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Mucopolysaccharidosis type IIIB (MPS IIIB) is caused by deficiency of alpha-N-acetylglucosaminidase, leading to storage of heparan sulphate. The disease is characterized by intellectual disability and hyperactivity, among other neurological and somatic features. Here we studied retrospective data from a total of 19 MPS IIIB patients from Brazil, aiming to evaluate disease progression. Mean age at diagnosis was 7.2 years. Speech delay was one of the first symptoms to be identified, around 2-3 years of age. Behavioral alterations include hyperactivity and aggressiveness, starting around age four. By the end of the first decade, patients lost acquired abilities such as speech and ability to walk. Furthermore, as disease progresses, respiratory, cardiovascular and joint abnormalities were found in more than 50% of the patients, along with organomegaly. Most common cause of death was respiratory problems. The disease progression was characterized in multiple systems, and hopefully these data will help the design of appropriate clinical trials and clinical management guidelines.
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Mucopolysaccharidosis type IIIB is a rare autosomal recessive disorder characterized by deficiency of the enzyme N-acetyl-alpha-d-glucosaminidase (NAGLU), caused by biallelic pathogenic variants in the NAGLU gene, which leads to storage of heparan sulfate and a series of clinical consequences which hallmark is neurodegeneration. In this study clinical, epidemiological, and biochemical data were obtained from MPS IIIB patients diagnosed from 2004-2019 by the MPS Brazil Network ("Rede MPS Brasil"), which was created with the goal to provide an easily accessible and comprehensive investigation of all MPS types. One hundred and ten MPS IIIB patients were diagnosed during this period. Mean age at diagnosis was 10.9 years. Patients were from all over Brazil, with a few from abroad, with a possible cluster of MPS IIIB identified in Ecuador. All patients had increased urinary levels of glycosaminoglycans and low NAGLU activity in blood. Main clinical symptoms reported at diagnosis were coarse facies and neurocognitive regression. The most common variant was p.Leu496Pro (30% of alleles). MPS IIIB seems to be relatively frequent in Brazil, but patients are diagnosed later than in other countries, and reasons for that probably include the limited awareness about the disease by health professionals and the difficulties to access diagnostic tests, factors that the MPS Brazil Network is trying to mitigate.
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Mucopolissacaridose III , Alelos , Brasil/epidemiologia , Criança , Heparitina Sulfato , Humanos , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/epidemiologia , Mucopolissacaridose III/genéticaRESUMO
Mucopolysaccharidosis type II (MPS II) is an X-linked inherited disease caused by pathogenic variants in the IDS gene, leading to deficiency of the lysosomal enzyme iduronate-2-sulfatase and consequent widespread storage of glycosaminoglycans, leading to several clinical consequences, with progressive manifestations which most times includes cognitive decline. MPS II has wide allelic and clinical heterogeneity and a complex genotype-phenotype correlation. We evaluated data from 501 Brazilian patients diagnosed with MPS II from 1982 to 2020. We genotyped 280 of these patients (55.9%), which were assigned to 206 different families. Point mutations were present in 70% of our patients, being missense variants the most frequent. We correlated the IDS pathogenic variants identified with the phenotype (neuronophatic or non-neuronopathic). Except for two half-brothers, there was no discordance in the genotype-phenotype correlation among family members, nor among MPS II patients from different families with the same single base-pair substitution variant. Mothers were carriers in 82.0% of the cases. This comprehensive study of the molecular profile of the MPS II cases in Brazil sheds light on the genotype-phenotype correlation and helps the better understanding of the disease and the prediction of its clinical course, enabling the provision of a more refined genetic counseling to the affected families.
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Mucopolissacaridose II , Brasil , Genótipo , Humanos , Masculino , Mucopolissacaridose II/genética , Mutação , FenótipoRESUMO
Congenital Zika syndrome (CZS) constitutes a recently identified malformation caused by Zika virus infection during pregnancy. Limited data is available to date on the facial dysmorphic features of these patients. This study evaluated the facial dysmorphisms of children with CZS, compared with clinically healthy children, using clinical examination and standardized photographic images. Sixty-three children with CZS (9.70 ± 3.2 months-age), and 31 Controls (8.67 ± 6.2 months-age) joined the study. Seven out of 15 indices differed between groups: midfacial height (MFH)/horizontal facial reference (HFR) (p = .0003), interalar distance/HFR (p = .0027), nasal root depth/MFH (p = .0030), posterior nasal length/MFH (p = .0002), vertical position of the ear/MFH (p <.0001), ear length/MFH (p = .0005), chin height/total facial height (CH/TFH) (p <.0001). A CH/TFH of 0.229 showed 93.9% sensitivity and 80.6% specificity in diagnosing CZS. Children with CZS had broad, short faces, decreased intercanthal distance, short posterior nasal length, prominent nasal root, broad nasal wings, and high-set and long ears. Increased chin height index provided the most accurate diagnostic potential.
