A case of enamel renal syndrome from a novel genetic mutation, multidisciplinary management and long-term prognosis.

Background: The heterogeneous features of enamel renal syndrome (ERS) make diagnosis and treatment challenging. The main symptoms are disturbed amelogenesis and nephrocalcinosis. Bi-allelic likely pathogenic (LP) or pathogenic (P) variants in FAM20A have been associated with the syndrome since 2012. Affected patients often receive extensive dental treatment because of deviant orofacial morphology. However, knowledge about long-term prognosis and treatment guidelines are still lacking. The complex nature of ERS might endanger both dental and general health. The purpose of this article is to highlight the risks of overlooking the symptoms of the syndrome, and to discuss management strategies, surveillance and prognosis. Case presentation: We report the management of a case with suspected ERS after initial dental treatment elsewhere with no adjustment for the syndrome. Dental treatment was revised and followed for 8 years. Complementary medical examinations were conducted, and ERS was genetically confirmed, revealing homozygosity for a LP c.755_757del, p.(Phe252del) variant in FAM20A. The nephrological investigation revealed medullary calcium deposits, normal renal function and hypophosphatemia. Urine analysis revealed hypocitraturia and hypocalciuria. Accordingly, the patient now medicates with potassium citrate to decrease the risk of progressive renal stone formation. Conclusion: We herein describe a patient with confirmed ERS with an 8-year follow-up. Diagnostic delay until adulthood led to complicated dental treatment. The results of nephrological investigations are presented. The importance of dental and medical multidisciplinary management in syndromic disorders affecting the formation of the enamel is also exemplified. The dental prognosis after rehabilitation is likely affected by anatomical variations and patient cooperation. The prognosis for renal function seems to be good. However, lifelong surveillance of renal function is recommended. Registration: The ethics committee in Uppsala, Sweden, determined that ethical approval was not necessary in this case (2019-04835). Informed consent was obtained from the participant in writing and is documented in the medical records.

Developmental Defects of Enamel.

Amelogenesis, the intricate process governing enamel formation, is susceptible to a range of genetic, systemic, and environmental influences, resulting in distinct developmental defects of enamel (DDE), such as molar incisor hypomineralisation (MIH), enamel hypoplasia, dental fluorosis, and amelogenesis imperfecta (AI). This chapter aims to provide a comprehensive overview of amelogenesis and DDE, establishing correlations between histopathological findings and clinical manifestations. MIH, a qualitative enamel defect, occurs during the mineralisation and maturation phases, affecting first permanent molars and eventually incisors. Diagnostic challenges in MIH arise from the disorder's unique features, including variable tooth involvement and severity, influenced by a complex interplay of genetic, systemic, and environmental factors. Enamel hypoplasia, a quantitative defect, manifests in any tooth during enamel matrix secretion. Etiological factors include local, systemic, environmental, and genetic influences, with variable enamel matrix abnormalities depending on the stage of amelogenesis when aggression occurred. Dental fluorosis, a toxicological concern from chronic and excessive fluoride exposure, affects ameloblasts and compromises crystal growth of the homologous teeth during enamel development. Lastly, AI, an inherited condition, encompasses diverse phenotypes in enamel development. AI phenotypes, whether hypoplastic or hypomineralised, entail mutations in genes, such as AMELX, ENAM, MMP20, KLK4, WDR72, FAM83H, C4ORF26, amelotin, GPR68, and ACPT. Diagnosing AI involves considering family history and clinical observation. In conclusion, navigating the intricacies of amelogenesis, from MIH to AI, underscores the critical importance of accurate diagnosis for proper clinical management of DDE.

Salivary Molecular Spectroscopy with Machine Learning Algorithms for a Diagnostic Triage for Amelogenesis Imperfecta.

