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Objective: The current study delves into the accessibility of genetic evaluations for individuals with orofacial clefts (OC), comparing data between genetics and treatment centers across Brazil., Methods: This cross-sectional retrospective study analyzed primary data from 1463 OC individuals registered in the Brazilian Database of Craniofacial Anomalies (BDCA) between 2008 and 2018 without age or sex selection. Diagnostic exam results stemming from research projects until 2023 were considered., Results: Of the 1463 individuals with typical OC, 987 were non-syndromic, 462 were syndromic (SOC), 10 presented atypical forms, and three were not specified OC cases. The average age for accessing laboratory diagnosis was 8.5 years among SOC individuals. Notably, more SOC cases were registered in genetics centers than treatment and rehabilitation centers (37.1 % vs. 29 %, p = 0.0015). Those originating from genetics centers accessed diagnosis at an average age of 7.3 years, while those from treatment and rehabilitation centers experienced delays with an average age of 10.7 years (p = 0.0581)., Conclusions: Irrespective of the center of origin, the data highlight delayed diagnosis and challenges in accessing genetic tests for the syndromic group. Given the widespread reliance on the public health system by most of the Brazilian population, disseminating this data can significantly contribute to shaping an informed perspective on healthcare access. These insights can improve public policies tailored to the unique needs of individuals with OC., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2024 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: The Brazilian Policy for Comprehensive Care for People with Rare Diseases was implemented in 2014; however, national epidemiological data on rare diseases (RDs) are scarce and mainly focused on specific disorders. To address this gap, University Hospitals, Reference Services for Neonatal Screening, and Reference Services for Rare Diseases, all of which are public health institutions, established the Brazilian Rare Diseases Network (RARAS) in 2020. The objective of this study was to perform a comprehensive nationwide epidemiological investigation of individuals with RDs in Brazil. This retrospective survey collected data from patients receiving care in 34 healthcare facilities affiliated with RARAS in 2018 and 2019., Results: The survey included 12,530 participants with a median age of 15.0 years, with women representing 50.5% of the cohort. Classification according to skin color demonstrated that 5044 (47.4%) participants were admixed. Most had a confirmed diagnosis (63.2%), with a predominance of phenylketonuria (PKU), cystic fibrosis (CF), and acromegaly. Common clinical manifestations included global developmental delay and seizures. The average duration of the diagnostic odyssey was 5.4 years (± 7.9 years). Among the confirmed diagnoses, 52.2% were etiological (biochemical: 42.5%; molecular: 30.9%), while 47.8% were clinical. Prenatal diagnoses accounted for 1.2%. Familial recurrence and consanguinity rates were 21.6% and 6.4%, respectively. Mainstay treatments included drug therapy (55.0%) and rehabilitation (15.6%). The Public Health System funded most diagnoses (84.2%) and treatments (86.7%). Hospitalizations were reported in 44.5% of cases, and the mortality rate was 1.5%, primarily due to motor neuron disease and CF., Conclusion: This study marks a pioneering national-level data collection effort for rare diseases in Brazil, offering novel insights to advance the understanding, management, and resource allocation for RDs. It unveils an average diagnostic odyssey of 5.4 years and a higher prevalence of PKU and CF, possibly associated with the specialized services network, which included newborn screening services., (© 2024. The Author(s).)

Rare diseases (RD) are individually rare, although encompass a significant proportion of the population, affecting not only the individuals but also their families. In Brazil RD is defined by the Ministry of Health as a disorder that affects up to 65 individuals in 100,000, or 1.3 individuals in every 2,000. In this review the environment that led to the publication of a National Policy for Comprehensive Care for People of Rare Disease in 2014, a national plan with the aim to decrease morbidity and mortality of RD, improving the care of people with RD in the public health system are described. The process that finally led to such policy took over a decade, moving forward not only due to technical needs, but having patient organizations as essential actors and advocates. Specialized centers in RD were licensed and, since its publication, 33 centers have been accredited; such process, however, has been slow and concentrated in specific regions and larger cities of the country. Despite the incorporation of genetic tests in 2014 and exome sequencing later in 2020, many genetic tests are not offered by specialized centers, with unequal availability across the country. Public health system in Brazil uses ICD-10 for disease coding, preventing appropriate epidemiologic knowledge of RD in Brazil. Incorporation of new technologies as orphan drugs has been in place and regulation for expedite licensing for new RD drugs were issued, although high cost and availability to RD population has been a challenge., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The aim of this study was to evaluate the functioning and associated factors in children and adolescents with osteogenesis imperfecta (OI)., Methods: This is a cross-sectional study conducted on 30 children and adolescents with OI. Medical records, use of bisphosphonates, socioeconomic status, handgrip strength, balance, joint hypermobility, ambulatory level, and the Pediatric Evaluation of Disability Inventory-Computer Adaptative Test (PEDI-CAT) scores were assessed. Data is presented as mean and standard deviation and Student's t-test or Mann-Whitney U test. Categorical data is presented as frequency and analyzed using Fisher's exact test. Within-group analyses were conducted using ANCOVA or Wilcoxon signed-rank test. Correlations used Kendall's Tau-b test., Results: The participants involved in this study were 6-18 years old. The sample was separated into two groups according to disease severity. The moderate/severe OI group (n=10) presented a lower height and muscular strength than the mild group (n=20). Muscle weakness was observed in all participants with OI when compared with the normal population. No differences were observed between the groups in the PEDI-CAT scores except for the mobility domain. There were correlations between the PEDI-CAT mobility domain and the number of fractures, OI type, weight, and balance; there was also a correlation between the PEDI-CAT daily activities, mobility, responsibility, and social/cognitive domains., Conclusions: The findings suggest that children with moderate/severe forms of OI can achieve the same function levels as children with mild OI. Fractures can have a major influence on the functional level, and treatment should focus on the prevention and rehabilitation of these events when they occur.

