CYP26B1-related disorder: expanding the ends of the spectrum through clinical and molecular evidence.

CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.

Challenges in periodic revision of genetic testing results: Comparison of the main classification guidelines and report of a retrospective analysis involving BRCA1/BRCA2 variants of uncertain significance.

In the context of cancer predisposition syndromes, it is widely known that the correct interpretation of germline variants identified in multigene panel testing is essential for adequate genetic counseling and clinical decision making, in which variants of uncertain significance (VUS) are not considered actionable findings. Thus, their periodic re-evaluation using appropriate guidelines is notably important. In the present study, we compared the performance of the main variant classification guidelines (ACMG, Sherloc and ENIGMA) in variant reassessment, using as input a BRCA1/2 VUS case series (retrospective analysis) from Brazil, an ethnically diverse and admixed country with substantial challenges in VUS reclassification. As main findings, two of the 15 VUS analyzed were reclassified as likely pathogenic by the 3 guidelines, BRCA1 c.4987-3C > G (rs397509213) and BRCA2 c.7868A > G (rs80359012). Moreover, challenges in variant classification and reassessment are described and additional in silico data about structural impact of the variant BRCA2 c.7868A > G are provided. We hypothesize that the establishment of a framework to reassess VUS could improve this process in health centers that have not yet implemented this practice. Results of this study underscore that periodic monitoring of the functional, clinical, and bioinformatics data of a VUS by a multidisciplinary team are of utmost importance in clinical practice. When there is a specific guideline for a given gene, such as ENIGMA for BRCA1/2, it should be considered the first option for variant assessment. Finally, recruitment of VUS carriers and their relatives to participate in variant segregation studies and publication of VUS reclassification results in the international scientific literature should be encouraged.

Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes.

The ultrarare hepatoblastoma (HB) is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB and the presence of additional clinical signs. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Putative pathogenic or likely pathogenic monoallelic germline variants mapped to 10 cancer predisposition genes (CPGs: APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several potentially deleterious variants mapped to genes impacting liver functions were disclosed. To our knowledge, this is the largest assessment of rare germline variants in HB patients to date, contributing to elucidate the genetic architecture of HB risk.

Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diagnosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chompret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p.Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and independent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligomerization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H heterozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants.

Elevated holo-transcobalamin in Gaucher disease type II: A case report.

Gaucher disease (GD), one of the most common lysosomal disorders, is caused by deficiency of ß-glucocerebrosidase. Based on the presence and severity of neurological complications, GD is classified into types I, II (the most severe form), and III. Abnormalities in systemic markers of vitamin B12 (B12 ) metabolism have been reported in GD type I patients, suggesting a higher prevalence of B12 deficiency in these patients. A 2-month-old male with GD type II was admitted to the hospital presenting jaundice, hepatosplenomegaly, and ichthyosis. At admission, cholestasis and ascites, abnormal liver function enzymes, prolonged prothrombin time, and high levels of B12 were confirmed. Analysis of biomarkers of B12 status revealed elevated B12 and holo-transcobalamin (holo-TC) levels. The B12 profile found in our patient is the opposite to what is described for GD type I patients. Holo-TC may increase in inflammatory states or due to liver diseases. In GD, the accumulation of glucocerebroside may be a trigger that initiates a systemic inflammatory reaction, characterized by macrophage activation. We suggest higher levels of holo-TC could be associated with a more severe (neuronopathic) GD, and be a biomarker of GD type II.

TP53 variants of uncertain significance: increasing challenges in variant interpretation and genetic counseling.

