explorers as part of the national dental survey. The results of this survey indicated an 11.31% prevalence of geographic tongue. This number is higher than that reported in studies previously performed in different countries. The occurrence of double teeth in primary dentition was found to be 2.14%. Ankyloglossia had a frequency of 1.22%, and primary talon cusp a frequency of 0.61%. Seven (0.71%) children exhibited fissured tongues. Thirteen (1.33%) cases of hypodontia were found. These values were different from those reported in several other countries, which may be attributed to differences in the ethnic and racial composition of the population studied.

Consideraciones bucodentales en pacientes con Síndrome de Morquio / Dental considerations of the morquio síndrome

La mucopolisacaridosis tipo IV (MPS-IV) también conocida como enfermedad de Morquio en recuerdo del pediatra uruguayo Luis Morquio que la describió por primera vez, es una enfermedad congénita causada por la deficiencia de la enzima N-acetilgalactosamina 6 sulfatasa o de la enzima B-Galactosidasa. Estas anomalías enzimáticas tienen como consecuencia que se acumulen en diferentes tejidos del organismo cantidades elevadas de mucopolisacaridos. En la bibliografía se describe con detalle los defectos del esmalte que presentan los pacientes diagnosticados del síndrome de Morquio. Estos defectos son una característica aparentemente constante en la enfermedad y, por lo tanto, hace necesaria las visitas al odontólogo para su control evitándose problemas mayores. Dichos defectos consisten en un esmalte anormalmente delgado, que es áspero debido a los numerosos hoyos diminutos y a una superficie irregular. La delgadez del esmalte da como resultado una forma alterada y decoloración de los dientes que, añadido a los diastemas interdentales, provocan alteraciones en la oclusión. Aparte de estos defectos, el esmalte es histológicamente normal y tiene una du-reza y radiodensidad normales. El trata-miento odontológico de los pacientes con MPS-IV requiere colaboración multidisciplinar, debido a que las manifestaciones orales de la enfermedad pueden aparecer a cualquier edad, resultando en ocasiones tedioso para el paciente y complicado para el profesional. Especial mención merecen las terapias utilizadas como trata-miento sintomático de la enfermedad, así como el manejo de la vía aérea en el caso de intervenciones bajo anestesia general o sedación para tratar ciertas patologías del territorio bucomaxilodental

Mucopolysaccharidosis type IV (MPS-IV) also known as Morquio’s disease in memory of the Uruguayan pediatrician Luis Morquio who described it for the first time, is a congenital disease caused by the deficiency of the enzyme N-acetylgalactosamine 6 sulfatase or enzyme B -Galactosidase. These enzymatic anomalies result in high amounts of mucopolysaccharides accumulating in different tissues of the organism. The enamel defects presented by patients diagnosed with Morquio syndrome are described in detail in the bibliography. These defects are an apparently constant feature in the disease and, therefore, make visits to the dentist necessary for their control, avoiding major problems. These defects consist of an abnormally thin enamel that is rough due to numerous tiny holes and an irregular surface. The thinness of the enamel results in an altered form and discoloration of the teeth, which added to the interdental diastemas, cause alterations in the occlusion. Apart from these defects, the enamel is histologically normal and has a normal hardness and radiodensity.Dental treatment of patients with MPS-IV requires multidisciplinary collaboration, because the oral manifestations of the disease can appear at any age, being sometimes tedious for the patient and complicated for the professional. Special mention should be made of the therapies used as a symptomatic treatment of the disease, as well as the management of the airway in the case of interventions under general anesthesia or sedation to treat certain pathologies of the bucomaxillodental territory

Living naked: first case of lack of skin-related structures in an elasmobranch, the blackmouth catshark (Galeus melastomus).

As far as is known, in this paper the first case of lacking of skin-related structures (epidermis, stratum laxum, dermal denticles and teeth) in a free-swimming elasmobranch, the blackmouth catshark, Galeus melastomus, is reported. The individual was caught by trawl in Sardinian waters (central-western Mediterranean) in July 2019 at a depth of 500 m. Although this kind of morphological abnormality is potentially fatal, the observations suggested that the specimen was in good health and well developed.

CDH1-related blepharocheilodontic syndrome is associated with diffuse gastric cancer risk.

We report the first case of diffuse gastric cancer in an individual with familial blepharocheilodontic syndrome (BCD) due to a germline CDH1 likely pathogenic variant. To date, other BCD affected relatives are nonpenetrant for diffuse gastric cancer posing challenges to counseling regarding gastric and breast cancer surveillance, and preventative total gastrectomy.

