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.

Tratamento sintomático (blindagem do esmalte) em paciente com hipersensibilidade dentinária seguido de clareamento dentário: relato de caso / Symptomatic treatment (enamel shielding) in a patient with dentin hypersensitivity followed by tooth bleaching: acase report / Tratamiento sintomático (blindaje del esmalte) en un paciente con hipersensibilidad dentinaria seguido de blanqueamiento dental: informe de un caso

Introdução:A hipersensibilidade é uma doença que acomete grande parte da população que, por muitas vezes, também almejam uma melhor estética dos dentes através do clareamento e não alcançam seu objetivo devido sua condição sintomática.Objetivo:Verificar se uma paciente com hipersensibilidade dentinária e trincas no esmalte, ficaria sem dor após realização da blindagem do esmaltecom agentes dessensibilizantes de ação neural e oclusiva em sessão única e, ainda, se continuaria sem dor após o clareamento de consultório utilizando o peróxido de carbamida a 37%. Relato de caso:Paciente do sexo feminino, 31 anos, apresentava todos os elementos dentários com alta translucidez, muitas trincas e desgaste dental erosivo restrito à ponta de cúspide nos elementos 36 e 46. Após estes achados e associado àhistória clínica relatada de alta sensibilidade na dieta principalmente gelada, fechou-se o diagnóstico de um caso de hipersensibilidade dentinária. Foi realizado um procedimento dessensibilizante, em sessão única, com agentes de ação neural e oclusiva e, sequencialmente, clareamento dentário de consultório. A paciente relatou eliminação da sensibilidade com o tratamento dessensibilizante (blindagem do esmalte), o que levou àconcordância da paciente em realizar o clareamento com produto àbase de peróxido de carbamida a 37% que promete ausência de dor. Conclusões:o protocolo dessensibilizante utilizado cumpriu seu papel no quesito eliminação da dor com retorno da paciente às atividades diárias antes impossibilitadas (como ingerir bebidas geladas) e propiciou a realização de clareamento dentário sem dor, porém sem muito sucesso na mudança de cor alcançada (AU).

Introduction:Hypersensitivity is a disease that affects a large part of the population who, very often, also seek to improve the esthetics of their teeth through tooth bleaching and fail to achieve their goal due to their symptomatic condition.Objective:To ascertain whether a patient with dentin hypersensitivity and cracked enamel would be pain-free after enamel shielding with neuraland occlusive desensitizing agents in a single session, and whether she would continue to be pain-free after in-office tooth bleaching using 37% carbamide peroxide. Case report:A 31-year-old female patient who showcased high translucency in all dental elements, with many cracks and erosive tooth wear restricted to the cusp tips of elements 36 and 46. Following these findings and in association with the reported clinical history of high sensitivity, especially to cold diets, a diagnosis of dentin hypersensitivity was made. A single-session desensitizing procedure was carried out with neural and occlusive agents, and subsequently followed by in-office tooth bleaching. The patient reported the elimination of sensitivity with the desensitizing treatment (enamel shielding), which led to the patient agreeing to undergo teeth bleaching with a 37% carbamide peroxide-based product that guarantees no pain. Conclusions:The desensitizing protocol utilized fulfilled its role in terms of eliminating pain, with the patient returning to daily activities that had previously been impossible (such as drinking cold beverages) and allowing pain-free tooth bleaching to be carried out, but without much success in the color change achieved (AU).