Li-Fraumeni syndrome (LFS) and Li-Fraumeni Like (LFL) are autosomal dominant cancer predisposition syndromes caused by pathogenic germline variants in the TP53 gene. Recent studies have shown that the incorporation of next-generation sequencing by using multigene panels in clinical practice has resulted in the frequent identification of variants of uncertain significance (VUS). Given that there is no established medical management for VUS carriers, the identification of these variants may cause confusion and anxiety for both patients and practitioners. Herein, we aimed to verify VUS frequency and review VUS classification and interpretation in 1844 patients submitted for comprehensive germline TP53 testing independent of clinical criteria. Variant characterization was done assessing clinical information whenever available, variant frequency in population databases, pathogenicity predictions using in silico tools and previous functional studies. All variants were classified based on the guidelines proposed by the American College of Medical Genetics and Genomics (2015) and by the Sherloc framework (2017). Of the twelve VUS (0.65%) identified in TP53, two were classified as likely pathogenic and two were classified as likely benign after re-evaluation, potentially resulting in significant management modification for the proband and relatives. This report cases highlights the challenges and impact of TP53 variant interpretation especially when there is no clear LFS/LFL phenotype.

Screening and characterization of BRCA2 c.156_157insAlu in Brazil: Results from 1380 individuals from the South and Southeast.

Portuguese immigration to Brazil occurred in several waves and greatly contributed to the genetic composition of current Brazilian population. In this study, we evaluated the frequency of a Portuguese founder Alu insertion in BRCA2 exon 3 (c.156_157insAlu) among individuals fulfilling Hereditary Breast and Ovarian Cancer (HBOC) syndrome criteria in 1,380 unrelated families originated from three distinct Brazilian States. We identified the c.156_157insAlu BRCA2 mutation in nine (9/1,380; 0.65%) probands analised. In carrier probands, European ancestry had the highest proportion (80%), followed by the African (10%) and Amerindian and in most families with the rearrangement, haplotype analyses were compatible with the Portuguese ancestral haplotype. In conclusion, the present study reports a low albeit relevant frequency of the Portuguese BRCA2 founder mutation c.156_157insAlu in Brazilian patients at-risk for HBOC Brazilian population.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Correction: BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

[This corrects the article DOI: 10.1371/journal.pone.0187630.].

CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.

BACKGROUND: Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine ß-synthase (CßS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU. METHODS: gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon-intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT-PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site-directed mutagenesis. RESULTS: Parental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty-one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli-expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT-PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases. CONCLUSIONS: Most patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype-phenotype relationship was observed within families and for the four most common mutations.

Diagnosis and Management of Classica Homocystinuria in Brazil: A Summary of 72 Late-Diagnosed Patients

Abstract This study described a broad clinical characterization of classical homocystinuria (HCU) in Brazil. This was a cross-sectional, observational study including clinical and biochemical data from 72 patients (60 families) from Brazil (South, n = 13; Southeast, n = 37; Northeast, n = 8; North, n = 1; and Midwest, n = 1). Parental consanguinity was reported in 42% of families. Ocular manifestations were the earliest detected symptom (53% of cases), the main reason for diagnostic suspicion (63% of cases), and the most prevalent manifestation at diagnosis (67% of cases). Pyridoxine responsiveness was observed in 14% of patients. Only 22% of nonresponsive patients on treatment had total homocysteine levels <100 mmol/L. Most commonly used treatment strategies were pyridoxine (93% of patients), folic acid (90%), betaine (74%), vitamin B12 (27%), and low-methionine diet + metabolic formula (17%). Most patients diagnosed with HCU in Brazil are late diagnosed, express a severe phenotype, and poor metabolic control. Milder forms of HCU are likely underrepresented due to underdiagnosis.

BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

BACKGROUND: Germline pathogenic variants in BRCA1 and BRCA2 (BRCA) are the main cause of Hereditary Breast and Ovarian Cancer syndrome (HBOC). METHODS: In this study we evaluated the mutational profile and prevalence of BRCA pathogenic/likely pathogenic variants among probands fulfilling the NCCN HBOC testing criteria. We characterized the clinical profile of these individuals and explored the performance of international testing criteria. RESULTS: A pathogenic/likely pathogenic variant was detected in 19.1% of 418 probands, including seven novel frameshift variants. Variants of uncertain significance were found in 5.7% of individuals. We evaluated 50 testing criteria and mutation probability algorithms. There was a significant odds-ratio (OR) for mutation prediction (p ≤ 0.05) for 25 criteria; 14 of these had p ≤ 0.001. Using a cutoff point of four criteria, the sensitivity is 83.8%, and the specificity is 53.5% for being a carrier. The prevalence of pathogenic/likely pathogenic variants for each criterion ranged from 22.1% to 55.6%, and criteria with the highest ORs were those related to triple-negative breast cancer or ovarian cancer. CONCLUSIONS: This is the largest study of comprehensive BRCA testing among Brazilians to date, and the first to analyze clinical criteria for genetic testing. Several criteria that are not included in the NCCN achieved a higher predictive value. Identification of the most informative criteria for each population will assist in the development of a rational approach to genetic testing, and will enable the prioritization of high-risk individuals as a first step towards offering testing in low-income countries.

SIBLINGS AFFECTED BY ECTRODACTYLY-ECTODERMAL DYSPLASIA AND CLEFT LIP/PALATE (EEC) SYNDROME PRESENTING NORMAL PARENTS: GERMLINE MOSAICISM? / IRMÃOS AFETADOS PELA SÍNDROME DE ECTRODACTILIA, DISPLASIA ECTODÉRMICA E FISSURA LABIOPALATAL (EEC) COM PAIS HÍGIDOS: MOSAICISMO GERMINATIVO?

OBJECTIVE: EEC is an acronym for an autosomal dominant syndrome clinically characterized by ectrodactyly (E), ectodermal dysplasia (E) and cleft lip/palate (C). Our aim was to describe a rare case of siblings affected by ectrodactyly, ectodermal dysplasia and cleft lip/palate (EEC) syndrome presenting normal parents. CASE DESCRIPTION: The patient was the third son of young and healthy parents. The parents did not present any minor or major anomaly of hands, feet or skin, hair and teeth. The couple had a previous history of two children with hands and feet malformations similar to the present patient. The first was a stillborn, and the second one a preterm infant that died in the first days after birth due to the consequences of prematurity. After birth, the patient presented respiratory distress with need of endotracheal intubation and mechanic ventilation. At physical examination, there were cleft lip/palate, hands and feet ectrodactyly, with absence of the second and third fingers in both hands, and reduction defects affecting mainly the second toes. The child presented pneumothorax and cardiorespiratory arrest and died at 1 month and 26 days. COMMENTS: Herein we described a case of siblings with EEC syndrome, indicative of a germline mosaicism. In the literature review, there was the description of only three similar reports. The present case strengthens the possibility that germline mosaicism may be a more common inheritance mechanism than previously thought in cases of EEC syndrome.

OBJETIVO: EEC é um acrônimo para uma síndrome autossômica dominante caracterizada clinicamente por ectrodactilia (E), displasia ectodérmica efissura labiopalatal (C). Nosso objetivo foi relatar um caso raro de irmãos afetados pela síndrome de ectrodactilia, displasia ectodérmica efissura labiopalatal (EEC) com pais hígidos. DESCRIÇÃO DO CASO: O paciente era o terceiro filho de pais jovens e hígidos, os quais não apresentavam nenhuma anomalia menor ou maior de mãos e pés ou anomalias de pele, cabelos e dentes. O casal tinha história prévia de duas crianças com malformação de mãos e pés, similar à do paciente. O primeiro foi natimorto e o segundo, prematuro, falecendo nos primeiros dias de vida, pelas consequências da prematuridade. Após o nascimento, o paciente apresentou desconforto respiratório, com necessidade de intubação orotraqueal e ventilação mecânica. No exame físico, verificaram-se a presença de fissura labiopalatal e ectrodactilia de mãos e pés, com ausência do segundo e terceiro dedos em ambas as mãos e defeitos de redução acometendo principalmente o segundo dedo dos pés. A criança apresentou pneumotórax e parada cardiorrespiratória, morrendo com 1 mês e 26 dias de vida. COMENTÁRIOS: Descrevemos aqui um caso de irmãos com síndrome EEC, indicativo de mosaicismo germinativo. Na revisão da literatura, observaram-se apenas três relatos similares. Este caso reforça a possibilidade do mosaicismo germinativo ser um mecanismo de herança mais comum do que se acreditava previamente para casos da síndrome EEC.