Amelogenesis imperfecta (AI) is a genetic disease characterized by poor formation of tooth enamel. AI occurs due to mutations, especially in AMEL, ENAM, KLK4, MMP20, and FAM83H, associated with changes in matrix proteins, matrix proteases, cell-matrix adhesion proteins, and transport proteins of enamel. Due to the wide variety of phenotypes, the diagnosis of AI is complex, requiring a genetic test to characterize it better. Thus, there is a demand for developing low-cost, noninvasive, and accurate platforms for AI diagnostics. This case-control pilot study aimed to test salivary vibrational modes obtained in attenuated total reflection fourier-transformed infrared (ATR-FTIR) together with machine learning algorithms: linear discriminant analysis (LDA), random forest, and support vector machine (SVM) could be used to discriminate AI from control subjects due to changes in salivary components. The best-performing SVM algorithm discriminates AI better than matched-control subjects with a sensitivity of 100%, specificity of 79%, and accuracy of 88%. The five main vibrational modes with higher feature importance in the Shapley Additive Explanations (SHAP) were 1010 cm-1, 1013 cm-1, 1002 cm-1, 1004 cm-1, and 1011 cm-1 in these best-performing SVM algorithms, suggesting these vibrational modes as a pre-validated salivary infrared spectral area as a potential biomarker for AI screening. In summary, ATR-FTIR spectroscopy and machine learning algorithms can be used on saliva samples to discriminate AI and are further explored as a screening tool.

Full-mouth rehabilitation with lithium disilicate ceramic crowns in hypoplastic amelogenesis imperfecta: a case report and review of literature.

BACKGROUND: Amelogenesis imperfecta (AI) is a group of genetic disorders characterized by tooth discoloration and enamel defects. Patients with AI always exhibit generalized attrition and defective tooth structure, leading to the loss of occlusal vertical dimension (OVD). Appropriate rehabilitation is challenging and essential to improve patients' aesthetics and function. CASE PRESENTATION: This case report presents a comprehensive management of a 30-year-old woman with hypoplastic AI. A 52-month follow-up revealed satisfactory full-mouth rehabilitation performances of lithium disilicate ceramic crowns after clinical crown lengthening, with increased vertical dimension. CONCLUSIONS: Patients with severe hypoplastic AI require proper full-mouth rehabilitation. Using full-crown lithium disilicate restorations to increase the OVD by 2‒4 mm is a safe and predictable recommendation for such cases. In addition, patients with AI require complex and comprehensive management. The long-term effects of full-mouth rehabilitation with lithium disilicate ceramic crowns still necessitate further follow-ups.

Orthodontic bonding in special circumstances.

This clinical paper provides an in-depth exploration of advanced techniques for bonding orthodontic attachments under special circumstances. Challenges arise when bonding brackets to non-enamel surfaces, such as dental restorations, and in conditions such as amelogenesis imperfecta, which affect enamel integrity. Distinct approaches required for bonding to different restorative materials, including glassy ceramics, zirconia, resin composites and metals, are outlined. Moreover, we describe strategies to manage bonding in conditions including amelogenesis imperfecta, hypodontia and microdontia in a multidisciplinary context.

Orthodontic findings and treatment need in patients with amelogenesis imperfecta: a descriptive analysis.

INTRODUCTION: Amelogenesis imperfecta (AI) is a genetically determined, non-syndromic enamel dysplasia that may manifest as hypoplasia, hypomaturation, or hypocalcification and can commonly be classified into four primary groups. In this retrospective analysis, specific orofacial characteristics are described and associated with each of the AI types based on a patient cohort from Witten/Herdecke University, Germany. METHODS: Data from 19 patients (ten male and nine female, mean age 12.27 ± 4.06 years) with AI who presented at the Department of Orthodontics between July 2011 and December 2023 were analyzed. Baseline skeletal and dental conditions were assessed, including the presence of hypodontia, displacements, and taurodontism. AI was classified into classes I-IV based on phenotype. Treatment needs were evaluated according to the main findings following the German KIG classification, while the radiological enamel situation was determined using panoramic radiographs. RESULTS: An approximately equal distribution between classes II and III was found and a slight inclination toward a dolichofacial configuration (ΔML-NSL: 5.07 ± 9.23°, ΔML-NL: 4.24 ± 8.04°). Regarding orthodontic findings, disturbance in tooth eruption as well as open bite were the most prevalent issues (both 36.8%, n = 7). The most common AI classes were type I and II, which show an almost even distribution about the skeletal classes in sagittal dimension, while dolichofacial configuration was found most frequently in vertical dimension. CONCLUSION: Both clinical and radiological orthodontic findings in context with AI are subject to extensive distribution. It seems that no specific orofacial findings can be confirmed in association with AI with regard to the common simple classes I-IV. It may be more appropriate to differentiate the many subtypes according to their genetic aspects to identify possible associated orthodontic findings.

