Evaluation of newborn screening in the state of Mato Grosso from 2005 to 2019 / Avaliação da triagem neonatal no Estado de Mato Grosso no período de 2005 a 2019

ABSTRACT Objective: To evaluate quality indicators of the Neonatal Screening Referral Service of the state of Mato Grosso (NSRS-MT) from 2005 to 2019. Methods: Cross-sectional, retrospective, exploratory, descriptive, and observational study from 2005 to 2019. The following parameters were analyzed: age of newborns at the first collection, time between sample collection and arrival at the laboratory, time between the arrival and release of results and time between requesting the second sample and arrival at the NSRS. The population coverage of the program and the incidence of each clinical situation screened were also analyzed. Results: NSRS-MT coverage was analyzed and recorded as 76%. The incidence was analyzed for congenital hypothyroidism (CH) 1:1867, phenylketonuria (PKU) 1:33,311, sickle cell disease (SCD) 1:2004, cystic fibrosis (CF) 1:12,663, congenital adrenal hyperplasia (CAH) 1:15,843, and biotinidase deficiency (DB) 1:25,349. The median age (days) at the first consultation was: 44 for HC, 22 for PKU, 60 for DF, 52 for FC, 79 for HAC and 79 for DB. The mean time between exam collection and delivery to the NSRS was 8.4 days; between the arrival and release of results, 9 days; and for the return of recalls, 59 days. Conclusions: Regarding the coverage of the target population and collection at the ideal age, the NSRS-MT presents values below the national average. However, regarding the mean age at the time of the first consultation, the state's performance is better than the national.

RESUMO Objetivo: Avaliar indicadores de qualidade do Serviço de Referência em Triagem Neonatal do Estado de Mato Grosso (SRTN/MT) no período de 2005 a 2019. Métodos: Estudo transversal, retrospectivo, exploratório, descritivo e observacional, que utilizou dados do formulário FormSUS nos anos de 2005 a 2019. Foram analisados os seguintes parâmetros: idade dos recém-nascidos na primeira coleta, tempo entre coleta da amostra e chegada ao laboratório, tempo entre a chegada e a liberação dos resultados e tempo entre a solicitação da segunda amostra até a chegada ao SRTN. Foram analisadas, também, a cobertura populacional do programa e a incidência de cada situação clínica triada. Resultados: Cobertura do SRTN-MT: 76%. Incidências: hipotireoidismo congênito (HC) 1:1.867, fenilcetonúria (PKU) 1:33.311, doença falciforme (DF) 1:2.004, fibrose cística (FC) 1:12.663, hiperplasia adrenal congênita (HAC) 1:15.843 e deficiência de biotinidase (DB) 1:25.349. A mediana da idade (dias) na primeira consulta foi: 44 para HC, 22 para PKU, 60 para DF, 52 para FC, 79 para HAC e 79 para DB. A média entre a coleta do exame e a entrega no SRTN foi de 8,4 dias; entre a chegada e liberação dos resultados, de 9 dias; e para o retorno de reconvocados, de 59 dias. Conclusões: Com relação à cobertura da população alvo e a coleta na idade ideal, o SRTN apresenta valores abaixo da média nacional. Contudo, quanto à idade média no momento da primeira consulta, o desempenho de MT é melhor que a média nacional.

Hipoglicemia hipocetósica por deficiencia de carnitina en un niño

Durante el ayuno, la oxidación de ácidos grasos y la formación de cuerpos cetónicos son necesarios para la producción de energía. La carnitina es esencial para que los ácidos grasos de cadena larga se transfieran a la mitocondria para la oxidación de ácidos grasos. La deficiencia primaria de carnitina es un defecto recesivo que se expresa con un espectro clínico amplio que incluye descompensación metabólica, hipoglicemia hipocetósica o cardiomiopatía en la niñez, fatigabilidad en la adultez o ausencia de síntomas. En nuestro país no hay publicaciones sobre el tema, por lo que en el presente artículo se reporta el caso de un niño que presentó una deficiencia de carnitina expresada como hipoglicemia hipocetósica y se analiza sus hallazgos clínicos, bioquímicos e histopatológicos.