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Face/anormalidades , Microcefalia/genética , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/genética , Face/diagnóstico por imagem , Feminino , Humanos , Lactente , Masculino , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Gravidez , Zika virus/genética , Zika virus/patogenicidade , Infecção por Zika virus/patologia , Infecção por Zika virus/virologiaRESUMO
Femoral-facial syndrome (FFS, OMIM 134780), also known as femoral hypoplasia-unusual face syndrome, is a rare sporadic syndrome associated with maternal diabetes, and comprising femoral hypoplasia/agenesis and a distinct facies characterized by micrognathia, cleft palate, and other minor dysmorphisms. The evaluation of 14 unpublished Brazilian patients, prompted us to make an extensive literature review comparing both sets of data. From 120 previously reported individuals with FFS, 66 were excluded due to: not meeting the inclusion criteria (n = 21); not providing sufficient data to ascertain the diagnosis (n = 29); were better assigned to another diagnosis (n = 3); and, being fetuses of the second trimester (n = 13) due to the obvious difficult to confirm a typical facies. Clinical-radiological and family information from 54 typical patients were collected and compared with the 14 new Brazilian patients. The comparison between the two sets of patients did not show any relevant differences. Femoral involvement was most frequently hypoplasia, observed in 91.2% of patients, and the typical facies was characterized by micrognathia (97%), cleft palate (61.8%), and minor dysmorphisms (frontal bossing 63.6%, short nose 91.7%, long philtrum 94.9%, and thin upper lip 92.3%). Clubfoot (55.9%) was commonly observed. Other observed findings may be part of FFS or may be simply concurrent anomalies since maternal diabetes is a common risk factor. While maternal diabetes was the only common feature observed during pregnancy (50.8%), no evidence for a monogenic basis was found. Moreover, a monozygotic discordant twin pair was described reinforcing the absence of a major genetic factor associated with FFS.
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Fêmur/anormalidades , Síndrome de Pierre Robin/diagnóstico , Brasil/epidemiologia , Fácies , Feminino , Humanos , Masculino , Fenótipo , Síndrome de Pierre Robin/epidemiologia , Síndrome de Pierre Robin/genética , Gravidez , Radiografia , Fatores de Risco , Avaliação de Sintomas , Gêmeos MonozigóticosRESUMO
BACKGROUND: Although more than 14 loci may be involved in the development of nonsyndromic cleft lip and palate (NSCLP), the etiology has not been fully elucidated due to genetic and environmental risk factor interactions. Despite advances in identifying genes associated with the NSCLP development using traditional genetic mapping strategies of candidate genes, genome-wide studies, and epidemiologic and linkage analysis, microarray techniques have become important complementary tools in the search for potential causative oral clefts genes in genetic studies. Microarray hybridization enables scanning of the whole genome and detecting copy number variants (CNVs). Although common benign CNVs are often smaller, with sizes smaller than 20 kb, here we reveal small exonic CNVs based on the importance of the encompassed genes in cleft lip and palate phenotype. METHODS: Microarray hybridization analysis was performed in 15 individuals with NSCLP. RESULTS: We identified 11 exonic CNVs affecting at least one exon of the candidate genes. Thirteen candidate genes (COL11A1-1p21; IRF6-1q32.3; MSX1-4p16.2; TERT-5p15.33; MIR4457-5p15.33; CLPTM1L-5p15.33; ESR1-6q25.1; GLI3-7p13; FGFR-8p11.23; TBX1-22q11.21; OFD-Xp22; PHF8-Xp11.22; and FLNA-Xq28) overlapped with the CNVs identified. CONCLUSIONS: Considering the importance to NSCLP, the microdeletions that encompass MSX1, microduplications over TERT, MIR4457, CLPTM1L, and microduplication of PHF8 have been identified as small CNVs related to sequence variants associated with oral clefts susceptibility. Our findings represent a preliminary study on the clinical significance of small CNVs and their relationship with genes implicated in NSCLP.
