Outcomes of SARS-CoV-2 and seasonal viruses among 2 million adults hospitalized for severe acute respiratory infection during the COVID-19 pandemic in Brazil.

BACKGROUND: The outbreak of the COVID-19 pandemic has had a profound impact on the circulation of seasonal respiratory viruses. This study aimed to compare the outcomes of SARS-CoV-2 and seasonal viruses in adults hospitalized with severe acute respiratory infection (SARI) during the COVID-19 pandemic. METHODS: This population-based cohort study included patients aged > 18 years hospitalized for SARI in Brazil between February 2020 and February 2023. The primary outcome was in-hospital mortality. A competing risk analysis was used to account for competing events. RESULTS: In total, 2,159,171 patients were included in the study. SARS-CoV-2 was the predominant virus (98.7%). The cumulative incidence of in-hospital mortality was 33.1%, 31.5%, 21.0%, 18.7%, and 18.6%, for patients positive for SARS-CoV-2, adenovirus, RSV, influenza, and other viruses, respectively. SARS-CoV-2 accounted for 99.3% of the deaths. Older age, male sex, comorbidities, hospitalization in the northern region, and oxygen saturation <95% were the common risk factors for death among all viruses. CONCLUSIONS: In this large cohort study, individuals infected with SARS-CoV-2 or adenovirus had the highest risk of mortality. Irrespective of the virus type, older age, male sex, comorbidities, hospitalization in vulnerable regions, and low oxygen saturation were associated with an increased risk of fatality.

Vaccine Effectiveness against SARS-CoV-2 Variants in Adolescents from 15 to 90 Days after Second Dose: A Population-Based Test-Negative Case-Control Study.

OBJECTIVE: The objective of this study was to estimate the vaccine effectiveness (VE) against hospitalization and severe illness in adolescents due to infection with SARS-CoV-2 variants (gamma, delta, and omicron). STUDY DESIGN: A test-negative, case-control analysis was conducted in Brazil from July 2021 to March 2022. We enrolled 8458 eligible individuals (12-19 years of age) hospitalized with an acute respiratory syndrome, including 3075 cases with laboratory-proven COVID-19 and 4753 controls with negative tests for COVID-19. The primary exposure of interest was vaccination status. The primary outcome was SARS-CoV-2 infection during gamma/delta vs omicron-predominant periods. The aOR for the association of prior vaccination and outcomes was used to estimate VE. RESULTS: In the pre-omicron period, VE against COVID-19 hospitalization was 88% (95% CI, 83%-92%) and has dropped to 59% (95% CI, 49%-66%) during the omicron period. For hospitalized cases of COVID-19, considering the entire period of the analysis, 2-dose schedule was moderately effective against intensive care unit admission (46%, [95% CI, 27-60]), need of mechanical ventilation (49%, [95% CI, 32-70]), severe COVID-19 (42%, [95% CI, 17-60]), and death (46%, [95% CI, 8-67]). There was a substantial reduction of about 40% in the VE against all end points, except for death, during the omicron-predominant period. Among cases, 240 (6.6%) adolescents died; of fatal cases, 224 (93.3%) were not fully vaccinated. CONCLUSION: Among adolescents, the VE against all end points was substantially reduced during the omicron-predominant period. Our findings suggest that the 2-dose regimen may be insufficient for SARS-CoV-2 variants and support the need for updated vaccines to provide better protection against severe COVID-19.

Outcomes and risk factors for death among hospitalized children and adolescents with kidney diseases and COVID-19: an analysis of a nationwide database.