Brazil is a continent-size country with 203 million inhabitants, classified as a developing upper-middle-income country, although inequities remain significant. Most of the population is assisted by the public Unified Health System (SUS), along with a thriving private health sector. Congenital malformations are the second leading cause of infant mortality and chronic/genetic disorders and a significant burden in hospital admissions. The past two decades have been crucial for formalizing medical genetics as a recognized medical specialty in the SUS, as well as for implementing a new health policy by the Ministry of Health for comprehensive care for rare diseases. These public health policies had the broad support of the Brazilian Society of Medical Genetics and Genomics and patient organizations. Most comprehensive genetic services are concentrated in large urban centers in the South and Southeast regions of Brazil; with this new policy, new services throughout the country are progressively being integrated. The number of medical geneticists increased by 103% in a decade. Details on the policy and an overview of the availability of services, testing, human resources, newborn screening, research projects, patient organizations, and relevant issues regarding medical genetics in this vast and diverse country are presented.

22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus , pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.

Background: The minimum data set (MDS) is a collection of data elements to be grouped using a standard approach to allow the use of data for clinical and research purposes. Health data are typically voluminous, complex, and sometimes too ambiguous to generate indicators that can provide knowledge and information on health. This complexity extends further to the rare disease (RD) domain. MDSs are essential for health surveillance as they help provide services and generate recommended population indicators. There is a bottleneck in international literature that reveals a global problem with data collection, recording, and structuring in RD., Objective: This study aimed to identify and analyze the MDSs used for RD in health care networks worldwide and compare them with World Health Organization (WHO) guidelines., Methods: The population, concept, and context methodology proposed by the Joanna Briggs Institute was used to define the research question of this systematic review. A total of 4 databases were reviewed, and all the processes were reported using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. The data elements were analyzed, extracted, and organized into 10 categories according to WHO digital health guidelines. The quality assessment used the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist., Results: We included 20 studies in our review, 70% (n=14) of which focused on a specific health domain and 30% (n=6) of which referred to RD in general. WHO recommends that health systems and networks use standard terminology to exchange data, information, knowledge, and intelligence in health. However, there was a lack of terminological standardization of the concepts in MDSs. Moreover, the selected studies did not follow the same standard structure for classifying the data from their MDSs. All studies presented MDSs with limitations or restrictions because they covered only a specific RD, or their scope of application was restricted to a specific context or geographic region. Data science methods and clinical experience were used to design, structure, and recommend a fundamental global MDS for RD patient records in health care networks., Conclusions: Our study highlights the difficulties in standardizing and categorizing findings from MDSs for RD because of the varying structures used in different studies. The fundamental RD MDS designed in this study comprehensively covers the data needs in the clinical and management sectors. These results can help public policy makers support other aspects of their policies. We highlight the potential of our results to help strategic decisions related to RD., Trial Registration: PROSPERO CRD42021221593; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=221593., International Registered Report Identifier (irrid): RR2-10.1016/j.procs.2021.12.034., (©Filipe Andrade Bernardi, Bibiana Mello de Oliveira, Diego Bettiol Yamada, Milena Artifon, Amanda Maria Schmidt, Victória Machado Scheibe, Domingos Alves, Têmis Maria Félix. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 27.07.2023.)

Early diagnosis of genetic rare diseases is an unmet need in Brazil, where an estimated 10-13 million people live with these conditions. Increased use of chromosome microarray assays, exome sequencing, and whole genome sequencing as first-tier testing techniques in suitable indications can shorten the diagnostic odyssey, eliminate unnecessary tests, procedures, and treatments, and lower healthcare expenditures. A selected panel of Brazilian experts in fields related to rare diseases was provided with a series of relevant questions to address before a multi-day conference. Within this conference, each narrative was discussed and edited through numerous rounds of discussion until agreement was achieved. The widespread adoption of exome sequencing and whole genome sequencing in Brazil is limited by various factors: cost and lack of funding, reimbursement, awareness and education, specialist shortages, and policy issues. To reduce the burden of rare diseases and increase early diagnosis, the Brazilian healthcare authorities/government must address the barriers to equitable access to early diagnostic methods for these conditions. Recommendations are provided, including broadening approved testing indications, increasing awareness and education efforts, increasing specialist training opportunities, and ensuring sufficient funding for genetic testing., (© 2023. The Author(s).)