During fasting, the oxidation of fatty acids and the formation of ketone bodies are necessary for energy production. Carnitine is essential for long-chain fatty acids to be transferred to the mitochondria for fatty acid oxidation. Primary carnitine deficiency is a recessive defect that is expressed with a broad clinical spectrum that includes metabolic decompensation, hypoketotic hypoglycemia or cardiomyopathy in childhood, fatiguability in adulthood or absence of symptoms. In our country there are no publications on the subject, so this article reports the case of a child who had carnitine deficiency expressed as hypoketotic hypoglycemia and its clinical, biochemical and histopathological findings are analyzed.

Consideraciones éticas y científicas del inicio de la vida sobre el aborto eugenésico en enfermedades genéticas incapacitantes en Perú

El artículo expone conceptos actuales biológicos, así como algunos planteamientos filosóficos acerca del inicio de la vida, que se examinarán en relación con la necesidad del aborto eugenésico. Se presenta el concepto de "exdurantismo", en el que la combinación del nuevo genoma nuclear y mitocondrial hacen único al individuo; además, se concibe al complejo genómico como "integrador somático" que dirige el desarrollo embrionario, y se muestra la problemática en el caso de las violaciones que provocan embarazos, el aborto eugenésico en enfermedades genéticas incapacitantes o la utilización de embriones posterior a la fertilización in-vitro. Se plantea que la dignidad de la persona comienza desde la concepción. Frente a la detección de una enfermedad genética, grave o letal, se debe ofrecer soporte económico y social, de diagnóstico y tratamiento; además, desde la salud pública, una mayor inversión para plantear estrategias de tamizaje, diagnóstico, manejo e investigación.

The article presents current biological concepts, as well as some philosophical approaches to the beginning of life, which will be examined in relation to the need for eugenic abortion. The concept of "exdurantism" is presented, in which the combination of the new nuclear and mitochondrial genome makes the individual unique; furthermore, the genomic complex is conceived as a "somatic integrator" that directs embryonic development, and the problematic is shown in the case of rape that causes pregnancies, eugenic abortion in incapacitating genetic diseases or the use of embryos after in-vitro fertilization. The dignity of the person begins at conception. When a serious or lethal genetic disease is detected, economic and social support, diagnosis and treatment should be offered; in addition, public health should invest more in screening, diagnosis, management and research strategies.

O artigo apresenta conceitos biológicos atuais, bem como algumas abordagens filosóficas sobre o início da vida, que serão examinados em relação à necessidade do aborto eugênico. É apresentado o conceito de "exdurantismo", no qual a combinação do novo genoma nuclear e mitocondrial torna o indivíduo único; além disso, o complexo genômico é concebido como um "integrador somático" que dirige o desenvolvimento embrionário, e é mostrada a problemática no caso de estupro que resulta em gravidez, aborto eugênico em doenças geneticamente incapacitantes ou o uso de embriões após a fertilização in vitro. Argumenta-se que a dignidade da pessoa começa na concepção. Diante da detecção de uma doença genética, grave ou letal, devem ser oferecidos apoio econômico e social, diagnóstico e tratamento, bem como maior investimento em saúde pública em estratégias de triagem, diagnóstico, gestão e pesquisa.