BACKGROUND: Patients with kidney diseases (KD) appear to be at particularly high risk for severe COVID-19. This study aimed to characterize the clinical outcomes and risk factors for COVID-19-related death in a large cohort of hospitalized pediatric patients with KD. METHODS: We performed an analysis of all pediatric patients with KD and COVID-19 registered in SIVEP-Gripe, a Brazilian nationwide surveillance database, between February 16, 2020, and May 29, 2021. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk by using cumulative incidence function. RESULTS: Among 21,591 hospitalized patients with COVID-19, 290 cases (1.3%) had KD. Of these, 59 (20.8%) had a fatal outcome compared with 7.5% of the non-KD cohort (P < 0.001). Pediatric patients with KD had an increased hazard of death compared with the non-KD cohort (Hazard ratio [HR] = 2.85, 95% CI 2.21-3.68, P < 0.0001). After adjustment, the factors associated with the death among KD patients were living in Northeast (HR 2.16, 95% CI 1.13-4.31) or North regions (HR 3.50, 95% CI 1.57-7.80), oxygen saturation < 95% at presentation (HR 2.31, 95% CI 1.30-4.10), and presence of two or more associated comorbidities (HR 2.10, 95% CI 1.08-4.04). CONCLUSIONS: Children and adolescents with KD had a higher risk of death compared with the non-KD cohort. The higher risk was associated with low oxygen saturation at admission, living in socioeconomically disadvantaged regions, and presence of other pre-existing comorbidities. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical Impact and Risk Factors of Mortality in Hospitalized Children and Adolescents With Hematologic Diseases and COVID-19: An Observational Retrospective Cohort Study.

This study aimed to evaluate the risk factors for COVID-19-related death in a large cohort of hospitalized children with hematological disorders. We performed an analysis of all pediatric patients with COVID-19 registered in a Brazilian nationwide surveillance database between February 2020 and May 2021. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk by using the cumulative incidence function. Among 21,591 hospitalized pediatric patients with COVID-19, 596 cases (2.8%) had hematological diseases. Sixty-one children (27.4%) with malignant hematological diseases had a fatal outcome as compared with 4.2% and 7.4% of nonmalignant hematological and nonhematological cohorts, respectively ( P <0.0001). Children with hematological diseases had a significant increased hazard of death compared with those without these conditions (hazard ratio [HR],=2.40, 95% confidence interval, 1.98 - 2.91). In multivariable analysis, the factors associated with death were the presence of malignant hematological disease (HR, 2.22, 95% CI 1.47 - 3.36), age >10 years (HR 2.19, 95% CI 1.46 - 3.19), male (HR 1.52, 95% CI 1.02 - 2.27), oxygen saturation <95% (HR 2.02, 95% CI 1.38 - 2.96), and abdominal pain at admission (HR 2.75, 95% CI 1.76 - 4.27). Children with malignant hematological diseases had a higher risk of death compared with those without these disorders.

Ethnic Differences in the Brazilian Population Influence the Impact of BMP4 Genetic Variants on Susceptibility of Nonsyndromic Orofacial Clefts.

OBJECTIVE: The study evaluated the association of BMP4 tag-SNPs and SNP-SNP interactions involving genes active by BMP4 pathway during craniofacial development in the susceptibility of nonsyndromic orofacial clefts (NSOC) in the Brazilian population. DESIGN: Case-control study. SETTING: Brazilian Oral Cleft Group. PARTICIPANTS: The study included 881 healthy controls and 800 patients with different types of NSOC: 232 with cleft lip only (NSCLO), 568 with cleft lip and palate (NSCLP), and 274 with cleft palate only (NSCPO). INTERVENTIONS: The genomic DNA was genotyped with allelic discrimination assays for five BMP4 tag-SNPs (rs11623717, rs17563, rs2071047, rs2761887 and rs4898820), and analyzed their allelic and genotypic associations using multiple logistic regression. The interactions of these variants with genes involved in the BMP4 signaling pathway, including FGFR1, GREM1, NOG, VAX1 and the 4p16.2 locus, were explored. MAIN OUTCOME MEASURES: BMP4 variants in the NSOC risk. RESULTS: Although only nominal p values were identified when the whole sample was considered, subgroup analysis including the patients with high African genomic ancestry showed significant associations of rs2761887 with risk for nonsyndromic cleft lip with or without cleft palate (NSCL ± P)[(ORhom: 2.16; 95% CI: 1.21-3.85; p = 0.01) and (ORrec: 2.05; 95% CI: 1.21-3.47; p = 0.006)]. Thirteen significant SNP-SNP interactions involving BMP4 and the SNPs at FGFR1, GREM1, NOG and VAX1 and at locus 4p16.2 for increased risk of NSCL ± P were identified. CONCLUSIONS: Our results demonstrate an increased risk of NSCL ± P in Brazilian individuals with enrichment of African ancestry in the presence of the BMP4 rs2762887 polymorphism, and reveal relevant genetic contribution of SNP-SNP epistatic interactions involving BMP4 variants to NSCL ± P risk.