KBG syndrome in two patients from Egypt.

KBG syndrome is an intellectual disability (ID) associated with multiple congenital anomalies in which the macrodontia could be the clue for the diagnosis. It is caused either by heterozygous variant in ANKRD11 gene or 16q24.3 microdeletions that involve the ANKRD11 gene. Here, we report on two unrelated male patients who presented with ID, short stature, webbing of neck, and cryptorchidism. Noonan syndrome was suspected first but the presence of macrodontia in both patients pointed to KBG syndrome which was confirmed thereafter by the identification of a novel pathogenic variant in ANKRD11 gene, c.5488G>T (p.E1830*). Macrodontia was noticed in all the deciduous anterior teeth in Patient 1. This observation was reported previously in few patients, but it seems to be a common feature that could be misdiagnosed as premature eruption of teeth. Therefore, our results confirm that maxillary permanent central incisors may not be the only teeth affected in KBG but also all the deciduous teeth. Interestingly, desquamative gingivitis was additionally noted in Patient 1, which has not been reported previously, however; it could be a coincidental finding. To the best of our knowledge, this is the first report from Egypt.

Dental Manifestations of Ehlers-Danlos Syndromes: A Systematic Review.

Ehlers-Danlos syndromes (EDS) are a group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and variable tissue fragility. However, there are limited published data on the dental manifestations of EDS. This review systematically assessed the spectrum of published dental anomalies in various types of EDS. Twenty-four individual case reports/series and 3 longer case-control studies, reporting on a total of 84 individuals with a clinical diagnosis of EDS, were included in the data analysis. The main dental features listed in classical EDS were pulp calcification and localized root hypoplasia. Common dental abnormalities observed in vascular EDS were pulp shape modifications (52.2%), exceeding root length (34.8%), and molar root fusion (47.8%). Dentinogenesis imperfecta is a consistent finding in osteogenesis imperfecta/EDS overlap syndrome. Data on dental manifestations in other types of EDS are both rare and generally inconclusive.

KBG syndrome: Common and uncommon clinical features based on 31 new patients.

KBG syndrome (MIM #148050) is an autosomal dominant disorder characterized by developmental delay, intellectual disability, distinct craniofacial anomalies, macrodontia of permanent upper central incisors, skeletal abnormalities, and short stature. This study describes clinical features of 28 patients, confirmed by molecular testing of ANKRD11 gene, and three patients with 16q24 deletion encompassing ANKRD11 gene, diagnosed in a single center. Common clinical features are reported, together with uncommon findings, clinical expression in the first years of age, distinctive associations, and familial recurrences. Unusual manifestations emerging from present series include juvenile idiopathic arthritis, dysfunctional dysphonia, multiple dental agenesis, idiopathic precocious telarche, oral frenula, motor tics, and lipoma of corpus callosum, pilomatrixoma, and endothelial corneal polymorphic dystrophy. Facial clinical markers suggesting KBG syndrome before 6 years of age include ocular and mouth conformation, wide eyebrows, synophrys, long black eyelashes, long philtrum, thin upper lip. General clinical symptoms leading to early genetic evaluation include developmental delay, congenital malformations, hearing anomalies, and feeding difficulties. It is likely that atypical clinical presentation and overlapping features in patients with multiple variants are responsible for underdiagnosis in KBG syndrome. Improved knowledge of common and atypical features of this disorder improves clinical management.

Peripheral compound odontoma: A rare case report and literature review.

Peripheral odontoma is a very rare odontogenic hamartoma arising in soft tissues. Here, we report a case of peripheral odontoma in a pediatric patient and review the cases published in the literature. An 11-year-old male patient presented a nodular lesion in the anterior region of the palate for over 1 year. Under the clinical hypothesis of fibroma, an excisional biopsy was performed. Histopathological examination revealed the presence of tooth-like structures, formed by enamel, and dentin matrix, occasionally associated with the dental papilla and surrounding pulp tissue, thus, the histopathological diagnosis of peripheral odontoma was established. The patient has been undergoing follow-up for 6 months without any signs of lesion recurrence. Peripheral odontomas are uncommon lesions that usually affect young patients and display a preference for the maxilla and limited growth potential. The recognition of the clinical and histopathological features of the peripheral odontoma is indispensable for the establishment of its diagnosis.