Efficacy and safety of intravenous laronidase for mucopolysaccharidosis type I: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of IV laronidase for MPS I. METHODS: A systematic literature review was performed by searching the ClinicalTrials.gov, MEDLINE/PubMed, EMBASE, LILACS, and Cochrane Library databases, limited to clinical trials published until December 31, 2016. The first inclusion criterion was being a randomized controlled trial (RCT). If < five RCTs were identified, open-label and nonrandomized trials, controlled or uncontrolled (quasi-experimental), including ≥ five patients, and evaluating relevant outcomes defined a priori, would also be included. For meta-analysis, primary inferences were based on random-effects models. Assessment of article quality was performed in accordance with the GRADE criteria. The Cochrane Risk of Bias tool was used to examine the risk of bias for RCTs. RESULTS: The selection phase retrieved 632 articles. During the first phase of selection, 158 had the abstract or full text read for assessment of eligibility, of which nine (two RCTs) were included for qualitative synthesis. Four papers were included in the meta-analysis, which was performed for the following outcomes: occurrence of treatment-emergent or infusion-related adverse events (65%; 95%CI 53, 76), mild in most cases; development of IgG antibodies to laronidase (88%; 95%CI 67, 100); apnea-hypopnea index (not significant-NS), urinary glycosaminoglycans (GAGs) [mean change -65.5 µg/mg creatinine (95%CI -68.8, -62.3)], liver size [mean change -31.03% (95%CI -36.1, -25.9)], left ventricular mass index (LVMI) [mean change -1.8 (95%CI -2.32, -0.25)], and distance covered in the 6-minute walk test (NS). Among the outcomes not included in meta-analysis, we found evidence for benefit of laronidase only on shoulder flexion. CONCLUSIONS: Our findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population.

Leprosy in Southern Brazil: a twenty-year epidemiological profile.

INTRODUCTION:: This study evaluated leprosy rates in Rio Grande do Sul, an area with a historically low prevalence. However, recent studies are lacking. METHODS:: Data extracted from a National Database were analyzed for clinical features and compared to 1980s data. Tendency was assessed via stationarity analysis. RESULTS:: Between 1990 and 2011, 4,770 cases were reported (0.21/10,000 inhabitants; 95% CI = 0.19-0.24). Detection was slightly higher among males, 1.9% cases were among children and most multibacillary (74.7%) at diagnosis. CONCLUSIONS:: Leprosy is controlled in RS, but most cases are multibacillary. Early identification is important to avoid disabilities due to late diagnosis.

Irmãos afetados pela síndrome de ectrodactilia, displasia ectodérmica e fissura labiopalatal (eec) com pais hígidos: mosaicismo germinativo? / Siblings affected by ectrodactyly-ectodermal dysplasia and cleft lip/palate (eec) syndrome presenting normal parents: germline mosaicism?

RESUMO Objetivo: EEC é um acrônimo para uma síndrome autossômica dominante caracterizada clinicamente por ectrodactilia (E), displasia ectodérmica efissura labiopalatal (C). Nosso objetivo foi relatar um caso raro de irmãos afetados pela síndrome de ectrodactilia, displasia ectodérmica efissura labiopalatal (EEC) com pais hígidos. Descrição do caso: O paciente era o terceiro filho de pais jovens e hígidos, os quais não apresentavam nenhuma anomalia menor ou maior de mãos e pés ou anomalias de pele, cabelos e dentes. O casal tinha história prévia de duas crianças com malformação de mãos e pés, similar à do paciente. O primeiro foi natimorto e o segundo, prematuro, falecendo nos primeiros dias de vida, pelas consequências da prematuridade. Após o nascimento, o paciente apresentou desconforto respiratório, com necessidade de intubação orotraqueal e ventilação mecânica. No exame físico, verificaram-se a presença de fissura labiopalatal e ectrodactilia de mãos e pés, com ausência do segundo e terceiro dedos em ambas as mãos e defeitos de redução acometendo principalmente o segundo dedo dos pés. A criança apresentou pneumotórax e parada cardiorrespiratória, morrendo com 1 mês e 26 dias de vida. Comentários: Descrevemos aqui um caso de irmãos com síndrome EEC, indicativo de mosaicismo germinativo. Na revisão da literatura, observaram-se apenas três relatos similares. Este caso reforça a possibilidade do mosaicismo germinativo ser um mecanismo de herança mais comum do que se acreditava previamente para casos da síndrome EEC.