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Congenital Zika virus infection can cause microcephaly and severe brain abnormalities (1). Congenital Zika syndrome comprises a spectrum of clinical features (2); however, as is the case with most newly recognized teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly (3). To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (4).
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Microcefalia/epidemiologia , Infecção por Zika virus/congênito , Infecção por Zika virus/diagnóstico , Zika virus/isolamento & purificação , Brasil/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Complicações Infecciosas na Gravidez , Estudos RetrospectivosRESUMO
PURPOSE: This study aimed to describe the orofacial features of 26 unrelated Brazilian patients with mucopolysaccharidosis and to verify any possible associations between these findings and specific types of mucopolysaccharidosis. METHODS: Patients were diagnosed with mucopolysaccharidosis and clinically evaluated. Following consent, a clinical assessment form was completed. Facial and intraoral examination was performed by evaluating facial pattern, malocclusions, dental caries, and tooth identification. RESULTS: Midface deficiency, increased lower facial third, anterior open bite, convex profile, macroglossia, gingival enlargement, and spaced arches were the most frequently observed features. These findings did not allow a differential diagnosis among the different types of mucopolysaccharidosis, except for pitting enamel, which significantly associated with mucopolysaccharidosis IVA (P < .001). Open bite was associated with mucopolysaccharidosis types I, II, III, and VI; however, only one patient with mucopolysaccharidosis IVA expressed this feature (P = .043). CONCLUSIONS: Our results suggest that pitted enamel in patients with mucopolysaccharidosis is most likely a feature of mucopolysaccharidosis type IVA; whereas, open bite is rarely observed in these patients. Orofacial features in mucopolysaccharidosis may help pediatric dentists recognize this disorder and minimize the delay between the initial signs/symptoms and diagnosis of the disease. Future studies should focus on the longitudinal manifestations, expression, and severity of mucopolysaccharidosis-associated orofacial anomalies.
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Mucopolissacaridoses/patologia , Doenças Estomatognáticas/patologia , Brasil , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , MasculinoRESUMO
OBJECTIVES: The aim of this study was to describe clinical features in subjects with palatal abnormalities and to assess the distribution of these features among those with and without 22q11.2 deletion. DESIGN: Descriptive cohort. PATIENTS: One hundred patients with palatal abnormalities and suspicion of 22q11.2 DS were included. METHODS: All patients were evaluated by a clinical geneticist, who completed a standardized clinical protocol. The 22q11.2 deletion screening was performed with fluorescence in situ hybridization using the TUPLE1 probe and multiplex ligation-dependent probe amplification using the P250-A1 kit. RESULTS: The 22q11.2 deletion was detected in 35 patients, in whom the most frequent clinical features were congenital heart disease (15/30 - 50%), developmental delay (19/35 - 54%), speech delay (20/35 - 57%), learning disabilities (27/35 - 77%), immunologic alterations (18/29 - 62%). In addition, the most common facial dysmorphisms in this group were long face (27/35 - 77%), typical nose (24/35 - 69%), and hooded eyelids (19/35 - 54%). Comparing features in patients with or without the deletion revealed significant differences (positively correlated with the deletion) for speech delay, learning disabilities, conductive hearing loss, number of dysmorphisms, long face, and hooded eyelids. Cleft lip and palate was negatively correlated with the deletion. CONCLUSIONS: The presence of speech delay, learning disabilities, conductive hearing loss, long face, and hooded eyelids should reinforce the suspicion of 22q11.2 DS in patients with palatal abnormalities and would help professionals direct clinical follow-up of these patients.
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Anormalidades Múltiplas , Deleção Cromossômica , Cromossomos Humanos Par 22 , Síndrome de DiGeorge/diagnóstico , Palato/anormalidades , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , MasculinoRESUMO
Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34) and at a median time of 2.5 years later (T2; n = 24/34). The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype); B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype). For all variables in which there was no between-group difference at baseline, a delta of ≥ ± 20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed.
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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.