AMELX Mutations and Genotype-Phenotype Correlation in X-Linked Amelogenesis Imperfecta.

AMELX mutations cause X-linked amelogenesis imperfecta (AI), known as AI types IE, IIB, and IIC in Witkop's classification, characterized by hypoplastic (reduced thickness) and/or hypomaturation (reduced hardness) enamel defects. In this study, we conducted whole exome analyses to unravel the disease-causing mutations for six AI families. Splicing assays, immunoblotting, and quantitative RT-PCR were conducted to investigate the molecular and cellular effects of the mutations. Four AMELX pathogenic variants (NM_182680.1:c.2T>C; c.29T>C; c.77del; c.145-1G>A) and a whole gene deletion (NG_012494.2:g.307534_403773del) were identified. The affected individuals exhibited enamel malformations, ranging from thin, poorly mineralized enamel with a "snow-capped" appearance to severe hypoplastic defects with minimal enamel. The c.145-1G>A mutation caused a -1 frameshift (NP_001133.1:p.Val35Cysfs*5). Overexpression of c.2T>C and c.29T>C AMELX demonstrated that mutant amelogenin proteins failed to be secreted, causing elevated endoplasmic reticulum stress and potential cell apoptosis. This study reveals a genotype-phenotype relationship for AMELX-associated AI: While amorphic mutations, including large deletions and 5' truncations, of AMELX cause hypoplastic-hypomaturation enamel with snow-capped teeth (AI types IIB and IIC) due to a complete loss of gene function, neomorphic variants, including signal peptide defects and 3' truncations, lead to severe hypoplastic/aplastic enamel (AI type IE) probably caused by "toxic" cellular effects of the mutant proteins.

Advances in clinical diagnosis and management of amelogenesis imperfecta in children and adolescents.

OBJECTIVE: To summarize studies published between 2017 and 2023 examining the clinical diagnosis and restorative management of amelogenesis imperfecta (AI) in children and adolescents. DATA: The review incorporated publications on clinical diagnosis, patient-reported outcomes, clinical trials, cohort studies, and case reports that included individuals below 19 years of age with non-syndromic AI. SOURCES: A literature search was conducted across electronic databases, PubMed, Web of Science, and CINAHL, including papers published between 2017 and 2023. The search yielded 335 unique results, of which 38 were eligible for inclusion. RESULTS: New evidence on the genetic background of AI makes it now advisable to recommend genetic testing to supplement a clinical AI diagnosis. The discussions of the dental profession and the public on social media do not always incorporate recent scientific evidence. Interview studies are finding that the impact of AI on quality of life is more severe than previously appreciated. New evidence suggests that single-tooth ceramic crowns should be the first choice of treatment. Due to incomplete reporting, case reports have been of limited value. CONCLUSION: In young patients with AI symptoms of pain and hypersensitivity decreased, and aesthetics were improved following all types of restorative therapy. Resin composite restorations were mainly performed in cases with hypoplastic AI and mild symptoms. Single tooth ceramic crown restorations have a high success rate in all types of AI and can be used in young individuals with AI. CLINICAL SIGNIFICANCE: Prosthetic rehabilitation in adolescents with severe AI is cost effective, improves esthetics, reduces tooth sensitivity, and improves oral health-related quality of life.