Introduction: Hearing loss etiology depends on the population studied as well as on the ethnicity and the socio-economic condition of the analyzed region. Etiological diagnosis contributes to the improvement of preventive measures and to the early identification of this deficiency., Objective: To identify the etiological factors of hearing loss and its prevalence in a tertiary hospital in southern Brazil, to verify the frequency of mutations in GJB2 and GJB6 genes, and to correlate the degree of hearing loss with the etiological factors of deafness., Methods: This prevalence study involved 140 children with bilateral sensorineural or mixed hearing loss. Medical history, physical examination, audiometry, and evoked auditory brainstem response were conducted. Imaging and genetic examinations were also performed., Results: Etiologies and their prevalence were as follows: (a) indeterminate causes, 31.4%; (b) conditions related to neonatal period, 22.1%; (c) genetic, 22.1%; (d) auditory neuropathy, 10%; (e) other factors (cortical malformation, intracranial hemorrhage, and internal ear malformations), 7.9% and (f) congenital infections, 6.4%. Within the genetic cases, ten homozygous and seven heterozygotes of the 35delG mutation were identified, besides two cases of rare variants of GJB2: p.Try172* and p.Arg184Pro. One case with homozygosis of del(GJB6-D13S1830) was found. Regarding severity of hearing loss, in 78.6% of the cases the degree of hearing loss was profound and there were no significant differences when comparing between etiologies., Conclusion: The number of indeterminate etiologies is still high and congenital CMV infection may be a possible cause of undiagnosed etiology for hearing loss. The predominance of etiologies related to neonatal conditions and infectious causes are characteristic of developing countries. The most prevalent mutation was 35delG, the main GJB2 gene, probably because of the European influence in the genotype of our population., (Copyright © 2021 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Background and Objectives: Fragile X syndrome (FXS) is a neurodevelopmental disorder, identified as the most common cause of hereditary intellectual disability and monogenic cause of autism spectrum disorders (ASDs), caused by the loss of fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein, a regulator of translation that plays an important role in neurodevelopment, and its loss causes cognitive and behavioral deficits. MicroRNAs (miRNAs) are small molecules that regulate gene expression in diverse biological processes. Previous studies found that the interaction of FMRP with miR-125b and miR-132 regulates the maturation and synaptic plasticity in animal models and miRNA dysregulation plays a role in the pathophysiology of FXS. The present study aimed to analyze the expression of miR-125b-5p and miR-132-3p in the serum of patients with FXS., Methods: The expressions of circulating miRNAs were studied in the serum of 10 patients with FXS and 20 controls using the real-time quantitative retrotranscribed method analyzed by relative quantification. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were generated to assess the diagnostic values of the miRNAs., Results: We found that both miR-125b and miR-132 were increased in the serum of patients with FXS compared with controls and likely involved with FMRP loss. The AUC (95% confidence interval) of miR-125b and miR-132 was 0.94 (0.86-1.0) and 0.89 (0.77-1.0), respectively. Databases allowed for the identification of possible target genes for miR-125b and miR-132, whose products play an important role in the homeostasis of the nervous system., Discussion: Our results indicate that serum miR-125b and miR-132 may serve as potential biomarkers for FXS. The increased expression of circulating miR-125b and miR-132 seems to be associated with the genotype of FXS. Predicted gene targets of the differentially regulated miRNAs are involved in cognitive performance and ASD phenotype., Classification of Evidence: This study provides Class III evidence that miR-125b and miR-132 distinguish men with FXS from normal controls., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Achondroplasia is the most common bone dysplasia associated with disproportionate short stature, and other comorbidities, such as foramen magnum stenosis, thoracolumbar kyphosis, lumbar hyperlordosis, genu varum and spinal compression. Additionally, patients affected with this condition have higher frequency of sleep disorders, ear infections, hearing loss and slowed development milestones. Considering these clinical features, we aimed to summarize the regional experts' recommendations for the multidisciplinary management of patients with achondroplasia in Latin America, a vast geographic territory with multicultural characteristics and with socio-economical differences of developing countries., Methods: Latin American experts (from Argentina, Brazil, Chile and Colombia) particiáted of an Advisory Board meeting (October 2019), and had a structured discussion how patients with achondroplasia are followed in their healthcare centers and punctuated gaps and opportunities for regional improvement in the management of achondroplasia., Results: Practical recommendations have been established for genetic counselling, prenatal diagnosis and planning of delivery in patients with achondroplasia. An outline of strategies was added as follow-up guidelines to specialists according to patient developmental phases, amongst them neurologic, orthopedic, otorhinolaryngologic, nutritional and anthropometric aspects, and related to development milestones. Additionally, the role of physical therapy, physical activity, phonoaudiology and other care related to the quality of life of patients and their families were discussed. Preoperative recommendations to patients with achondroplasia were also included., Conclusions: This study summarized the main expert recommendations for the health care professionals management of achondroplasia in Latin America, reinforcing that achondroplasia-associated comorbidities are not limited to orthopedic concerns., (© 2022. The Author(s).)

Objective: To evaluate the impact of the Universal Neonatal Hearing Screening (UNHS) on the age at diagnosis, beginning of treatment, and first cochlear implant surgery., Methods: A retrospective cohort study with children up to 12 years old with bilateral hearing loss were divided into two groups: patients who underwent UNHS and the ones who didn't. The groups were compared according to their age at the beginning of the evaluation at a specialized center, at the beginning of the intervention, and, for the ones who had indication, at the cochlear implant surgery. The group who underwent UNHS was divided between the ones who passed the screening test and the ones who didn't. They were compared according to their ages at the same moments as the first two groups., Results: 135 patients were included. The median age at the first appointment in a specialized center was 1.42 (0.50 and 2.50) years, at the beginning of treatment 2.00 (1.00 and 3.52) years, and the cochlear implant surgery 2.83 (1.83 and 4.66) years. Children who underwent UNHS were younger than those who didn't, at the three evaluated moments (p < 0.001). In a subanalysis, children who passed the UNHS but were later diagnosed with hearing loss reached the first appointment with a specialist and started treatment older than those who failed the tests., Conclusion: Performing UNHS interfered with the timing of deafness diagnosis and treatment. However, children who passed the screening but were later diagnosed with hearing loss were the category with the most important delay., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

