Identifying Genetic Etiology in Patients with Intellectual Disability: An Experience in Public Health Services in Northeastern Brazil.

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.

22q11.2 Deletion Syndrome: Influence of Parental Origin on Clinical Heterogeneity.

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.

Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa.

Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. Materials and methods: A retrospective study was conducted in five Latin-American countries, using clinical records from patients with CLN2. Clinical follow-up and treatment variables are described. A descriptive and bivariate statistical analysis was performed. Results: A total of 36 patients were observed (range of follow-up of 61-110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values. Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes.

Disease progression in Sanfilippo type B: Case series of Brazilian patients.

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.

Síndrome de Aarskog: um relato de caso / Aarskog syndrome: a case report

Introdução: A Síndrome de Aarskog-Scott (AAS) é uma rara displasia faciogenital ligada ao gene FGD1, afetando principalmente meninos. Relato de caso: Descreve-se um caso de um menino de 4 anos com AAS, destacando sua importância científica devido à raridade, escassez de descrições e morbidade associada. Ele apresentou fenda sacral, criptorquidia bilateral, atrasos no crescimento e histórico familiar semelhante. A AAS é caracterizada por estatura baixa, anomalias faciais e diversos comprometimentos. Este caso ressalta a importância do acompanhamento médico especializado. Considerações finais: A escassez de estudos comparáveis destaca a relevância dos relatos de casos para aprofundar a compreensão de condições clínicas singulares.

Introduction: Aarskog-Scott Syndrome (AAS) is a rare faciogenital dysplasia linked to the FGD1 gene, primarily affecting boys. Case report: We describe a case of a 4-year-old boy with AAS, highlighting its scientific importance due to its rarity, scarcity of descriptions, and associated morbidity. He presented with sacral cleft, bilateral cryptorchidism, growth delays, and similar family history. AAS is characterized by short stature, facial anomalies, and various impairments. Final considerations: This case underscores the importance of specialized medical care, and the scarcity of comparable studies highlights the relevance of case reports in deepening the understanding of unique clinical conditions.

Molecular investigation in individuals with orofacial clefts and microphthalmia-anophthalmia-coloboma spectrum.

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.

Higher Prevalence of Nonsense Pathogenic DMD Variants in a Single-Center Cohort from Brazil: A Genetic Profile Study That May Guide the Choice of Disease-Modifying Treatments.

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.

Bailey-Bloch Congenital Myopathy in Brazilian Patients: A Very Rare Myopathy with Malignant Hyperthermia Susceptibility.

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.

Language skills development in children with congenital Zika virus syndrome.

BACKGROUND: The characterization of the phenotype of children with congenital Zika virus syndrome (CZS) is an ongoing process, since many characteristics can only be described with the advancing age of children providing some insights into the long-term sequelae. AIMS: To describe emerging findings on the impact of CZS on language development in children with CZS in a 4-year longitudinal study. METHODS AND PROCEDURES: 39 boys and 44 girls with CZS were allocated into four groups according to age ranging from 12 to 36 months. Language development was assessed using the Early Language Milestone Scale. OUTCOMES AND RESULTS: Visual, expressive, and receptive auditory skills of patients were lower than expected for their age. Despite producing vowel sounds, they did not babble; despite present hearing, the majority of the children did not understand simple commands. In over 4 years of follow-up, there was no evolution in language parameters, with the children stagnating at the language skills corresponding to 3 months of age. CONCLUSIONS AND IMPLICATIONS: Most children with CZS are not able to produce vocalic sounds, but some may be able to communicate basic needs through alternative communication. WHAT THIS PAPER ADDS?: Some babies with CZS died prenatally, at birth, or in the first year of life due to associated complications such as respiratory infection, dysphagia, and epilepsy. However, the functionality of the future remains uncertain for surviving babies. This study adds information about the impact of Zika Virus on the central nervous system and, consequently, the severity and complexity of the CZS language. Over 4 years of follow-up, no evolution in language parameters was observed in children with CSZ. Children with CZS demonstrate severe neurodevelopmental impairment, stagnating in language skills at the age of 3 months. In the future, some of them may be able to communicate their basic needs through alternative communication.

Neuropsychological and quality of life outcomes in PKU patients: expert recommendations of assessment tools in Brazil / Desfechos neuropsicológicos e de qualidade de vida em pacientes com PKU: recomendações de especialistas sobre ferramentas de avaliação no Brasil

Abstract 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). Conclusions These instruments may be easily incorporated into clinical practice and improve the quality of multidisciplinary care of patients with PKU.

Resumo 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). Conclusões Estes instrumentos podem ser facilmente incorporados na prática clínica e melhorar a qualidade dos cuidados multidisciplinares dos pacientes com PKU.

Neuropsychological and quality of life outcomes in PKU patients: expert recommendations of assessment tools in Brazil.

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.