Introducción: La hipersensibilidad es una enfermedad que afecta a gran parte de la población la cual, muchas veces, también pretende mejorar la estética de sus dientes a través del blanqueamiento y no alcanza su objetivo debido a su condición sintomática.Objetivo: Comprobar si una paciente con hipersensibilidad de la dentina y grietas en el esmalte estaría libre de dolor tras el blindaje del esmalte con agentes desensibilizantes neurales y oclusivos en una sola sesión, y, además, si seguiría estando libre de dolor tras el blanqueamiento dental en clínica utilizando peróxido de carbamida al 37%.Informe de caso: Una paciente de 31 años presentaba todos los elementos dentales con alta translucidez, con muchas grietas y desgaste dental erosivo restringido a las puntas de las cúspides de los elementos 36 y 46.Tras estos hallazgos y junto a la historia clínica descrita de alta sensibilidad especialmentefrente a una dieta fría, se realizó un diagnóstico de hipersensibilidad dentinaria. Se llevó a cabo un procedimiento de desensibilización en una sola sesión, con agentes neurales y oclusivos, seguido de un blanqueamiento dental clínico. La paciente declaró la eliminación de la sensibilidad con el tratamiento desensibilizante (blindaje del esmalte), lo que la llevó a aceptar el blanqueamiento con un producto a base de peróxido de carbamida al 37% que promete ser indoloro. Conclusiones: El protocolo de desensibilización utilizado cumplió su función en cuanto a la eliminación del dolor, permitiendo que la paciente volviera a realizar actividades cotidianas que antes le resultaban imposibles (como tomar bebidas frías) y permitiendo realizar el blanqueamiento dental sin dolor, pero sin mucho éxito en el cambio de color conseguido (AU).

Association of defects of enamel with polymorphisms in the vitamin D receptor and parathyroid hormone genes.

This cross-sectional study aimed to investigate the association between developmental defects of enamel (DDE) and single nucleotide polymorphisms (SNPs) in the genes encoding the vitamin D receptor (VDR) and parathyroid hormone (PTH). Orthodontic patients receiving treatment at a dental school were selected through convenience sampling. Intra-oral photographs were used to assess DDE, which were classified according to the criteria proposed by Ghanim et al. (2015) by a single calibrated examiner (Kappa>0.80). Enamel hypoplasia, molar-incisor hypomineralization (MIH), hypomimineralized second primary molar (HSPM), and non-MIH/HSPM demarcated opacities were considered for the analysis. Genomic DNA was extracted from buccal cells. The SNPs in VDR (rs7975232) and PHT (rs694, rs6256, and rs307247) were genotyped using real-time polymerase chain reactions (PCR). Statistical analyses were performed using the PLINK software (version 1.03, designed by Shaun Purcell, EUA). Chi-square or Fisher's exact tests were performed at a significance level of 5%. Ninety-one (n=91) patients (49 females and 42 males) (mean age of 14.1±5.8 years) were included. The frequency of DDE was 38.5% (35 patients). Genotype distributions were in Hardy-Weinberg equilibrium. No significant statistical association was found between DDE and the SNPs evaluated. A borderline association (p=0.09) was observed between DDE and the CC haplotype for SNP rs7975232 in VDR. In conclusion, the selected SNPs in VDR and PTH genes were not associated with DDE in the studied samples.

[Research progress in regional odontodysplasia].

Regional odontodysplasia (ROD) is a rare localized dental developmental anomaly. The typical clinical manifestations of ROD are abnormal tooth eruption, abnormal development of enamel and dentin. The radiographic characteristic is "ghost teeth". Its etiology still remains unknown. The care and treatment of a patient with ROD needs a multidisciplinary approach. And the treatment should be taken after the assessment of each individual case of ROD. This paper reviews the definition, etiology, epidemiological features, clinical manifestations, imaging features, dental microstructure and treatment strategies of ROD to provide reference for clinical diagnosis and treatment.

Dental caries and developmental defects of enamel in cerebral palsy: A meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to compare the occurrence of dental caries and developmental defects of enamel (DDE) in individuals with and without cerebral palsy (CP). MATERIALS AND METHODS: We conducted searches across five databases and the grey literature. Data were organized using EndNote 20. Reporting followed the MOOSE checklist. A random-effects model meta-analyses were conducted using RStudio, presenting results as mean difference (MD), odds ratio (OR), and 95% confidence interval (CI). The risk of bias of studies was analyzed using the Newcastle-Ottawa Scale, and the certainty of evidence was assessed using GRADE. RESULTS: Among 1336 identified records, 25 studies involving 59,997 participants (mean age: 11.1 years) were included. Data of 12 were pooled into meta-analyses. No significant differences were found between CP and non-CP individuals across indices: DMFT (k = 7) (MD = 0.31; 95% CI [-0.42-1.05]), dmft (k = 4) (MD = 0.31; 95% CI [-0.50-1.14]), DMFS (k = 2) (MD = -0.61; 95% CI [-20.56-19.33]), dmfs (k = 3) (MD = 0.54; 95% CI [-1.09-2.17]), and DDE (k = 3) (OR = 0.80, 95% CI [0.09-7.31]). The certainty of evidence was very low. CONCLUSION: Individuals with CP do not appear to differ significantly from those without CP in terms of dental caries experience and DDE.