The Brazilian Policy of Comprehensive Care for People with Rare Diseases (BPCCPRD) was established by the Ministry of Health to reduce morbidity and mortality and improve the quality of life of people with rare diseases (RD). Several laboratory tests, most using molecular genetic technologies, have been incorporated by the Brazilian Public Health System, and 18 specialised centres have so far been established at university hospitals (UH) in the capitals of the Southern, Southeastern and Northeastern regions. However, whether the available human and technological resources in these services are appropriate and sufficient to achieve the goals of care established by the BPCCPRD is unknown. Despite great advances in diagnosis, especially due to new technologies and the recent structuring of clinical assessment of RD in Brazil, epidemiological data are lacking and when available, restricted to specific disorders. This position paper summarises the performance of a nationally representative survey on epidemiology, clinical status, and diagnostic and therapeutic resources employed for individuals with genetic and non-genetic RD in Brazil. The Brazilian Rare Disease Network (BRDN) is under development, comprising 40 institutions, including 18 UH, 17 Rare Diseases Reference Services and five Newborn Screening Reference Services. A retrospective study will be initially conducted, followed by a prospective study. The data collection instrument will use a standard protocol with sociodemographic data and clinical and diagnostic aspects according to international ontology. This great collaborative network is the first initiative of a large epidemiological data collection of RD in Latin America, and the results will increase the knowledge of RD in Brazil and help health managers to improve national public policy on RD in Brazil., (© 2022. The Author(s).)

DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. In this study, we report two unrelated individuals with DOORS syndrome without deafness. Exome sequencing revealed a homozygous missense variant in PIGF (NM&#95;173074.3:c.515C>G, p.Pro172Arg) in both. We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis through flow cytometry analysis. We thus describe the causal role of a novel disease gene, PIGF, in DOORS syndrome and highlight the overlap between this condition and GPI deficiency disorders. For each gene implicated in DOORS syndrome and/or inherited GPI deficiencies, there is considerable clinical variability so a high index of suspicion is warranted even though not all features are noted.

Objective: This article presents a clinical and cytogenomic approach that focuses on the diagnosis of syndromic oral clefts (OCs)., Methods: The inclusion criteria were individuals with OC presenting four or more minor signs and no major defects (non-syndromic oral clefts [NSOCs]) as well as individuals with OC presenting at least another major defect, regardless of the number of minor signs (syndromic oral clefts [SOCs]). The exclusion criteria included NSOC with less than four minor signs, SOC with known etiology, as well as atypical oral clefts., Results: Of 1647 individuals with OC recorded in the Brazilian Database of Craniofacial Anomalies, 100 individuals were selected for chromosome microarray analysis (CMA). Among these, 44 individuals were clinically classified as NSOC and 56 as SOC. CMA was performed for both groups, and abnormal CMA was identified in 9%, all previously classified as SCO. The clinical and CMA data analyses showed a significant predominance of abnormal CMA in individuals classified as SOC (p = 0.0044); prematurity, weight, length, and head circumference at birth were significantly lower in the group with abnormal CMA. Besides, minor signs were significantly higher in this group (p = 0.0090)., Conclusion: The rigorous selection of cases indicates that the significant variables could help in early recognition of SOC. This study reinforces the importance of applying the CMA technique to establish the diagnosis of SOC. This is an important and universal issue in clinical practice for intervention, care, and genetic counseling., (Copyright © 2020 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: A rare disease is a medical condition with low prevalence in the general population, but these can collectively affect up to 10% of the population. Thus, rare diseases have a significant impact on the health care system, and health professionals must be familiar with their diagnosis, management, and treatment., Objective: This paper aims to provide health indicators regarding the rare diseases in Brazil and to create a network of reference centers with health professionals from different regions of the country. RARASnet proposes to map, analyze, and communicate all the data regarding the infrastructure of the centers and the patients' progress or needs. The focus of the proposed study is to provide all the technical infrastructure and analysis, following the World Health Organization and the Brazilian Ministry of Health guidelines., Methods: To build this digitized system, we will provide a security framework to assure the privacy and protection of each patient when collecting data. Systems development life cycle methodologies will also be applied to align software development, infrastructure operation, and quality assurance. After data collection of all information designed by the specialists, the computational analysis, modeling, and results will be communicated in scientific research papers and a digital health observatory., Results: The project has several activities, and it is in an initial stage. Initially, a survey was given to all health care centers to understand the technical aspects of each network member, such as the existence of computers, technical support staff, and digitized systems. In this survey, we detected that 59% (23/39) of participating health units have electronic medical records, while 41% (16/39) have paper records. Therefore, we will have different strategies to access the data from each center in the data collection phase. Later, we will standardize and analyze the clinical and epidemiological data and use these data to develop a national network for monitoring rare diseases and a digital health observatory to make the information available. The project had its financing approved in December 2019. Retrospective data collection started in October 2020, and we expect to finish in January 2021. During the third quarter of 2020, we enrolled 40 health institutions from all regions of Brazil., Conclusions: The nature of rare disease diagnosis is complex and diverse, and many problems will be faced in the evolution of the project. However, decisions based on data analysis are the best option for the improvement of the rare disease network in Brazil. The creation of RARASnet, along with all the digitized infrastructure, can improve the accessibility of information and standardization of rare diseases in the country., International Registered Report Identifier (irrid): DERR1-10.2196/24826., (©Domingos Alves, Diego Bettiol Yamada, Filipe Andrade Bernardi, Isabelle Carvalho, Márcio Eloi Colombo Filho, Mariane Barros Neiva, Vinícius Costa Lima, Têmis Maria Félix. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 22.01.2021.)