Do Orofacial Clefts Impair Breastfeeding and Increase the Prevalence of Anemia?

OBJECTIVE: This study aimed to correlate the prevalence of iron deficiency anemia and breastfeeding with orofacial clefts in children. DESIGN: Data on the participant profile, presence and type of the cleft lip and/or palate (CL/P), and records on anemia and breastfeeding were collected from patients' charts, and submitted to statistical analysis by χ2 test (p < .05; software SPSS 23.0). RESULTS: Two-hundred and ten files were divided according to: CL/P presence (cleft group; n = 132) or absence (control group; n = 78). Group CL/P was subdivided according to the type of cleft: CL/P-I (cleft lip; n = 35); CL/P-II (cleft lip and palate; n = 45); CL/P-III (cleft palate; n = 43); and CL/P-IV (rare orofacial clefts; n = 9). Group CL/P had significantly more records on anemia (p = .016) and fewer records on breastfeeding (P<.01) than controls. More records on anemia occurred in CL/P-II (p = .004) and CL/P-IV (p = .006) than the control group. The comparison among the orofacial cleft types regarding the anemia records showed no statistically significant differences (p = .123). Group CL/P-I had more records on breastfeeding than the other cleft types (p < .01). CONCLUSIONS: Thus, it is suggested that the breastfeeding process is more complex, and the history of anemia is more frequent, in children with cleft lip and palate or rare orofacial clefts than in children without clefts.

Isolated nonsyndromic cleft palate: multicenter epidemiological study in the Brazil.

BACKGROUND: Nonsyndromic orofacial clefts (NSOC) are the craniofacial most common congenital malformations. There are evidences that the nonsyndromic cleft palate (NSCP) development differs from other NSOC. However, most of the publications treat NSCP without considering that information. Furthermore, few studies focus on NSCP. The aim of this study was to describe epidemiological findings of patients with isolated NSCP in Brazil. METHODS: In this cross-sectional multicenter study, four reference Centers for treatment in three different Brazilian states was investigated. Data were obtained from clinical records of patients, between November 2021 and June 2022. Researched variables were sociodemographic, clinical characteristics and pregnancy and family history. Pearson's chi-square and ANOVA One-way tests were used for associations. RESULTS: Majority were female (58.1%), white (60.7%) with incomplete NSCP (61.2%). There was an association between complete NSCP and a positive history of medical problems during pregnancy (p = 0.016; 27.9%; OR: 1.94; 1.12-3.35). Systemic alterations were perceived in 40.6% of the sample with odds ratio for development of the complete type (OR: 1.21; 0.74-1.97). Higher OR was visualized in medication use during pregnancy (OR: 1.35; 0.76-2.37) and positive family history of oral cleft (OR: 1.44; 0.80-2.55). Dental and surgical care was associated with higher age groups (p < 0.050). CONCLUSIONS: NSCP was most prevalent in white skin color female. Complete NSCP is associated with medical problems during pregnancy. Medication use during pregnancy and positive family history of oral cleft increase the chance of developing complete NSCP.

Comparison of the First and Second Waves of the Coronavirus Disease 2019 Pandemic in Children and Adolescents in a Middle-Income Country: Clinical Impact Associated with Severe Acute Respiratory Syndrome Coronavirus 2 Gamma Lineage.