A novel mutation in GPR68 causes hypomaturation amelogenesis imperfecta.

OBJECTIVES: To identify the genetic cause of a Chinese family with hypomaturation amelogenesis imperfecta (AI) and to characterize the structure of GPR68 mutated enamel in order to develop a deeper understanding of the role of the GPR68 protein during the intricate process of amelogenesis. DESIGN: One Chinese family with generalized hypomaturation AI was recruited. Two of the third molars from the proband were subjected to scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). Whole exome sequencing (WES) was performed, and the identified mutation was confirmed by Sanger sequencing. Bioinformatics studies were further conducted to analyze the potential deleterious effects of the mutation. RESULTS: The proband presented with a hypomaturation AI phenotype, characterized by fragile and discolored enamel surface. The AI enamel showed prismatic structure, which was sporadically obscured by areas of amorphous material and porous structure. EDX analysis showed the proband's enamel demonstrated a significant decrease in calcium and phosphorus content and a significant increase in oxygen compared with normal enamel. A novel homozygous mutation of G protein-coupled receptor 68 (GPR68) (c .149 T > A, p.Ile50Asn) was identified in the proband. Bioinformatics analysis indicated that the mutation site displayed a high level of evolutionary conservation among species, and the mutation might impact the stability and conformation of the protein. CONCLUSION: The novel homozygous GPR68 mutation resulted in hypomaturation AI. We first described the effect of GPR68 mutation on enamel structure. Our results provide new genetic evidence that mutations involved in GPR68 contribute to hypomaturation AI.

Ameloblastin and its multifunctionality in amelogenesis: A review.

Extracellular matrix proteins play crucial roles in the formation of mineralized tissues like bone and teeth via multifunctional mechanisms. In tooth enamel, ameloblastin (Ambn) is one such multifunctional extracellular matrix protein implicated in cell signaling and polarity, cell adhesion to the developing enamel matrix, and stabilization of prismatic enamel morphology. To provide a perspective for Ambn structure and function, we begin this review by describing dental enamel and enamel formation (amelogenesis) followed by a description of enamel extracellular matrix. We then summarize the established domains and motifs in Ambn protein, human amelogenesis imperfecta cases, and genetically engineered mouse models involving mutated or null Ambn. We subsequently delineate in silico, in vitro, and in vivo evidence for the amphipathic helix in Ambn as a proposed cell-matrix adhesive and then more recent in vitro evidence for the multitargeting domain as the basis for dynamic interactions of Ambn with itself, amelogenin, and membranes. The multitargeting domain facilitates tuning between Ambn-membrane interactions and self/co-assembly and supports a likely overall role for Ambn as a matricellular protein. We anticipate that this review will enhance the understanding of multifunctional matrix proteins by consolidating diverse mechanisms through which Ambn contributes to enamel extracellular matrix mineralization.

ENAM Mutations Can Cause Hypomaturation Amelogenesis Imperfecta.

Amelogenesis imperfecta (AI) is a diverse group of inherited diseases featured by various presentations of enamel malformations that are caused by disturbances at different stages of enamel formation. While hypoplastic AI suggests a thickness defect of enamel resulting from aberrations during the secretory stage of amelogenesis, hypomaturation AI indicates a deficiency of enamel mineralization and hardness established at the maturation stage. Mutations in ENAM, which encodes the largest enamel matrix protein, enamelin, have been demonstrated to cause generalized or local hypoplastic AI. Here, we characterized 2 AI families with disparate hypoplastic and hypomaturation enamel defects and identified 2 distinct indel mutations at the same location of ENAM, c588+1del and c.588+1dup. Minigene splicing assays demonstrated that they caused frameshifts and truncation of ENAM proteins, p.Asn197Ilefs*81 and p.Asn197Glufs*25, respectively. In situ hybridization of Enam on mouse mandibular incisors confirmed its restricted expression in secretory stage ameloblasts and suggested an indirect pathogenic mechanism underlying hypomaturation AI. In silico analyses indicated that these 2 truncated ENAMs might form amyloid structures and cause protein aggregation with themselves and with wild-type protein through the added aberrant region at their C-termini. Consistently, protein secretion assays demonstrated that the truncated proteins cannot be properly secreted and impede secretion of wild-type ENAM. Moreover, compared to the wild-type, overexpression of the mutant proteins significantly increased endoplasmic reticulum stress and upregulated the expression of unfolded protein response (UPR)-related genes and TNFRSF10B, a UPR-controlled proapoptotic gene. Caspase, terminal deoxynucleotidyl transferase UTP nick-end labeling (TUNEL), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays further revealed that both truncated proteins, especially p.Asn197Ilefs*81, induced cell apoptosis and decreased cell survival, suggesting that the 2 ENAM mutations cause AI through ameloblast cell pathology and death rather than through a simple loss of function. This study demonstrates that an ENAM mutation can lead to generalized hypomaturation enamel defects and suggests proteinopathy as a potential pathogenesis for ENAM-associated AI.