Japanese 17q12 Deletion Syndrome with Complex Clinical Manifestations.

17q12 deletion syndrome is a rare chromosomal anomaly with variable phenotypes, caused by the heterozygous deletion of chromosome 17q12. We herein report a 35-year-old Japanese patient with chromosomal 17q12 deletion syndrome identified by de novo deletion of the 1.46 Mb segment at the 17q12 band by genetic analyses. He exhibited a wide range of phenotypes, such as maturity-onset diabetes of the young (MODY) type 5, structural or functional abnormalities of the kidney, liver, and pancreas; facial dysmorphic features, electrolyte disorders; keratoconus, and acquired perforating dermatosis. This case report provides valuable resources concerning the clinical spectrum of rare 17q12 deletion syndrome.

Linear enamel hypoplasia in Homo naledi reappraised in light of new Retzius periodicities.

OBJECTIVES: Among low-latitude apes, developmental defects of enamel often recur twice yearly, linkable to environmental cycles. Surprisingly, teeth of Homo naledi from Rising Star in South Africa (241-335 kya), a higher latitude site with today a single rainy season, also exhibit bimodally distributed hypoplastic enamel defects, but with uncertain timing and etiology. Newly determined Retzius periodicities for enamel formation in this taxon enable a reconstruction of the temporal patterning of childhood stress. METHODS: Using high resolution casts of 31 isolated anterior teeth from H. naledi, 82 enamel defects (linear enamel hypoplasia [LEH]) were identified. Seventeen teeth are assigned to three individuals. Perikymata in the occlusal wall of enamel furrows and between the onsets of successive LEH were visualized with scanning electron microscopy and counted. Defects were measured with an optical scanner. Conversion of perikymata counts to estimates of LEH duration and inter-LEH interval draws upon Retzius periodicities of 9 and 11 days. RESULTS: Anterior teeth record more than a year of developmental distress, expressed as two asymmetric intervals centered on 4.5 and 7.5 months bounded by three LEH. Durations, also, show bimodal distributions, lasting 3 or 12 weeks. Short duration LEH are more severe than long duration. Relative incisor/canine rates of formation are indistinguishable from modern humans. DISCUSSION: We invoke a disease and dearth model, with short episodes of distress reflecting onset of disease in young infants, lasting about 3 weeks, followed by a season of undernutrition, possibly intensified by secondary plant compounds, spanning about 12 weeks, inferably coincident with austral winter.

The prevalence of developmental defects of enamel in a cohort of adults with cystic fibrosis - A cross sectional study.

OBJECTIVES: Cystic Fibrosis is an autosomal recessive condition. It is a multisystem disease treated with a broad range of pharmacological therapies, diet and nutrition, and physiotherapy. Previous studies suggest that people with cystic fibrosis have a higher prevalence of developmental defects of enamel which may place this population at a greater risk of developing oral diseases such as caries. The aim of this study was to assess a cohort of people with cystic fibrosis (PwCF) for the presence of developmental defects of enamel and compare the results with a control group of people without cystic fibrosis. METHODS: A cross sectional study involving 92 participants with cystic fibrosis and 92 controls was conducted in Cork University Dental School & Hospital. All participants completed a detailed questionnaire prior to undergoing a full clinical examination. The Developmental Defect of Enamel Index was used as a measurement index. All data was statistically analysed with the help of statisticians from Cystic Fibrosis Registry of Ireland. RESULTS: 64 % (n = 59) of PwCF had enamel defects compared to just 30 % (n = 28) of people without cystic fibrosis. The median number of teeth affected by enamel defects in the study group was 1.5, compared to 0 in the control group. CONCLUSION: In this study the cohort of PwCF had more enamel defects than people without CF. Further research is required to investigate the aetiology of these findings. CLINICAL SIGNIFICANCE: Clinicians should be vigilant after teeth have erupted in PwCF as they may have an increased susceptibility to developmental defects of enamel.