Perfil de atención de pacientes con errores congénitos del metabolismo en un hospital pediátrico entre 2008 y 2018 / Profile of care of patients with inborn errors of metabolism in a pediatric hospital between 2008 and 2018 / Perfil do atendimento de pacientes com erros inatos do metabolismo em um hospital pediátrico entre 2008 e 2018

Resumen Los errores congénitos del metabolismo (ECM) son un grupo de enfermedades poco frecuentes que generan gran morbimortalidad. El objetivo de este trabajo fue describir el perfil de atención clínico y bioquímico de los ECM no incluidos en la pesquisa neonatal en menores de 15 años atendidos en un hospital pediátrico, entre enero de 2008 y diciembre de 2018. Se realizó un estudio descriptivo y retrospectivo en el que se evaluaron los registros hospitalarios: motivo de consulta, diagnóstico, evolución clínica, tiempos y costos diagnósticos de pacientes con sospecha y diagnóstico confirmado de ECM entre 2008 y 2018 en un hospital público pediátrico de Mendoza, Argentina. Se incluyeron 59 pacientes con ECM: enfermedades de depósito lisosomal (32,2%) y alteración metabólica de aminoácidos y acidurias orgánicas (27,1%), entre otros. La edad media fue de 2,6 años y la relación varón/mujer 1,5. La media de tiempo entre la primera consulta por sospecha de ECM y el diagnóstico fue de 11 meses. Hubo correspondencia entre el diagnóstico y el motivo de consulta (p=0,003). El 22% evolucionó al deterioro progresivo, 25,4% permanecieron estables, 28,8% con secuelas y 23,8% fallecieron. El costo directo total de los exámenes bioquímicos fue 61 560 UB=1 809 248 pesos argentinos=46 785 dólares estadounidenses (valor a finales de 2018). En conclusión, este trabajo refleja la variabilidad de los ECM, su evolución clínica, similar a lo publicado y el perfil bioquímico local.

Abstract Inborn errors of metabolism (IEM) are a group of rare diseases that cause high morbidity and mortality. The objective of the present study was to describe the clinical-biochemical profile of patients, under 15 years old, with IEM not included in newborn screening, in a pediatric hospital, from January 2008 to December 2018. A descriptive and retrospective study was carried out in which hospital records were evaluated: reason for consultation, diagnosis, clinical evolution, diagnostic times and costs of patients with suspected and confirmed diagnosis of IEM between 2008 and 2018 in a public pediatric hospital from Mendoza, Argentina. A total of 59 patients with IEM were evaluated: lysosomal storage diseases (32.2%) and metabolic alteration of amino acids and organic acidurias (27.1%), among others. The mean age was 2.6 years and the male/female ratio was 1.5. The mean time between the first consultation for suspected IEM and diagnosis was 11 months. There was correspondence between the diagnosis and the reason for consultation (p=0.003). Twenty-two percent evolved to progressive deterioration, 25.4% remained stable, 28.8% with sequelae and 23.8% died. The total direct cost of the biochemical tests was 61 560 UB=1 809 248 Argentine pesos=46 785 US dollars (value at the end of 2018). Concluding, this work reflects the variability of IEM and its clinical evolution, similar to what has been published, and the local biochemical profile.

Resumo Os erros inatos do metabolismo (EIM) são um grupo de doenças pouco frequentes que geram alta morbimortalidade. O objetivo deste trabalho foi descrever o perfil clínico e bioquímico de atendimento dos EIM não incluídos na triagem neonatal em menores de 15 anos atendidos em um hospital pediátrico, entre janeiro de 2008 e dezembro de 2018. Foi realizado um estudo descritivo e retrospectivo em que foram avaliados os registros hospitalares: motivo da consulta, diagnóstico, evolução clínica, tempos e custos diagnósticos de pacientes com diagnóstico suspeito e confirmado de EIM entre 2008 e 2018 em um hospital pediátrico público em Mendoza, Argentina. Foram avaliados 59 pacientes com EIM: doenças de depósito lisossômico (32,2%) e alteração metabólica de aminoácidos e acidúrias orgânicas (27,1%), entre outras. A média de idade foi de 2,6 anos e a relação homem/mulher foi de 1,5. O tempo médio entre a primeira consulta por suspeita de EIM e o diagnóstico foi de 11 meses. Houve correspondência entre o diagnóstico e o motivo da consulta (p=0,003). Evoluíram 22% para piora progressiva, 25,4% permaneceram estáveis , 28,8% com sequelas e 23,8% faleceram. O custo direto total dos testes bioquímicos foi de 61 560 UB=1 809 248 pesos argentinos=46 785 U$S (valor no final de 2018). Concluindo, este trabalho reflete a variabilidade da EIM e sua evolução clínica, semelhante ao que vem sendo publicado, e o perfil bioquímico local.