ABSTRACT Objective: EEC is an acronym for an autosomal dominant syndrome clinically characterized by ectrodactyly (E), ectodermal dysplasia (E) and cleft lip/palate (C). Our aim was to describe a rare case of siblings affected by ectrodactyly, ectodermal dysplasia and cleft lip/palate (EEC) syndrome presenting normal parents. Case description: The patient was the third son of young and healthy parents. The parents did not present any minor or major anomaly of hands, feet or skin, hair and teeth. The couple had a previous history of two children with hands and feet malformations similar to the present patient. The first was a stillborn, and the second one a preterm infant that died in the first days after birth due to the consequences of prematurity. After birth, the patient presented respiratory distress with need of endotracheal intubation and mechanic ventilation. At physical examination, there were cleft lip/palate, hands and feet ectrodactyly, with absence of the second and third fingers in both hands, and reduction defects affecting mainly the second toes. The child presented pneumothorax and cardiorespiratory arrest and died at 1 month and 26 days. Comments: Herein we described a case of siblings with EEC syndrome, indicative of a germline mosaicism. In the literature review, there was the description of only three similar reports. The present case strengthens the possibility that germline mosaicism may be a more common inheritance mechanism than previously thought in cases of EEC syndrome.

Leprosy in Southern Brazil: a twenty-year epidemiological profile

Abstract INTRODUCTION: This study evaluated leprosy rates in Rio Grande do Sul, an area with a historically low prevalence. However, recent studies are lacking. METHODS: Data extracted from a National Database were analyzed for clinical features and compared to 1980s data. Tendency was assessed via stationarity analysis. RESULTS: Between 1990 and 2011, 4,770 cases were reported (0.21/10,000 inhabitants; 95% CI = 0.19-0.24). Detection was slightly higher among males, 1.9% cases were among children and most multibacillary (74.7%) at diagnosis. CONCLUSIONS: Leprosy is controlled in RS, but most cases are multibacillary. Early identification is important to avoid disabilities due to late diagnosis.

Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations.

Germline mutations in BRCA1 or BRCA2 (BRCA) are responsible for 5-15% of breast (BC) and ovarian cancers (OC), predisposing to the development of early onset and often multiple primary tumors. Since mutation carriers can benefit from risk-reducing interventions, the identification of individuals with hereditary breast and ovarian cancer (HBOC) syndrome has a significant clinical impact. We assessed whether a panel assay for recurrent Hispanic BRCA mutations (HISPANEL) has an adequate breadth of coverage to be suitable as a cost effective screening tool for HBOC in a cohort of patients from Southern Brazil. A multiplex, PCR-based panel was used to genotype 232 unrelated patients for 114 germline BRCA mutations, finding deleterious mutations in 3.5% of them. This mutation prevalence is within the range detected by the HISPANEL among BC patients unselected for family history in other Latin American settings. The HISPANEL would have accounted for 27% of the BRCA mutations detected by complete sequencing in a comparison cohort (n = 193). This prevalence may be region-specific since significant differences in population structure exist in Brazil. Comprehensive analysis of BRCA in a larger set of HBOC patients from different Brazilian regions is warranted, and the results could inform customization of the HISPANEL as an affordable mutation screening tool.