[Total rehabilitation in case of amelogenesis imperfecta].

The aim of the treatment of this case was to restore the form, function and aesthetics of all teeth in a patient with amelogenesis imperfecta within the age limit of the disability insurance (IV). Single-tooth zirconia crowns were selected as the treatment of choice and cemented with a conventional glass ionomer cement. For the maintenance of the oral rehabilitation and the protection of the reconstructions a michigan splint was produced and instructed to be carried over night.

Is Italian Dentists' Knowledge of Enamel Development Defects Adequate? A Nationwide Survey.

OBJECTIVES: Correct identification and management of Developmental Defects of Enamel (DDEs) are essential to provide the best possible treatment. The present survey aims to investigate Italian dentists' knowledge of DDEs, their ability to recognise the different clinical pictures, and to choose the most appropriate clinical approach. METHODS: A cross-sectional survey was planned based on a questionnaire including 27 closed-ended questions, and that proposed 4 clinical pictures, molar incisor hypomineralisation (MIH), amelogenesis imperfecta (AI), dental fluorosis (DF), and an initial caries lesion (ICL). It was distributed by e-mail to all Italian dentists (N = 63,883) through the Italian Federation of Doctors and Dentists. Discrete variables were expressed as absolute and relative frequencies (%). A multivariate analysis assessed whether socio-demographic variables correlated with the answers' truthfulness. RESULTS: About 5017 questionnaires were included and analysed. Although 90.19% of the sample stated that they had received information on DDEs, a significant percentage did not recognise MIH (36.36%), AI (48.34%), DF (71.50%), and ICL (46.62%). Only 57.07% correctly classified enamel hypomineralisation as a qualitative defect, and even fewer, 54.45%, classified enamel hypoplasia as a quantitative defect. According to the logistic regressions, female dentists, dentists who treat mainly children and received information about DDEs, were more likely to recognise the 4 clinical pictures (P < .01). CONCLUSIONS: Italian dentists showed many knowledge gaps on DDEs that need to be filled; those who received formal training were more capable of correctly identifying the defects and were more likely to prescribe an appropriate management approach for the defects. CLINICAL SIGNIFICANCE: Increasing university courses and continuing education on diagnosing and managing DDEs seems reasonable to fill the knowledge gap on DDEs.

Enamel Renal Gingival Syndrome in an Adolescent.

Enamel renal gingival syndrome is a rare clinical condition characterized by the presence of amelogenesis imperfecta hypoplastic type, gingival fibromatosis and delayed tooth eruption, in addition to nephrocalcinosis with normal blood calcium levels. It is inherited as an autosomal recessive trait caused by mutations in the FAM20A gene located on chromosome 17q24.2. The purpose of this report is to describe a case of enamel renal gingival syndrome and discuss its distinct features and management.

Gingival proteomics reveals the role of TGF beta and YAP/TAZ signaling in Raine syndrome fibrosis.

Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFß/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFß/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFß-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFß-YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.

Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability.