Treatment of moderate and severe forms of osteogenesis imperfecta (OI) with cyclic pamidronate at the Reference Center for OI Treatment in Southern Brazil was studied. A retrospective cohort study was conducted from 2002 to 2012. Data were obtained during inpatient (drug infusion) and outpatient care. Clinical data, including the presence of blue sclerae, dentinogenesis imperfecta, history and site of the fractures, biochemical data, including calcium, phosphorus, and alkaline phosphatase levels, were systematically collected. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry (DXA). Forty-five patients (26 females) were included in the study, and the age of the patients at the time of diagnosis ranged from 1 to 144 months, with a median age (p25-p75) of 38 (5-96) months. Most cases presented OI-4 (51.1%), and the median age of the patients at the start of treatment was 3.3 years (25-75 percentiles: 0.5 - 8.7 years). Twenty-four patients (54.5%) had some adverse events or intercurrences during treatment, and the treatment compliance mean was 92.3% (± 10.7). The treatment with intravenous pamidronate has shown to be safe, well-tolerated, and effective in regard to the improvement of BMD and the reduction of the number of fractures in children and adolescents with OI.

Background: Osteogenesis imperfecta (OI) is a disorder of bone formation leading to low mineral density and fractures. Children and adolescents with OI require periodic medical follow up, corrective surgery, drug therapy and physical therapy, as well as specific daily care practices. In addition, they have an increased incidence of fractures, which require immobilization and cause severe discomfort and short-term disability. This study evaluated the health-related quality of life of children and adolescents with OI in two reference centers for OI treatment in southern Brazil., Methods: In this prospective cross-sectional study, the Pediatric Quality of Life Inventory (PedsQL TM ) was applied in two university-affiliated reference centers for OI treatment in southern Brazil. Children and adolescents aged ≥ 5 years with clinical diagnoses of OI were included. Clinical data and socioeconomic status was evaluated., Results: The sample consisted of 52 children and adolescents with OI (aged 5-17 years); 26 (50%) participants with type I OI, 13 (25%) type IV, 12 (23.1 %) type III, and 1 (1.9%) type V OI. Physical and social functioning domains differed significantly according to clinical presentation of OI with lowest scores in the severe type (OI type III). Pain seems to be the variable that is most associated with impact on the PedsQL domains., Conclusions: Overall, this study revealed differences in physical functioning and social functioning in relation to OI clinical presentation. These results reinforcing the importance of the clinical management of these patients with the aim of functional improvement and importance of pain control.

Objective: To identify pathogenic genomic imbalances in patients presenting congenital heart disease (CHD) with extra cardiac anomalies and exclusion of 22q11.2 deletion syndrome (22q11.2 DS)., Methods: 78 patients negative for the 22q11.2 deletion, previously screened by fluorescence in situ hybridization (FISH) and/or multiplex ligation probe amplification (MLPA) were tested by chromosomal microarray analysis (CMA)., Results: Clinically significant copy number variations (CNVs ≥300kb) were identified in 10% (8/78) of cases. In addition, potentially relevant CNVs were detected in two cases (993kb duplication in 15q21.1 and 706kb duplication in 2p22.3). Genes inside the CNV regions found in this study, such as IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1, and LTPB1 are known to participate in cardiac development and could be candidate genes for CHD., Conclusion: These data showed that patients presenting CHD with extra cardiac anomalies and exclusion of 22q11.2 DS should be investigated by CMA. The present study emphasizes the possible role of CNVs in CHD., (Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Introduction: The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity., Methods: All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed., Results: Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.-183G>A and c.-514C>T were also present in 10/37 concordant patients., Conclusions: The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.

Objective: To characterize the fracture pattern and the clinical history at the time of diagnosis of osteogenesis imperfecta., Methods: In this retrospective study, all patients with osteogenesis imperfecta, of both genders, aged 0-18 years, who were treated between 2002 and 2014 were included. Medical records were assessed to collect clinical data, including the presence of blue sclerae, dentinogenesis imperfecta, positive familial history of osteogenesis imperfecta, and the site of the fractures. In addition, radiographic findings at the time of the diagnosis were reviewed., Results: Seventy-six patients (42 females) were included in the study. Individuals' age ranged from 0 to 114 months, with a median (interquartile range) age of 38 (6-96) months. Blue sclerae were present in 93.4% of patients, dentinogenesis imperfecta was observed in 27.6% of patients, and wormian bones in 29.4% of them. The number of fractures at diagnosis ranged from 0 to 17, with a median of 3 (2-8) fractures. Forty (57%) patients had fractures of the upper and lower extremities, and 9 patients also had spinal fractures. The diagnosis was performed at birth in 85.7% of patients with type 3, and 39.3% of those with type 4/5 of the disorder., Conclusions: Osteogenesis imperfecta is a genetic disorder with distinctive clinical features such as bone fragility, recurrent fractures, blue sclerae, and dentinogenesis imperfecta. It is important to know how to identify these characteristics in order to facilitate the diagnosis, optimize the treatment, and differentiate osteogenesis imperfecta from other disorders that also can lead to fractures.