Hirschsprung disease and hepatoblastoma: case report of a rare association / Doença de Hirschsprung e hepatoblastoma: relato de caso de uma associação rara

ABSTRACT CONTEXT: Hirschsprung disease is a developmental disorder of the enteric nervous system that is characterized by absence of ganglion cells in the distal intestine, and it occurs in approximately 1 in every 500,000 live births. Hepatoblastoma is a malignant liver neoplasm that usually occurs in children aged 6 months to 3 years, with a prevalence of 0.54 cases per 100,000. CASE REPORT: A boy diagnosed with intestinal atresia in the first week of life progressed to a diagnosis of comorbid Hirschsprung disease. Congenital cataracts and sensorineural deafness were diagnosed. A liver mass developed and was subsequently confirmed to be a hepatoblastoma, which was treated by means of surgical resection of 70% of the liver volume and neoadjuvant chemotherapy (ifosfamide, cisplatin and doxorubicin). CONCLUSION: It is known that Hirschsprung disease may be associated with syndromes predisposing towards cancer, and that hepatoblastoma may also be associated with certain congenital syndromes. However, co-occurrence of hepatoblastoma and Hirschsprung disease has not been previously described. We have reported a case of a male patient born with ileal atresia, Hirschsprung disease and bilateral congenital cataract who was later diagnosed with hepatoblastoma.

RESUMO CONTEXTO: A doença de Hirschsprung é uma desordem do desenvolvimento do sistema nervoso entérico, que é caracterizada pela ausência de células ganglionares no intestino distal, ocorrendo em cerca de 1 a cada 500.000 nascimentos. O hepatoblastoma é uma neoplasia maligna do fígado que geralmente ocorre em crianças de 6 meses a 3 anos, com prevalência de 0,54 casos por 100.000. RELATO DE CASO: Um menino com diagnóstico de atresia intestinal na primeira semana de vida evoluiu com diagnóstico concomitante de doença de Hirschsprung. Catarata congênita e surdez neurossensorial foram diagnosticadas. Surgiu lesão hepática com posterior confirmação de hepatoblastoma, tratado com ressecção cirúrgica de 70% do volume hepático e quimioterapia neoadjuvante (ifosfamida, cisplatina e doxorubicina). CONCLUSÃO: Sabe-se que a doença de Hirschsprung pode estar associada a síndromes de predisposição ao câncer, da mesma forma que o hepatoblastoma já foi correlacionado a certas síndromes congênitas malformativas. No entanto, até o momento, a associação de hepatoblastoma com a doença de Hirschsprung não foi descrita. Relatamos o caso de um menino que nasceu com atresia ileal, doença de Hirschsprung, catarata congênita bilateral e com posterior diagnóstico de hepatoblastoma.

Hirschsprung disease and hepatoblastoma: case report of a rare association.

CONTEXT: Hirschsprung disease is a developmental disorder of the enteric nervous system that is characterized by absence of ganglion cells in the distal intestine, and it occurs in approximately 1 in every 500,000 live births. Hepatoblastoma is a malignant liver neoplasm that usually occurs in children aged 6 months to 3 years, with a prevalence of 0.54 cases per 100,000. CASE REPORT: A boy diagnosed with intestinal atresia in the first week of life progressed to a diagnosis of comorbid Hirschsprung disease. Congenital cataracts and sensorineural deafness were diagnosed. A liver mass developed and was subsequently confirmed to be a hepatoblastoma, which was treated by means of surgical resection of 70% of the liver volume and neoadjuvant chemotherapy (ifosfamide, cisplatin and doxorubicin). CONCLUSION: It is known that Hirschsprung disease may be associated with syndromes predisposing towards cancer, and that hepatoblastoma may also be associated with certain congenital syndromes. However, co-occurrence of hepatoblastoma and Hirschsprung disease has not been previously described. We have reported a case of a male patient born with ileal atresia, Hirschsprung disease and bilateral congenital cataract who was later diagnosed with hepatoblastoma.