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Geographic and sociodemographic aspects may influence the natural history and epidemiology of mucopolysaccharidoses (MPS). The main objective in this work was to evaluate the clinical, molecular, and geographic profile of MPS in a population from Ceará (Northeast Brazil). For this, we have performed a descriptive cross-sectional study based on clinical evaluation, interviews with patients and/or family members, and review of medical records of 76 MPS patients. MPS II was the most common type, with the most affected individuals presenting missense pathogenic variants. Patients with MPS I proved to be the most severe clinical phenotype, presenting the first symptoms (mean: 7.1 months; SD = 4.5) and being diagnosed earlier (2.2 years; SD = 2.1) in comparison with the other types. In addition, we have shown that 13 individuals with MPS VI were born of consanguineous marriages in small, nearby cities, in a place where geographical isolation, consanguinity, and clusters of genetic diseases were previously reported. Ten of these individuals (at least, seven different families) presented a rare pathogenic variant in the ARSB gene, c.1143-8T > G in homozygosity, previously reported only among Iberian and South American patients. The results presented here provide a comprehensive picture of MPS in an important state of the Brazilian Northeast, a region that concentrates many risk factors for rare genetic diseases, such as endogamy, inbreeding, and reproductive isolation. We discuss the possible evolutionary processes and biosocial dynamics that can help to explain this finding in terms of population medical genetics and public health.
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Intellectual disability (ID) is considered a common neuropsychiatric disorder that affects up to 3% of the population. The etiologic origin of ID may be genetic, environmental, and multifactorial. Chromosomopathies are relatively common among the genetic causes of ID, especially in the most severe cases and those associated with dysmorphic features. Currently, the application of new molecular cytogenetics technologies has increasingly allowed the identification of microdeletions, microduplications, and unbalanced translocations as causes of ID. The objective of this study was to investigate the etiology of ID in patients admitted to a public hospital in Northeastern Brazil. In total, 119 patients with ID who had normal karyotypes and fragile X exams participated in this study. The patients were initially physically examined for microdeletion syndromes and then tested using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), methylation-sensitive polymerase chain reaction (MS-PCR), and chromosome microarray analysis (CMA), according to clinical suspicion. Patients with no diagnoses after FISH, MLPA, and/or MS-PCR evaluations were subsequently tested by CMA. The rate of etiologic diagnoses of ID in the current study was 28%. FISH diagnosed 25 out of 79 tested (31%), MLPA diagnosed 26 out of 79 tested (32%), MS-PCR diagnosed 7 out of 20 tested (35%), and the single nucleotide polymorphism array diagnosed 6 out of 27 tested (22%). Although the CMA is the most complete and recommended tool for the diagnosis of microdeletions, microduplications, and unbalance translocations in patients with ID, FISH, MLPA, and MS-PCR testing can be used as the first tests for specific syndromes, as long as the patients are first physically screened clinically, especially in the public health networks system in Brazil, where resources are scarce.
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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.
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Síndrome de DiGeorge , Humanos , Feminino , Síndrome de DiGeorge/genética , Masculino , Criança , Adolescente , Polimorfismo de Nucleotídeo Único , Fenótipo , Pré-Escolar , Adulto , Cromossomos Humanos Par 22/genética , Lactente , Adulto JovemRESUMO
BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism caused by deficient activity of phenylalanine hydroxylase. In Brazil, the National Neonatal Screening Program enables early treatment of patients with PKU, which prevents them from developing severe neurological damage and mental disabilities. However, between 20 and 30% of early-treated patients with PKU present focal cognitive deficits, including deficits in working memory, processing speed, and psychiatric symptoms such as anxiety, depression, and attention deficit hyperactivity disorder (ADHD). Therefore, age-specific neuropsychiatric and cognitive tests are important components of PKU patient care. To date, there are no officially approved guidelines or recommendations of tools in Portuguese validated for use in Brazil that could be applied to assess these parameters in patients with PKU. OBJECTIVE: To recommend tools validated for use in Brazil that can be used in daily clinical practice to assess quality of life and neuropsychological outcomes in patients with PKU. METHODS: Six Brazilian experts discussed about eligible tools based on their clinical experience, the feasibility of their use in clinical routines, and their availability in public health services. Before the meeting, an independent review of the literature was conducted to identify the currently validated tools in Brazil, using the MEDLINE and SciELO databases. RESULTS: The experts recommended nine tools to assess quality of life (Peds-QL, SF-36 or WHOQOL-bref), executive function (BRIEF or Bayley-III), IQ (SONR 2½-7[a] or WASI) and ADHD (MTA-SNAP-IV and ASRS). CONCLUSION: These instruments may be easily incorporated into clinical practice and improve the quality of multidisciplinary care of patients with PKU.