Identifying the genetic etiology in a person with hearing loss (HL) is challenging due to the extreme genetic heterogeneity in HL and the population-specific variability. In this study, after excluding GJB2 variants, targeted resequencing of 180 deafness-related genes revealed the causative variants in 11 of 19 (58%) Brazilian probands with autosomal recessive HL. Identified pathogenic variants were in MYO15A (10 families) and CLDN14 (one family). Remarkably, the MYO15A p.(Val1400Met) variant was identified in eight families from the city of Monte Santo in the northeast region of Brazil. Haplotype analysis of this variant was consistent with a single founder. No other cases with this variant were detected among 105 simplex cases from other cities of northeastern Brazil, suggesting that this variant is confined to a geographical region. This study suggests that it is feasible to develop population-specific screening for deafness variants once causative variants are identified in different geographical groups., (© 2016 John Wiley & Sons Ltd/University College London.)

Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5'UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity.

Background: Osteogenesis imperfecta (OI) is a group of genetic disorders of collagen biosynthesis, characterized by low bone density leading to fractures. Most patients exhibit functional impairment and require the aid of a caregiver. The aim of this study is to assess the quality of life (QoL) of caregivers of patients with OI., Methods: In this cross-sectional study, a convenience sampling strategy was used to enroll adult caregivers of children and adolescents with OI who attended a referral center in southern Brazil. The WHOQOL-BREF instrument was used to assess QoL., Results: Twenty-four caregivers of 27 patients (10 with type I, 4 with type III, and 13 with type IV OI) were included in the study. Eighteen caregivers were the patients' mothers, two had OI, and 22 cared for only one patient. Mean WHOQOL-BREF scores were 14.59 for the physical health domain, 13.80 for the psychological domain, 15.19 for the social relationships domain, and 12.87 for the environmental domain; the mean total QoL score was 14.16. QoL scores did not differ significantly according to patients' OI type or number of fractures. Economic status was not correlated significantly with QoL scores., Conclusions: QoL appears to be impaired in caregivers of patients with OI. Additional studies are required to confirm these findings and to ascertain which factors account for this phenomenon.

Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.

Purpose: To analyze clinical and functional features of children and adolescents with osteogenesis imperfecta (OI)., Methods: A cross-sectional study of 62 participants examined clinical, body structure and function and activity features., Results: A total of 31 participants had OI type I, 9 had type III, and 22 had type IV. Mild (type I) and moderate/severe (types III and IV) OI differed significantly in occurrence of fractures, presence of bone deformities, the use of intramedullary rods, bone mineral density, and bisphosphonate therapy. Age of gait acquisition showed an association with overall joint range of motion and an inverse relationship with overall muscle strength. Level of ambulation was associated with overall muscle strength and inversely associated with overall joint range of motion., Conclusions: Features vary according to OI type. Moderate and severe forms of OI are associated with greater functional limitation, influenced by fracture history, which negatively affects the acquisition and level of ambulation.

Holoprosencephaly (HPE) is a spectrum of brain and facial malformations primarily reflecting genetic factors, such as chromosomal abnormalities and gene mutations. Here, we present a clinical and molecular analysis of 195 probands with HPE or microforms; approximately 72% of the patients were derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and 82% of the patients were newborns. Alobar HPE was the predominant brain defect in almost all facial defect categories, except for patients without oral cleft and median or lateral oral clefts. Ethmocephaly, cebocephaly, and premaxillary agenesis were primarily observed among female patients. Premaxillary agenesis occurred in six of the nine diabetic mothers. Recurrence of HPE or microform was approximately 19%. The frequency of microdeletions, detected using Multiplex Ligation-dependant Probe Amplification (MLPA) was 17% in patients with a normal karyotype. Cytogenetics or QF-PCR analyses revealed chromosomal anomalies in 27% of the probands. Mutational analyses in genes SHH, ZIC2, SIX3 and TGIF were performed in 119 patients, revealing eight mutations in SHH, two mutations in SIX3 and two mutations in ZIC2. Thus, a detailed clinical description of new HPE cases with identified genetic anomalies might establish genotypic and phenotypic correlations and contribute to the development of additional strategies for the analysis of new cases.

Nonsyndromic oral clefts (NSOC) are the most common craniofacial birth defects in humans. The etiology of NSOC is complex, involving both genetic and environmental factors. Several genes that play a role in cellular proliferation, differentiation, and apoptosis have been associated with clefting. For example, variations in the homeobox gene family member MSX1, including a CA repeat located within its single intron, may play a role in clefting. The aim of this study was to investigate the association between MSX1 CA repeat polymorphism and NSOC in a Southern Brazilian population using a case-parent triad design. We studied 182 nuclear families with NSOC recruited from the Hospital de Clínicas de Porto Alegre in Southern Brazil. The polymorphic region was amplified by the polymerase chain reaction and analyzed by using an automated sequencer. Among the 182 families studied, four different alleles were observed, at frequencies of 0.057 (175 bp), 0.169 (173 bp), 0.096 (171 bp) and 0.67 (169 bp). A transmission disequilibrium test with a family-based association test (FBAT) software program was used for analysis. FBAT analysis showed overtransmission of the 169 bp allele in NSOC (P=0.0005). These results suggest that the CA repeat polymorphism of the MSX1 gene may play a role in risk of NSOC in populations from Southern Brazil.