Cervical enamel projections from a periodontal perspective: A scoping review.

Cervical enamel projections (CEPs) represent a unique developmental and anatomical anomaly wherein the enamel structure extends apically beyond the cemento-enamel junction of the tooth. In this scoping review, the existing literature on CEPs was evaluated to delineate their characteristics, prevalence, predilection for specific teeth and surfaces, clinical significance, and management approaches. Searches were conducted on MEDLINE (PubMed), Cochrane Library, and Embase databases using the keywords "enamel projection(s)" or "ectopic enamel." In total, 24 studies meeting inclusion criteria were included in the review. The prevalence of CEPs varied widely (8.3%-85.1%), predominantly manifesting as grade I or grade III. Mandibular first and second molars exhibited a higher incidence of CEPs, with a notable predilection for buccal surfaces. The consensus in most studies was that CEPs are associated with localized periodontal diseases. Recommendations inclined toward the removal of ectopic enamel during periodontal surgery to enhance periodontal attachment formation. However, decision-making should involve careful consideration of the benefits and drawbacks based on individual circumstances.

Chapter 4: Development Defects of Enamel and Dentine and Coronal Caries.

The development of the human dentition is prone to disruption due to its delicate and complex nature - including variations in tooth number and anatomical form and in the characteristics of enamel, dentine, and cementum. This chapter will focus on developmental defects of dental enamel (DDE) and dentine (DDD), which can be associated with considerable treatment burden on an individual, often related to the change in dental hard tissue characteristics in those at increased caries risk. DDE are prevalent and can be related to genetic conditions such as amelogenesis imperfecta and environmental challenges such as direct physical trauma to the developing tooth or systemic insults during the different phases of amelogenesis. Phenotypical variability can be great, making diagnosis difficult in many cases. There are two major enamel defects - the quantitative defect of hypoplasia and the qualitative defect of hypomineralization. DDDs are less prevalent than DDEs, with two major DDD types: dentinogenesis imperfecta and dentine dysplasia. The main features of the DDDs are enamel fracture exposing the dentine and subsequent wear, with enlarged pulp spaces in some variants. The appearance may be affected, with bulbous teeth and grey-blue to brown opalescent colouring. With respect to dental caries, developmental defects of the teeth, in themselves, do not cause caries risk; however, they can change the manifestation of the disease due to creating niches for biofilm accumulation and thereby increasing cleaning difficulty and changing the physical and chemical characteristics of dental hard tissues and how they react to cariogenic challenges.

Prevalence and influence of dental development anomalies in smile esthetics: a cross-sectional analysis

Aim: To determine the prevalence of dental development anomalies and type of influence on the smile of adolescent students. Method: This was a cross-sectional and analytical study carried out in two public (A1) and two private (A2) schools chosen by lot in the city of Parnaíba-Piauí. The sample calculation was based on the target population: number of people enrolled in public and private schools between 15 and 19 years, in the city of Parnaíba-PI, which totaled 6209 students in 2020, according to a survey carried out by the Brazilian Institute of Geography and Statistics ­ IBGE. A questionnaire on epidemiological data and aesthetic self-perception of the smile was applied to 160 adolescents between 15 and 19 years old, from August 2020 to July 2021. The clinical examination was carried out under natural light, to check for the presence of anomaly(s) in the dental development. Students who presented only one pathology would be called group 1 (G1), those who presented two would be called group 2 (G2) and those who presented 3 or more would be called group 3 (G3). On the other hand, adolescents in whom no anomaly was evidenced would participate in the control group (CG), both in A1 and A2. Results: It was observed that 37.5% of the sample had only a type of dental anomaly, corresponding to 60 individuals. The most prevalent were enamel hypoplasia, fusion, transposition, agenesis, ectopic eruption, microdent and dens-in-dent. It was possible to verify a higher prevalence in the maxilla, private schools (76.6%) and females (86.6%). In 45% of adolescents with dental anomalies, embarrassment was observed when smiling. Conclusion: The prevalence was relatively high, highlighting the enamel hypoplasia, influencing the smile esthetics of a reasonable number of adolescents, whether for acquaintances, strangers or even for photographs

The Association of Developmental Dental Defects and the Clinical Consequences in the Primary Dentition: A Systematic Review of Observational Studies.