ANTECEDENTES: A fenilcetonúria (PKU) é um erro inato do metabolismo causado pela atividade deficiente da fenilalanina hidroxilase. No Brasil, o Programa Nacional de Triagem Neonatal permite o tratamento precoce de pacientes com PKU, o que os impede de desenvolver danos neurológicos e deficiências intelectuais graves. No entanto, já foi descrito que de 20 a 30% dos pacientes tratados precocemente com PKU apresentam déficits cognitivos focais, incluindo déficits na memória de trabalho, velocidade de processamento e sintomas psiquiátricos como ansiedade, depressão e Transtorno de Déficit de Atenção e Hiperatividade (TDAH). Neste sentido, testes neuropsiquiátricos e cognitivos são componentes importantes no cuidado destes pacientes. Atualmente, não existe um compêndio científico ou recomendações de ferramentas validadas em português para avaliar a saúde mental em pacientes brasileiros com PKU. OBJETIVO: Recomendar ferramentas validadas localmente para avaliar a qualidade de vida e aspectos neuropsicológicos de pacientes com PKU. MéTODOS: Seis especialistas brasileiros discutiram as ferramentas mais apropriadas com base em suas experiências clínicas, a viabilidade de realizar as avaliações na rotina clínica, e o acesso às ferramentas na saúde pública. Antes da reunião, foi realizada uma revisão independente da literatura para identificar as ferramentas validadas no Brasil, utilizando as bases de dados MEDLINE e Scielo. RESULTADOS: Os especialistas recomendaram nove ferramentas para avaliar a qualidade de vida (Peds-QL, SF-36 ou WHOQOL-bref), função executiva (BRIEF ou Bayley-III), QI (SONR 2½-7[a] ou WASI) e TDAH (MTA-SNAP-IV e ASRS). CONCLUSãO: Estes instrumentos podem ser facilmente incorporados na prática clínica e melhorar a qualidade dos cuidados multidisciplinares dos pacientes com PKU.
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Transtorno do Deficit de Atenção com Hiperatividade , Fenilcetonúrias , Recém-Nascido , Humanos , Brasil , Qualidade de Vida , Função Executiva , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/tratamento farmacológicoRESUMO
BACKGROUND: Congenital myopathy-13 (CMYP13), also known as Bailey-Bloch congenital myopathy and Native American myopathy (NAM), is a condition caused by biallelic missense pathogenic variants in STAC3, which encodes an important protein necessary for the excitation-relaxation coupling machinery in the muscle. Patients with biallelic pathogenic variants in STAC3 often present with congenital weakness and arthrogryposis, cleft palate, ptosis, myopathic facies, short stature, kyphoscoliosis, and susceptibility to malignant hyperthermia provoked by anesthesia. We present two unrelated cases of Bailey-Bloch congenital myopathy descendants of non-consanguineous parents, which were investigated for delayed psychomotor development and generalized weakness. To the best of our knowledge, these are the first descriptions of CMYP13 in Brazil. In both patients, we found the previously described pathogenic missense variant p.Trp284Ser in homozygosity. CONCLUSION: We seek to highlight the need for screening for CMYP13 in patients expressing the typical phenotype of the disease even in the absence of Lumbee Native American ancestry, and to raise awareness to possible complications like malignant hyperthermia in Bailey-Bloch congenital myopathy.
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This study describes genomic findings among individuals with both orofacial clefts (OC) and microphthalmia/anophthalmia/coloboma (MAC) recorded in the Brazilian Database on Craniofacial Anomalies (BDCA). Chromosomal microarray analysis (CMA) and Whole Exome Sequencing (WES) were performed in 17 individuals with OC-MAC. Clinical interpretation of molecular findings was based on data available at the BDCA and on re-examination. No copy number variants (CNVs) classified as likely pathogenic or pathogenic were detected by CMA. WES allowed a conclusive diagnosis in six individuals (35.29%), two of them with variants in the CHD7 gene, and the others with variants in the TFAP2A, POMT1, PTPN11, and TP63 genes with the following syndromes: CHARGE, CHD7-spectrum, Branchiooculofacial, POMT1-spectrum, LEOPARD, and ADULT. Variants of uncertain significance (VUS) possibly associated to the phenotypes were found in six other individuals. Among the individuals with VUSes, three individuals presented variants in genes associated to defects of cilia structure and/or function, including DYNC2H1, KIAA0586, WDR34, INTU, RPGRIP1L, KIF7, and LMNA. These results show that WES was the most effective molecular approach for OC-MAC in this cohort. This study also reinforces the genetic heterogeneity of OC-MAC, and the importance of genes related to ciliopathies in this phenotype.