Objectives: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth., Patients and Methods: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates., Results: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group., Conclusions: The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth.

Background. High-quality clinical and genetic descriptions are crucial to improve knowledge of orofacial clefts and support specific healthcare polices. The objective of this study is to discuss the potential and perspectives of the Brazilian Database on Orofacial Clefts. Methods. From 2008 to 2010, clinical and familial information on 370 subjects was collected by geneticists in eight different services. Data was centrally processed using an international system for case classification and coding. Results. Cleft lip with cleft palate amounted to 198 (53.5%), cleft palate to 99 (26.8%), and cleft lip to 73 (19.7%) cases. Parental consanguinity was present in 5.7% and familial history of cleft was present in 26.3% subjects. Rate of associated major plus minor defects was 48% and syndromic cases amounted to 25% of the samples. Conclusions. Overall results corroborate the literature. Adopted tools are user friendly and could be incorporated into routine patient care. The BDOC exemplifies a network for clinical and genetic research. The data may be useful to develop and improve personalized treatment, family planning, and healthcare policies. This experience should be of interest for geneticists, laboratory-based researchers, and clinicians entrusted with OC worldwide.

Prenatal alcohol exposure can have serious and permanent adverse effects. The developing brain is the most vulnerable organ to the insults of prenatal alcohol exposure. A behavioral phenotype of prenatal alcohol exposure including conduct disorders is also described. This study on a sample of Brazilian adolescents convicted for criminal behavior aimed to evaluate possible clinical features of Fetal Alcohol Syndrome (FAS). These were compared to a control group of school adolescents, as well as tested for other environmental risk factors for antisocial behavior. A sample of 262 institutionalized male adolescents due to criminal behavior and 154 male students aged between 13 and 21 years comprised the study population. Maternal use of alcohol was admitted by 48.8% of the mothers of institutionalized adolescents and by 39.9% of the school students. In this sample of adolescents we could not identify individual cases with a clear diagnosis of FAS, but signs suggestive of FASD were more common in the institutionalized adolescents. Social factors like domestic and family violence were frequent in the risk group, this also being associated to maternal drinking during pregnancy. The inference is that in our sample, criminal behavior is more related to complex interactions between environmental and social issues including prenatal alcohol exposure.

We report a study of TGFA/ Taq I polymorphisms and environmental factors in non-syndromic oral cleft in Southern Brazil. Nonsyndromic cleft case-parent triads were recruited to participate. Clinical data was collected with an emphasis on tobacco and alcohol use during pregnancy. DNA was extracted from peripheral blood and TGFA/ Taq I polymorphisms were analyzed by PCR/RFLP with Taq I restriction enzyme. Association of clefts and TGFA/ Taq I polymorphisms was determined using a transmission disequilibrium test (TDT). Association of environmental factors, clefts, and genotypes was evaluated with Fisher's exact test. The minor allele frequency was 0.064. We found no evidence of association between TGFA/ Taq I polymorphisms and clefting (TDT p = 0.335). We also found no association between TGFA/ TaqI polymorphisms and environmental factors (alcohol and/or tobacco). Therefore, no evidence was found that TGFA/ Taq I polymorphisms play a role in clefting in this population. No evidence was found that tobacco or alcohol exposure during pregnancy was related to clefting, however a larger sample size is needed to confirm these results.

Cleft lip with or without palate (CL±P) is common congenital anomalies in humans. Experimental evidence has demonstrated that bone morphogenetic protein 4 gene (Bmp4) is involved in the etiology of CL±P in animal models. The nonsynonymous polymorphism rs17563 T>C (p.V152A) in the BMP4 gene has been associated to the risk of nonsyndromic CL±P in Chinese population and microforms from different ethnic backgrounds. The aim of this study was to investigate the role of BMP4 gene in CL±P in Brazilian sample using genetic association approach. Our sample was composed by 123 patients with nonsyndromic CL±P and 246 controls, in which absence of CL±P was confirmed in 3 generations. The rs17563 polymorphism was genotyped by PCR-RFLP technique. Logistic regression was performed to evaluate allele and genotype association. Our data showed statistical power to detect association (86.83%) in this sample. Logistic regression results showed significant association between C allele and CL±P (P = 0.00018, OR = 0.40, and 95% CI = 0.25-0.65), as well as CC genotype and CL±P (P = 0.00018, OR = 0.35, and 95% CI = 0.19-0.66). So, there is a strong association between nonsyndromic CL±P and BMP4 rs17563 polymorphism in our sample and the C allele had a protective effect against the occurrence of nonsyndromic CL±P.

Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.