Purpose: Assess whether children with developmental defects of enamel (DDE) in primary teeth have a higher risk of having dental caries or a higher prevalence of clinical consequences due to the disease than those without DDE. Methods: Search was performed in PubMed, Scopus, Web of Science™, Cochrane Library, LILACS, BBO, Embase databases and in gray literature. Three independent reviewers were involved in study selection, data extraction, and bias assessment. Risk of bias was evaluated by the Newcastle-Ottawa scale. DDE and its subtypes (demarcated opacities, hypoplasia, hypomineralized second primary molars (HSPM), and fluorosis) were regarded as exposure. Dental caries and clinical consequences of untreated caries were also assessed. In the meta-analyses, odds ratio (OR) was used in the random effects model for dichotomous outcomes. Quality of evidence was assessed using the Grading Recommendations Assessment, Development and Evaluation (GRADE). Results: The search yielded 5,750 studies, 39 of which were included in the systematic review and 20 in the meta-analysis. The risk of bias ranged from 4 to 9 points. Children with DDE were more prone to primary tooth caries (OR=2.79; 95% CI:1.29-6.03), and so were those with demarcated opacities (OR=1.75; 95% CI:1.09-2.78), hypoplasia (OR=2.84; 95% CI:1.73-4.67), and HSPM (OR=2.89; 95% CI:1.65-5.06). Fluorosis was not associated with caries (OR=1.39; 95% CI:0.97-1.98). Regarding tooth as a unit of analysis, DDE was highly associated with caries (OR=2.34; 95% CI:1.74-3.16). As for the clinical consequences of caries, only the qualitative analysis was conducted and there was no consensus in the studies. Conclusion: DDE is associated with higher primary tooth caries experience.

The Clinical Characteristics and Gene Mutations of Maturity-Onset Diabetes of the Young Type 5 in Sixty-One Patients.

Aims: Maturity-onset diabetes of the young type 5 (MODY5), a rare disease, is very easy to be misdiagnosed as type 2 diabetes. To get better understanding of the disease, we analyzed the clinical characteristics and gene mutations of MODY5. Methods: PubMed, Cochrane, the China National Knowledge Infrastructure, and Wanfang were searched with the following search terms: "MODY5" OR "HNF1B maturity-onset diabetes of the young" OR "maturity-onset diabetes of the young type 5" OR "renal cysts and diabetes syndrome". Clinical characteristics and gene mutations of MODY5 were analyzed. The demography, clinical characteristics, and blood indicators of patients were described utilizing simple summary statistics. Variables were analyzed by t-test, Wilcoxon signed rank test, and Fisher exact test. Spearman's correlation analysis was used for bi-variate analysis. All tests were two-sided, and a p-value < 0.05 was considered statistically significant. Statistical analysis was performed using the Statistical Package for the Social Sciences version 26 for Windows (SPSS). Results: A total of 48 literatures were included in this study, including 61 eligible patients and 4 different mutations. Of the 39 patients with available body weight index, 15 (38.46%) were underweight, 21 (53.85%) were normal weight and 3 (7.69%) were overweight or obese. Of the 38 patients with available family history, 25 (65.79%) reported a family history of diabetes. Of the 34 patients with available age of diabetes diagnosis, the median age of diabetes diagnosis was 16.00 years old and 88.24% (30/34) of patients were under 25 years old when they were first diagnosed with diabetes. Renal cysts were presented in 72.41%, hypomagnesemia in 91.67%, and pancreatic dysplasia in 71.88% of the patients. Patients with hepatocyte nuclear factor 1B (HNF1B) deletion had lower serum magnesium, serum creatinine, and higher eGFR than patients with other gene mutations, and the difference was statistically significant. Conclusions: The young onset of diabetes with low or normal BMI, renal cysts, hypomagnesemia, and pancreatic dysplasia should be recommended to genetic testing in order to differentiate MODY5 from other types of diabetes earlier.