OBJECTIVE: To evaluate the severity and clinical outcomes of the SARS-CoV-2 gamma variant in children and adolescents hospitalized with COVID-19 in Brazil. STUDY DESIGN: In this observational retrospective cohort study, we performed an analysis of all 21 591 hospitalized patients aged <20 years with confirmed SARS-CoV-2 infection registered in a national database in Brazil. The cohort was divided into 2 groups according to the predominance of SARS-CoV-2 lineages (WAVE1, n = 11 574; WAVE2, n = 10 017). The characteristics of interest were age, sex, geographic region, ethnicity, clinical presentation, and comorbidities. The primary outcome was time to death, which was evaluated by competing-risks analysis, using cumulative incidence functions. A predictive Fine and Gray competing-risks model was developed based on the WAVE1 cohort with temporal validation in the WAVE2 cohort. RESULTS: Compared with children and adolescents admitted during the first wave, those admitted during the second wave had significantly more hypoxemia (52.5% vs 41.1%; P < .0001) and intensive care unit admissions (28.3% vs 24.9%; P < .0001) and needed more noninvasive ventilatory support (37.3% vs 31.6%; P < .0001). In-hospital deaths and death rates were 896 (7.7%) in the first wave and 765 (7.6%) in the second wave (P = .07). The prediction model of death included age, ethnicity, region, respiratory symptoms, and comorbidities. In the validation set (WAVE2), the C statistic was 0.750 (95% CI, 0.741-0.758; P < .0001). CONCLUSIONS: This large national study found a more severe spectrum of risk for pediatric patients with COVID-19 caused by the gamma variant. However, there was no difference regarding the probability of death between the waves.

Risk factors for COVID-19-related mortality in hospitalized children and adolescents with diabetes mellitus: An observational retrospective cohort study.

BACKGROUND: Diabetes has been recognized as a major comorbidity for COVID-19 severity in adults. This study aimed to characterize the clinical outcomes and risk factors for COVID-19-related death in a large cohort of hospitalized pediatric patients with diabetes. METHODS: We performed an analysis of all pediatric patients with diabetes and COVID-19 registered in SIVEP-Gripe, a Brazilian nationwide surveillance database, between February 2020 and May 2021. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk by using cumulative incidence function. RESULTS: Among 21,591 hospitalized pediatric patients with COVID-19, 379 (1.8%) had diabetes. Overall, children and adolescents with diabetes had a higher prevalence of ICU admission (46.6% vs. 26%), invasive ventilation (16.9% vs. 10.3%), and death (15% vs. 7.6%) (all P < 0.0001). Children with diabetes had twice the hazard of death compared with pediatric patients without diabetes (Hazard ratio [HR] = 2.0, 95% CI, 1.58-2.66). Among children with diabetes, four covariates were independently associated with the primary outcome, living in the poorest regions of the country (Northeast, HR, 2.17, 95% CI 1.18-4.01, and North, (HR 4.0, 95% CI 1.79-8.94), oxygen saturation < 95% at admission (HR 2.97, 95% CI 1.64-5.36), presence of kidney disorders (HR 3.39, 95% CI 1.42-8.09), and presence of obesity (HR 3.77, 95% CI 1.83-7.76). CONCLUSION: Children and adolescents with diabetes had a higher risk of death compared with patients without diabetes. The higher risk of death was associated with clinical and socioeconomic factors.

Relationship between non-syndromic oral clefts and cancer: A systematic review and meta-analysis.