Background: Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial disorder caused by frameshift deletions or duplications in the TCOF1 gene. These mutations cause premature termination codons, which are predicted to lead to mRNA degradation by nonsense mediated mRNA decay (NMD). Haploinsufficiency of the gene product (treacle) during embryonic development is the proposed molecular mechanism underlying TCS. However, it is still unknown if TCOF1 expression levels are decreased in post-embryonic human cells., Methods: We have estimated TCOF1 transcript levels through real time PCR in mRNA obtained from leucocytes and mesenchymal cells of TCS patients (n = 23) and controls (n = 18). Mutational screening and analysis of NMD were performed by direct sequencing of gDNA and cDNA, respectively., Results: All the 23 patients had typical clinical features of the syndrome and pathogenic mutations were detected in 19 of them. We demonstrated that the expression level of TCOF1 is 18-31% lower in patients than in controls (p < 0.05), even if we exclude the patients in whom we did not detect the pathogenic mutation. We also observed that the mutant allele is usually less abundant than the wild type one in mesenchymal cells., Conclusions: This is the first study to report decreased expression levels of TCOF1 in TCS adult human cells, but it is still unknown if this finding is associated to any phenotype in adulthood. In addition, as we demonstrated that alleles harboring the pathogenic mutations have lower expression, we herein corroborate the current hypothesis of NMD of the mutant transcript as the explanation for diminished levels of TCOF1 expression. Further, considering that TCOF1 deficiency in adult cells could be associated to pathologic clinical findings, it will be important to verify if TCS patients have an impairment in adult stem cell properties, as this can reduce the efficiency of plastic surgery results during rehabilitation of these patients.

Non-syndromic cleft lip and palate (CL/P) occurs due to interaction between genetic and environmental factors. Abnormalities in homocysteine metabolism may play a role in its etiology due to polymorphisms in genes involved in this pathway. Because of the involvement of MTHFR, MTR and MTRR genes with folate metabolism and the evidence that maternal use of folic acid in early pregnancy reduces the risk for CL/P, we evaluated the influence of their polymorphisms on the etiology of CL/P through a case-control study. The analyses involved 114 non-syndromic phenotypically white children with clefts (case) and 110 mothers, and 100 non-affected (control) children and their mothers. The polymorphisms 677C>T of MTHFR, 2756A>G of MTR, and 66A>G of MTRR genes were analyzed by PCR-RFLP. Allelic frequencies did not differ from other studies conducted on white populations for MTHFR 677T allele (0.35) and for MTR 2756G allele (0.17), but MTRR 66G allele frequency (0.35) was lower than observed elsewhere. The genotypic distribution of the 677C>T polymorphisms under study did not show significant differences between CL/P patients, their mothers and controls. These results suggest that the alterations of folate metabolism related to these polymorphisms are not involved in clefting in the population under study.

Nonsyndromic or isolated cleft lip with or without cleft palate (CL/P) occurs in wide geographic distribution with an average birth prevalence of 1/700. We used direct sequencing as an approach to study candidate genes for CL/P. We report here the results of sequencing on 20 candidate genes for clefts in 184 cases with CL/P selected with an emphasis on severity and positive family history. Genes were selected based on expression patterns, animal models, and/or role in known human clefting syndromes. For seven genes with identified coding mutations that are potentially etiologic, we performed linkage disequilibrium studies as well in 501 family triads (affected child/mother/father). The recently reported MSX1 P147Q mutation was also studied in an additional 1,098 cleft cases. Selected missense mutations were screened in 1,064 controls from unrelated individuals on the Centre d'Etude du Polymorphisme Humain (CEPH) diversity cell line panel. Our aggregate data suggest that point mutations in these candidate genes are likely to contribute to 6% of isolated clefts, particularly those with more severe phenotypes (bilateral cleft of the lip with cleft palate). Additional cases, possibly due to microdeletions or isodisomy, were also detected and may contribute to clefts as well. Sequence analysis alone suggests that point mutations in FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of isolated cleft lip with or without cleft palate, and the linkage disequilibrium data support a larger, as yet unspecified, role for variants in or near MSX2, JAG2, and SKI. This study also illustrates the need to test large numbers of controls to distinguish rare polymorphic variants and prioritize functional studies for rare point mutations., Competing Interests: Competing interests. The authors have declared that no competing interests exist.

In some autosomal dominant conditions, there is a correlation between new mutations and paternal age, with new mutations arising almost exclusively in the male germ line. To test this hypothesis in Treacher Collins syndrome, we analyzed 22 sporadic cases, determining the parental origin of the pathogenic mutation in 10 informative families. Mutations were found to be of both paternal and maternal origin, without a detectable parental age effect, confirming that a paternal age effect is not universal to all autosomal dominant disorders. A discussion on the parental origin of mutations and paternal age effect in other diseases is included.

The Associação dos Pais e Amigos dos Excepcionais (APAE) is an institution for mentally retarded patients located at Caxias do Sul in the south of Brazil. A genetic diagnostic survey of 202 individuals from this institution is presented. The patients had a male:female ratio of 1.3:1 and their ages varied from 1 month to 47 years with a mean of 5.5 years. Using personal and family data, careful clinical examination and laboratory investigation, the authors established a definitive diagnosis in 132 patients (65.34%). A constitutional disorder was present in 111 patients (54.95%). Down's syndrome patients represented 32.15%, while 1.98% had other chromosomal anomalies. In 25 patients (12.37%) a disorder of Mendelian inheritance was diagnosed. In 8 patients (3.96%) a multiple congenital anomalies/mental retardation (MCA/MR) syndrome was recorded. Eight patients (3.96%) had a central nervous system (CNS) malformation. An acquired condition was observed in 21 patients (10.39%), including pre- or post-natal infections. In the remaining 70 patients (34.65%) a conclusive diagnosis was not possible.