A case of familial recurrent 17q12 microdeletion syndrome presenting with severe diabetic ketoacidosis.

BACKGROUND: Heterozygous intragenic mutations of the hepatocyte nuclear factor 1 homeobox b gene (HNF1B) located on chromosome 17 and microdeletion of 17q12 region (17q12MD) leads to the complete loss of this gene, which causes renal cystic disease, diabetes mellitus (MODY5), hypomagnesemia, hyperuricemia, liver enzyme abnormalities, genital tract abnormalities and exocrine pancreatic insufficiency. In addition, patients with 17q12MD also have facial dysmorphism, neuro-developmental and neuropsychiatric disorders. CASE: A 16-year-old girl with obesity and mild facial dysmorphism was admitted to the hospital with symptoms of diabetes that started two days prior to her admission. She was diagnosed with severe diabetic ketoacidosis and treated accordingly. She had been followed up with the diagnoses of multicystic renal disease, hydronephrosis, hepatosteatosis, hypomagnesemia and hyperuricemia since the age of six. She had mild intellectual disability. Her menarche started two months ago. Cranial magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy and a partial empty sella. Her mother had diabetes, hypomagnesemia and mild intellectual disability and her maternal grandfather and uncle had diabetes. Her grandfather also had renal cystic disease. All of them are on oral antidiabetic medication. The genetic analysis of the patient and her mother revealed a loss of 1.6 megabases in chromosome 17q12. CONCLUSIONS: MODY5 should be kept in mind in patients with diabetes who present with extra pancreatic findings, especially with renal cystic disease, more over, a genetic analysis including the study of 17q12MD should be carried out in patients who present with additional neuropsychiatric findings. Ketoacidosis can be seen in patients with MODY5. Ketoacidosis and renal anomalies and dysfunction are factors that increase and affect the severity of each other in these patients.

Maternal-Child Health Indicators Associated with Developmental Defects of Enamel in Primary Dentition.

Purpose: To assess the prevalence and severity of developmental defects of enamel (DDE) in primary teeth and maternal-associated factors. Methods: This cross-sectional study included 336 two- to four-year-old children who attended the National Day of Children's Vaccination in São Paulo State, Brazil. The modified DDE index was used for diagnosis. Mothers completed sociodemographic and health questionnaires. Descriptive and Poisson regression analyses were performed. Results: The prevalence of DDE was 50.6 percent. The most frequent defects were demarcated opacities (45.0 percent), diffuse (36.0 percent) opacities, and hypoplasia (5.8 percent). White opacities were predominant (64.8 percent) in the teeth with defects, followed by cream (20.4 percent), yellow (5.2 percent), and brown (1.9 percent). Most defects involved less than one-third of the tooth surface (80.2 percent). The prevalence of DDE was associated with maternal-child factors such as alcohol consumption during pregnancy (prevalence ratio [PR] equals 1.27; 95 percent confidence interval [95% CI] equals 1.03 to 1.55), child hospitalization for infectious disease in the first year of life (PR equals 1.32; 95% CI equals 1.05 to 1.67), and breastfeeding for the first 12 months of life (PR equals 0.53; 95% CI equals 0.45 to 0.62). Conclusions: Developmental defects of enamel showed high prevalence and mild severity in the primary dentition. Alcohol consumption during pregnancy and child hospitalization for infectious diseases in the first year of life were associated with an increased prevalence of DDE. Moreover, children who breastfed for 12 months had a lower prevalence of DDE in primary teeth.

Establishment of PLAFMCi005-A induced pluripotent stem cells derived from PBMC from a patient with renal cysts and diabetes syndrome.