OBJECTIVE: To summarize the clinical evidence on the relationship between cancer and non-syndromic oral cleft (NSOC). METHODS: The review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist, and a literature search was conducted in six databases and gray literature. Studies published in any language mentioning cancer in patients with NSOC and their relatives and NSOC in patients with cancer and their relatives were included. Risk of bias was assessed using the Joanna Briggs Institute appraisal tool. The certainty of the evidence was evaluated using the GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) assessment. After a 2-step selection process, 33 studies were included: 17 case-control studies, 13 cross-sectional studies, and 3 case reports. RESULTS: The study evaluated 206,096 patients from 20 countries. Of these, 0.35% of patients with cancer (95% CI: 0.0%-1.1%; I2  = 86%), 3.0% of relatives of patients with cancer (95% CI: 1.19%-5.46%; I2  = 55%), and 0.26% of controls (95% CI: 0.0%-0.83%; I2  = 87%) had NSOC. Among the studies that examined the prevalence of cancer, 2.4% (95% CI: 0.0%-19.3%; I2  = 99%) of patients with NSOC, 15.4% of relatives of patients with NSOC (95% CI: 2.0%-37.6%; I2  = 99%), and 5.3% of controls (95% CI: 0.0%-22.8%; I2  = 99%) had cancer. Although no relationship was observed between the risk of cancer in patients with NSOC and the risk of NSOC in patients with cancer, there was an association for an increased risk of cancer in relatives of patients with NSOC (OR: 9.96, 95% CI: 1.55-63.99; p = 0.01) and a significant association for the NSOC risk in relatives of patients with leukemia (OR: 9.31; 95% CI: 1.13-76.67; p = 0.03). CONCLUSION: Our findings demonstrate an increased risk of cancer in relatives of patients with NSOC and that relatives of patients with leukemia were more frequently affected by NSOC. Together, these findings can help guide cancer screening in patients with NSOC and their relatives and shed light on the risk of NSOC in families with a history of cancer.

Global scientific production in the pre-Covid-19 Era: An analysis of 53 countries for 22 years.

Based on an extensive analysis of public databases, we provide an overview of the global scientific output and describe the dynamics of the profound changes in the scientific enterprise during the last decades. The analysis included the scientific production of 53 countries over the 1996-2018 period. During this period, the production of articles per year has tripled. There was a strong correlation between the growth of the global gross domestic product and the increase in the number of articles (R2 = 0.973, P<0.001). Six countries showed a robust increment of their scientific production and are currently among the top 20 in the ranking of world scientific production (China, India, South Korea, Brazil, Turkey, and Iran). The mean annual growth rate was about 12.7% for these six countries. The share of the global scientific production of these countries increased from 7% in 1996 to 27.8% in 2018. Conversely, the participation of the 10 most traditional countries has dropped from 73% to 45% during the same period. In conclusion, we believe that our findings may contribute to further studies aiming to evaluate the impact and changes of the scientific endeavor over the next years in light of the forthcoming new world framework.

Syndromes with gingival fibromatosis: A systematic review.

OBJECTIVE: The aim of systematic review was to describe the phenotypes and molecular profiles of syndromes with gingival fibromatosis (GF). METHODS: A comprehensive search of PubMed, LILACS, Livivo, Scopus, and Web of Science was conducted using key terms relevant to the research questions and supplemented by a gray literature search. The Methodological Quality and Synthesis of Case Series and Case Reports in association with the Case Series and Prevalence Studies from the Joanna Briggs Institute critical appraisal tools were used for the risk of bias. We followed the PRISMA checklist guidelines. RESULTS: Eighty-four studies reporting GF as an oral manifestation of a syndrome were identified in this review. Enamel renal syndrome was the most frequently reported syndrome with GF, represented by 54 individuals in 19 studies, followed by Zimmermann-Laband syndrome with 24 individuals in 15 studies and Costello syndrome, which was presented in a case series study with 41 individuals. Among reported cases, other clinical manifestations such as hypertrichosis, ectopic gingival calcification, and cherubism were described. CONCLUSIONS: The results emphasize the need of systematic oro-dental-facial phenotyping for future descriptions as well as further molecular analysis in order to better understand the occurrence of syndromic GF.

COVID-19 pandemic and the answer of science: a year in review.