Dental treatment before surgery in a patient with cleft lip and palate: case report / Efeito do Cissus quadrangularis na cicatrização de fraturas em animais de laboratório

Introduction: orofacial clefts are common congenital malformations with an important social, psychological, and economic impact. The treatment of this condition may include different surgical procedures that previously require an adequate oral condition. Case report: we report a case of dental treatment before palatoplasty in a male patient of 17 years-old with bilateral cleft lip and palate and lesion in the jugal mucosa. Final considerations: the adequacy of the oral environment is a fundamental step in the treatment of patients with orofacial clefts and aims to restore oral health regardless of the degree of complexity of the dental treatment through the reduction of the pathogenic microbiota, elimination of retentive niches, instructions on diet and adequate oral hygiene and constant patient motivation.

Objetivos: as fissuras orofaciais são malformações congênitas comuns, com importante impacto social, psicológico e econômico. O tratamento dessa condição pode incluir vários procedimentos cirúrgicos que requerem previamente uma adequada condição bucal. Relato de caso: Relatamos o caso de tratamento odontológico prévio a palatoplastia em um paciente do gênero masculino de 17 anos de idade, com fissura transforame incisivo bilateral e lesão em mucosa jugal. Considerações finais: A adequação do meio bucal é uma etapa fundamental no tratamento de pacientes com fissuras orofaciais e visa restabelecer a saúde bucal independente do grau de complexidade do tratamento odontológico por meio da redução da microbiota patogênica, eliminação de nichos retentivos, orientações sobre dieta e higiene bucal adequada e motivação constante do paciente.

Apresentação clínica de osteogênese XV em um menino brasileiro de 4 anos / Clinical presentation of osteogenesis imperfecta XV in a four-year-old brazilian boy

Introdução: Osteogênese Imperfeita (OI) é uma doença genética rara com fragilidade óssea. A classificação inclui muitos tipos. Além do risco de recorrência, o manejo pode variar com o tipo de OI. Relato do caso: Apresentamos um paciente do sexo masculino nascido com 39 semanas, de pais não consanguíneos e saudáveis. A hidrocefalia foi diagnosticada no pré-natal. Com 50 dias de vida, detectamos muitas fraturas e calos ósseos. O teste molecular identificou uma deleção em homozigose do éxon 4 do gene WNT1. Considerações finais: Concluímos que o caso apresentado tinha características clínicas de OI XV, e o teste molecular foi fundamental para o diagnóstico preciso e aconselhamento genético.

Introduction: Osteogenesis Imperfecta (OI) is a rare genetic disease with bone fragility. The classification includes many types. In addition, the risk of a recurrence, the management can vary with the kind of OI. Case report: We report a male patient born at 39 weeks from non-consanguineous healthy parents. The patient was diagnosed with Hydrocephalus at prenatal. At 50 days of life, we detected many fractures and bone calluses. The molecular test identified a homozygous deletion of exon 4 of the WNT1 gene. Final considerations: We conclude this case had clinical features of OI XV, and the molecular test was fundamental for the precise diagnosis and the genetic counseling.

Sanfilippo syndrome type B: Analysis of patients diagnosed by the MPS Brazil Network.

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.

Identification of genomic imbalances in oral clefts

Abstract 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.

Genotype-phenotype studies in a large cohort of Brazilian patients with Hunter syndrome.

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.

Craniofacial microsomia: Reflections on diagnosis and severity assessment based on a series of cases.

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.

Long-term impact of early initiation of enzyme replacement therapy in 34 MPS VI patients: A resurvey study.

Patients with mucopolysaccharidosis type VI (MPS VI) present with a wide range of disease severity and clinical manifestations, with significant functional impairment and shortened lifespan. Enzyme replacement therapy (ERT) with galsulfase has been shown to improve clinical and biochemical parameters including patient survival, quality of life and growth. The present study is a resurvey of 34 Brazilian MPS VI patients with rapidly progressive disease (classical phenotype) who initiated ERT with galsulfase under five years of age and had been on ERT until data collection in 2019, with few exceptions (n = 4 patients who died before 2019). Anthropometric measures, urinary glycosaminoglycans, and data regarding cardiac, orthopedic, neurologic, sleep apnea, hearing and ophthalmologic outcomes were filled in by specialists. Pubertal development, clinical complications, hospitalizations, and surgeries were also assessed. In this resurvey study, treatment with galsulfase has shown to be safe and well tolerated in MPS VI patients who initiated ERT under the age of 5 years and who have been undergoing ERT for approximately 10 years. Mortality rate suggests that early initiation of ERT may have a positive impact on patients' survival, improving but not preventing disease progression and death. MPS VI patients on ERT also showed improved growth velocity and the pubertal development was normal in all surviving patients. Follow-up data on pneumonia and hospitalization suggest that early ERT may have a protective effect against major respiratory complications. Cardiac valve disease progressed since their prior evaluation and spinal cord compression was observed in a large number of patients, suggesting that these disease complications were not modified by ERT.

Neurological growth and development of children asymptomatic at birth whose mothers had Zika during pregnancy.

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.

Defining dysmorphic facial features in congenital Zika syndrome.

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.