BACKGROUND: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. CONCLUSION: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.

Heimler syndrome with a complaint of blurred vision caused by compound heterozygous variants in PEX1.

INTRODUCTION: Heimler syndrome (HS) is a rare disorder that includes sensorineural hearing loss (SNHL), nail abnormalities, and enamel hypoplasia. Patients with this syndrome can also exhibit ocular manifestations. At present, only a few cases of HS have been reported, existing knowledge of this syndrome is limited, and many cases have been misdiagnosed or even missed. This is the first report of Heimler syndrome with blurred vision as the first complaint, which was diagnosed by genetic analysis in the ophthalmology department. CASE DESCRIPTION: An 8-year-old girl complained of bilateral visual blur and night blindness from birth. Ophthalmic examinations revealed bilateral retinitis pigmentosa with cystoid macular edema, visual impairment with hyperopia and astigmatism. Hearing test revealed bilateral severe sensorineural hearing loss. Dental examinations revealed enamel hypoplasia. In addition, whole-exome sequencing (WES) identified two pathogenic variants in PEX1: the previously reported missense variant c.2966T > C (p.I989 T), and the novel frameshift variant c.1671_1672del (p.G558Sfs*33). CONCLUSION: Heimler syndrome is caused by compound heterozygous PEX1 pathogenic variants, c.2966T > C (p.I989 T) and c.1671_1672del (p.G558Sfs*33), which contributed to the diversity of clinical and genetic profiles in this patient. The main clinical manifestations include bilateral retinitis pigmentosa with cystoid macular edema, sensorineural hearing loss, and enamel hypoplasia. Systemic examinations are suggested for patients suspected of having pigmentary retinal dystrophy, especially combined with hearing-related impairments. Genetic testing can help us to make a definitive diagnosis.

Orofacial Anomalies in Kindler Epidermolysis Bullosa.

Importance: Kindler epidermolysis bullosa is a genetic skin-blistering disease associated with recessive inherited pathogenic variants in FERMT1, which encodes kindlin-1. Severe orofacial manifestations of Kindler epidermolysis bullosa, including early oral squamous cell carcinoma, have been reported. Objective: To determine whether hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa. Design, Settings, and Participants: This longitudinal, 2-center cohort study was performed from 2003 to 2023 at the Epidermolysis Bullosa Centre, University of Freiburg, Germany, and the Special Care Dentistry Clinic, University of Chile in association with DEBRA Chile. Participants included a convenience sampling of all patients with a diagnosis of Kindler epidermolysis bullosa. Main Outcomes and Measures: The primary outcomes were the presence of hypoplastic pitted amelogenesis imperfecta, intraoral wounds, gingivitis and periodontal disease, gingival hyperplasia, vestibular obliteration, cheilitis, angular cheilitis, chronic lip wounds, microstomia, and oral squamous cell carcinoma. Results: The cohort consisted of 36 patients (15 female [42%] and 21 male [58%]; mean age at first examination, 23 years [range, 2 weeks to 70 years]) with Kindler epidermolysis bullosa. The follow-up ranged from 1 to 24 years. The enamel structure was assessed in 11 patients, all of whom presented with enamel structure abnormalities. The severity of hypoplastic pitted amelogenesis imperfecta varied from generalized to localized pitting. Additional orofacial features observed include gingivitis and periodontal disease, which was present in 90% (27 of 30 patients) of those assessed, followed by intraoral lesions (16 of 22 patients [73%]), angular cheilitis (24 of 33 patients [73%]), cheilitis (22 of 34 patients [65%]), gingival overgrowth (17 of 26 patients [65%]), microstomia (14 of 25 patients [56%]), and vestibular obliteration (8 of 16 patients [50%]). Other features included chronic lip ulcers (2 patients) and oral squamous cell carcinoma with lethal outcome (2 patients). Conclusions and Relevance: These findings suggest that hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa and underscore the extent and severity of oral manifestations in Kindler epidermolysis bullosa and the need for early and sustained dental care.