The world is looking forward to a prompt response by the scientific community in order to overcome the first pandemic of the 21st century. This study aimed to provide an overview of scientific output on COVID-19 during its first year. We assembled information regarding 60,830 articles related to COVID-19 indexed in the WoS database from January 24 to December 13, 2020. Only 4 countries accounted for about 60% of the articles (USA, China, Italy, and England) and 12 countries accounted for about 95% of the world scientific output on COVID-19 (USA, China, Italy, England, India, Canada, Germany, Spain, Australia, Brazil, Iran, and Turkey). 25 research centers around the world contributed with more than 500 papers on COVID-19. Papers were scattered throughout 6,133 journals, with 12 journals with > 250 articles. 20 articles (0.03%) have already received more than the 1,000 citations. The response of the scientific endeavor to this acute global public health emergency has been fast and robust. The overview provided by the analysis of the scientific response to the pandemic may contribute to further studies aiming to evaluate the impact and changes in the scientific endeavor for the next years in light of the forthcoming new world framework.

Machine learning in prediction of genetic risk of nonsyndromic oral clefts in the Brazilian population.

OBJECTIVES: Genetic variants in multiple genes and loci have been associated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL ± P). However, the estimation of risk remains challenge, because most of these variants are population-specific rendering the identification of the underlying genetic risk difficult. Herein we examined the use of machine learning network in previously reported single nucleotide polymorphisms (SNPs) to predict risk of NSCL ± P in the Brazilian population. MATERIALS AND METHODS: Random forest and neural network methods were applied in 72 SNPs in a case-control sample composed by 722 NSCL ± P and 866 controls for discrimination of NSCL ± P risk. SNP-SNP interactions and functional annotation biological processes associated with the identified NSCL ± P risk genes were verified. RESULTS: Supervised random forest decision trees revealed high scores of importance for the SNPs rs11717284 and rs1875735 in FGF12, rs41268753 in GRHL3, rs2236225 in MTHFD1, rs2274976 in MTHFR, rs2235371 and rs642961 in IRF6, rs17085106 in RHPN2, rs28372960 in TCOF1, rs7078160 in VAX1, rs10762573 and rs2131960 in VCL, and rs227731 in 17q22, with an accuracy of 99% and an error rate of approximately 3% to predict the risk of NSCL ± P. Those same 13 SNPs were considered the most important for the neural network to effectively predict NSCL ± P risk, with an overall accuracy of 94%. Multivariate regression model revealed significant interactions among all SNPs, with an exception of those in FGF12 and MTHFD1. The most significantly biological processes for selected genes were those involved in tissue and epithelium development; neural tube closure; and metabolism of methionine, folate, and homocysteine. CONCLUSIONS: Our results provide novel clues for genetic mechanism studies of NSCL ± P and point out for a machine learning model composed by 13 SNPs that is capable of predicting NSCL ± P risk. CLINICAL RELEVANCE: Although validation is necessary, this genetic panel can be useful in the near future to assist in NSCL ± P genetic counseling.

Exploring GRHL3 polymorphisms and SNP-SNP interactions in the risk of non-syndromic oral clefts in the Brazilian population.

OBJECTIVE: To investigate the association of single-nucleotide polymorphisms (SNP) in grainyhead-like 3 (GRHL3) and to verify its possible interactions with others genes responsible for craniofacial development in the risk of non-syndromic oral cleft (NSOC). METHODS: Applying TaqMan allelic discrimination assays, we evaluated GRHL3 SNPs (rs10903078, rs41268753, and rs4648975) in an ancestry-structured case-control sample composed of 1,127 Brazilian participants [272 non-syndromic cleft palate only (NSCPO), 242 non-syndromic cleft lip only (NSCLO), 319 non-syndromic cleft lip and palate (NSCLP), and 294 healthy controls]. Additionally, SNP-SNP interactions of GRHL3 and previously reported variants in FAM49A, FOXE1, NTN1, and VAX1 were verified in non-syndromic cleft lip with or without cleft palate (NSCL ± P). To eliminate false-positive associations, Bonferroni correction or 1,000 permutation method was applied. RESULTS: The multiple logistic regression analysis showed that the CC genotype of rs10903078 (p = .03) and the haplotype C-C formed by the SNPs rs10903078 and rs41268753 (p = .04) were associated with NSCLO, but the p-values did not withstand Bonferroni correction. However, SNP-SNP test revealed significant interactions between GRHL3 SNPs and FAM49A (rs7552), FOXE1 (rs3758249), VAX1 (rs7078160 and rs751231), and NTN1 (rs9891446). CONCLUSIONS: Our results confirm the importance of GRHL3 and its interactions with previously NSOC-associated genes, including FAM49A, FOXE1, NTN1, and VAX1, in the pathogenesis of NSOC in the Brazilian population.