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Dystrophinopathies are muscle diseases caused by pathogenic variants in DMD, the largest gene described in humans, representing a spectrum of diseases ranging from asymptomatic creatine phosphokinase elevation to severe Duchenne muscular dystrophy (DMD). Several therapeutic strategies are currently in use or under development, each targeting different pathogenic variants. However, little is known about the genetic profiles of northeast Brazilian patients with dystrophinopathies. We describe the spectrum of pathogenic DMD variants in a single center in northeast Brazil. This is an observational, cross-sectional study carried out through molecular-genetic analysis of male patients diagnosed with dystrophinopathies using Multiplex Ligation-dependent Probe Amplification (MLPA) followed by Next-Generation Sequencing (NGS)-based strategies. A total of 94 male patients were evaluated. Deletions (43.6%) and duplications (10.6%) were the most recurring patterns of pathogenic variants. However, small variants were present in 47.1% of patients, most of them nonsense variants (27.6%). This is the largest South American single-center case series of dystrophinopathies to date. We found a higher frequency of treatment-amenable nonsense single-nucleotide variants than most previous studies. These findings may have implications for diagnostic strategies in less-known populations, as a higher frequency of nonsense variants may mean a higher possibility of treating patients with disease-modifying drugs.
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This study aims to discuss diagnostic criteria and severity assessment for craniofacial microsomia (CFM). A series of 61 patients with diverse CFM phenotypes had their clinical data collected by experienced dysmorphologists using a single protocol. Genetic abnormalities were searched through karyotype and chromosomal microarray analysis. Sex ratio, prenatal risk factors, and recurrence rate corroborated the literature. Despite the wide variability of clinical findings, ear disruption was universal. Eight patients were assigned as syndromic, four of whom had demonstrable genetic alterations. The majority of patients (67.2%) fulfilled four known diagnostic criteria, while 9.8% fulfilled one of them. Data strengthened disruptions of the ear and deafness as a semiotically valuable sign in CFM. Facial impairment should consider asymmetry as a mild expression of microsomia. Spinal and cardiac anomalies, microcephaly, and developmental delay were prevalent among extra craniofacial features and should be screened before planning treatment and follow up. The severity index was able to recognize the less and the most affected patients. However, it was not useful to support therapeutic decisions and prognosis in the clinical scenario due to syndromic and non-syndromic phenotypes overlapping. These issues make contemporary the debate on diagnostic methods and disease severity assessment for CFM. They also impact care and etiopathogenetic studies.
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Síndrome de Goldenhar , Cardiopatias Congênitas , Microcefalia , Face , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/genética , Humanos , Coluna VertebralRESUMO
INTRODUCTION: Newborn who had Zika vírus but did not show microcephaly at birth may have neuropsychomotor development problems. We aimed to evaluate the developmental and anthropometric milestones of asymptomatic children whose mothers had Zika during pregnancy in Northeastern Brazil in 2015 and 2016. METHODS: We conducted a descriptive cross-sectional case series study of children in Fortaleza born without microcephaly whose mothers had Zika during pregnancy. Home visits were undertaken to evaluate the developmental milestones and gather anthropometric data of the children and to conduct semi-structured interviews with the mothers to identify their socioeconomic and gestational profiles and assess the newborns after birth. RESULTS: In total, 30 cases were identified. Of these, 17 children and their mothers participated in the study. The median age of the mothers at the time of delivery was 26 years. All were symptomatic, and TORCH was negative. At the time of the home visit, all had growth profiles suitable for their age. However, nearly all children (15/17, 88.2%) presented at least one developmental delay, considering their age group. CONCLUSIONS: There were late changes in the neuropsychomotor development of children born to mothers who had Zika during pregnancy, suggesting the need for specialized medical follow-ups.