Renal cysts and diabetes syndrome (RCAD) is caused by gene mutations in hepatocyte nuclear factor 1-ß (HNF1B), but the underlying molecular mechanism is still unclear. This study established PLAFMCi005-A human induced pluripotent stem cells (iPSCs) by reprogramming peripheral blood mononuclear cells (PBMCs) from an RCAD patient. PLAFMCi005-A has differentiation potential and can be used to investigate the pathogenesis of RCAD caused by HNF1B gene mutations, thus promoting the development of related drugs.

Blood pressure in children with renal cysts and diabetes syndrome.

Cystic kidney diseases such as autosomal recessive or dominant polycystic kidney disease (ARPKD and ADPKD) are associated with high prevalence of arterial hypertension. On the contrary, studies on hypertension in children with renal cysts and diabetes (RCAD) syndrome caused by abnormalities in the HNF1B gene are rare. Therefore, the primary aim of our study was to investigate the prevalence of high blood pressure in children with RCAD syndrome due to HNF1B gene abnormalities and secondary to search for possible risk factors for development of high blood pressure. Data on all children with genetically proven RCAD syndrome from three pediatric nephrology tertiary centers were retrospectively reviewed (office blood pressure (BP), ambulatory blood pressure monitoring (ABPM), creatinine clearance, renal ultrasound, echocardiography, albuminuria/proteinuria). High blood pressure was defined as BP ≥ 95th percentile of the current ESH 2016 guidelines and/or by the use of antihypertensive drugs. Thirty-two children with RCAD syndrome were investigated. Three children received ACE inhibitors for hypertension and/or proteinuria. High blood pressure was diagnosed using office BP in 22% of the children (n = 7). In the 7 performed ABPM, 1 child (14%) was diagnosed with hypertension and one child with white-coat hypertension. Creatinine clearance, proteinuria, albuminuria, body mass index, enlargement, or hypodysplasia of the kidneys and prevalence of HNF1B-gene deletion or mutation were not significantly different between hypertensive and normotensive children.Conclusion: High blood pressure is present in 22% of children with RCAD syndrome. What is Known: • Arterial hypertension is a common complication in children with polycystic kidney diseases. What is New: • High office blood pressure is present in 22% and ambulatory hypertension in 14% of children with renal cyst and diabetes (RCAD) syndrome.

Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model.

Heterozygous mutations in HNF1B cause the complex syndrome renal cysts and diabetes (RCAD), characterized by developmental abnormalities of the kidneys, genital tracts and pancreas, and a variety of renal, pancreas and liver dysfunctions. The pathogenesis underlying this syndrome remains unclear as mice with heterozygous null mutations have no phenotype, while constitutive/conditional Hnf1b ablation leads to more severe phenotypes. We generated a novel mouse model carrying an identified human mutation at the intron-2 splice donor site. Unlike heterozygous mice previously characterized, mice heterozygous for the splicing mutation exhibited decreased HNF1B protein levels and bilateral renal cysts from embryonic day 15, originated from glomeruli, early proximal tubules (PTs) and intermediate nephron segments, concurrently with delayed PT differentiation, hydronephrosis and rare genital tract anomalies. Consistently, mRNA sequencing showed that most downregulated genes in embryonic kidneys were primarily expressed in early PTs and the loop of Henle and involved in ion/drug transport, organic acid and lipid metabolic processes, while the expression of previously identified targets upon Hnf1b ablation, including cystic disease genes, was weakly or not affected. Postnatal analyses revealed renal abnormalities, ranging from glomerular cysts to hydronephrosis and, rarely, multicystic dysplasia. Urinary proteomics uncovered a particular profile predictive of progressive decline in kidney function and fibrosis, and displayed common features with a recently reported urine proteome in an RCAD pediatric cohort. Altogether, our results show that reduced HNF1B levels lead to developmental disease phenotypes associated with the deregulation of a subset of HNF1B targets. They further suggest that this model represents a unique clinical/pathological viable model of the RCAD disease.

Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease.

Maturity-onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron-2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total ß-cell volume. These defects were associated with a 30% decrease in expression of the pro-endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.