The world haunted by Covid-19.

In this time of confinement due to COVID-19 pandemic some reflections have been made e it has never been as clear as people can benefit from science. From the simple gesture of washing your hands like many others used during the quarantine, they have been identified by previous studies. In this way, we reinforce the need to maintain investments in the science.

Science funding crisis in Brazil and COVID-19: deleterious impact on scientific output.

The Brazilian scientific community and health care workers are working hard to provide support for the political health measures to deal with this unprecedented crisis of the COVID-19 pandemic. Paradoxically, while the society is looking forward for an immediate response of the scientific community, Brazilian scientists are facing a dramatic reduction in financial support for research and graduate programs.

Clinical and molecular analysis in Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS; MIM#245000) is a rare recessive autosomal disorder characterized by palmar and plantar hyperkeratosis, and aggressively progressing periodontitis leading to premature loss of deciduous and permanent teeth. PLS is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. PLS clinical expressivity is highly variable and no consistent genotype-phenotype correlation has been demonstrated yet. Here we report the clinical and genetic features of five PLS patients presenting a severe periodontal breakdown in primary and permanent dentition, hyperkeratosis over palms and soles, and recurrent sinusitis and/or tonsillitis. Mutation analysis revealed two novel homozygous recessive mutations (c.947T>C and c.1010G>C) and one previous described homozygous recessive mutation (c.901G>A), with parents carrying them in heterozygous, in three families (four patients). The fourth family presented with the CTSC c.628C>T mutation in heterozygous, which was inherited maternally. Patient carrying the CTSC c.628C>T mutation featured classical PLS phenotype, but no PLS clinical characteristics were found in his carrier mother. All mutations were found to affect directly (c.901G>A, c.947T>C, and c.1010G>C) or indirectly (c.628C>T, which induces a premature termination) the heavy chain of the cathepsin C, the region responsible for activation of the lysosomal protease. Together, these findings indicate that both homozygous and heterozygous mutations in the cathepsin C heavy chain domain may lead to classical PLS phenotype, suggesting roles for epistasis or gene-environment interactions on determination of PLS phenotypes.

Association between GOLGB1 tag-polymorphisms and nonsyndromic cleft palate only in the Brazilian population.

Nonsyndromic oral clefts are common congenital birth defects that exhibit variable prevalence around the world, often influenced by population-dependent genetic predisposition. Few studies have been performed with nonsyndromic cleft palate only (NSCPO), limiting the knowledge of the genetic risk factors related to this type of oral cleft. Genetic variants in golgin subfamily B member 1 (GOLGB1), a gene that is essential for normal murine palatogenesis, were analyzed in this study to establish its potential association with NSCPO risk in the Brazilian population. Five tag-single nucleotide polymorphisms (SNPs) of GOLGB1 (rs1169, rs7153, rs9968051, rs9819530, and rs6794341), which capture the majority of alleles spanning within gene, were genotyped in a case-control study with 270 patients with NSCPO and 284 unrelated healthy controls. The samples were also genotyped for 40 biallelic polymorphic markers to characterize the genetic ancestry. After adjustment for co-variants, the GOLGB1 tag-SNPs and the haplotypes formed by those SNPs were not significantly associated with NSCPO in this Brazilian case-control cohort. Our results suggest that common polymorphisms of GOLGB1 are not associated NSCPO susceptibility in the Brazilian population.