Manejo inicial de la hiperamonemia aguda en pediatría / Initial management of acute hyperammonemia in pediatrics

La hiperamonemia constituye una emergencia médica. No existen publicaciones que hagan referencia a la disponibilidad de recursos, insumos y conocimientos necesarios para el manejo inicial de esta por parte del pediatra en nuestro país, pero, según la experiencia de los autores, los recursos necesarios no se encuentran disponibles los 365 días del año en una gran porción de nuestro territorio. Sobre la base de este estado de situación, de una revisión bibliográfica internacional sobre el tema y de la experiencia de los autores, se elaboraron una serie de recomendaciones para el manejo pediátrico inicial de esta emergencia, que tienen como objetivo poder reducir las deficiencias, permitir una sospecha clínica adecuada que lleve a un diagnóstico y tratamiento de emergencia oportunos, con utilización racional de recursos farmacológicos (algunos de ellos de alto costo), para reducir la morbimortalidad que asocia la patología.

Hyperammonemia is a medical emergency. There are no publications regarding the availability of resources, supplies, and knowledge necessary for the initial management of hyperammonemia by pediatricians in Argentina; however, according to the authors' experience, the necessary resources are not available all year round in a large portion of our territory. Based on such state of affairs, an international bibliographic review on this topic and the authors' experience, we developed a series of recommendations for the initial pediatric management of this emergency, with the objective of reducing deficiencies, allowing adequate clinical suspicion leading to a timely diagnosis and emergency management and a rational use of pharmacological resources (some of which are costly) to reduce the morbidity and mortality associated with hyperammonemia.

Nonalcoholic fatty liver disease in adolescents with phenylketonuria

Abstract Objective: This study aimed to investigate non-alcoholic fatty liver disease (NAFLD) occurrence and factors associated with the disease in phenylketonuria (PKU) patients undergoing exclusive dietary treatment. Method: This cross-sectional study included 101 adolescents 10 to < 20 years of age with PKU, who were undergoing exclusive dietary treatment and monitored since early diagnosis at a single reference service. Anthropometric and biochemical assessments were performed and food intake was documented, and an ultrasound diagnosis of NAFLD was established. Data were evaluated using the Student's t-test for continuous variables, the chi-square for categorical variables, and logistic regression using the Wald chi-squared test; differences with p < 0.05 were considered to be statistically significant. Results: NAFLD was detected in 26 (25.7%) teenagers. There was no difference in prevalence between the sexes or nutritional status. The final logistic regression model revealed low sensitivity (26.1%) and high specificity (94.7%). The specificity suggested a lower likelihood of NAFLD in older adolescents, in the presence of normal or high levels of alkaline phosphatase, lower carbohydrate intake, and adequate protein and lipid intake. Conclusions: The prevalence of NAFLD in adolescents with PKU was higher than that found in healthy Brazilian adolescents and similar to that found in obese Brazilian children, suggesting a higher risk for NAFLD in patients with PKU treated exclusively by dietary modification.

Vaccination strategies for people living with inborn errors of metabolism in Brazil

Abstract Objective: Through a literature review, make recommendations regarding immunizations in people living with Inborn Error of Metabolism (IEM) in Brazil, assess the possible impact on metabolic decompensations after immunization, and if this specific population may have an impaired immune response to vaccines. Source of data: The MeSH Terms vaccination OR vaccine OR immunization associated with the term inborn error of metabolism AND recommendation were used in combination with search databases. Only articles published after 1990, in the languages English, Spanish, French or Portuguese, human-related were included. Synthesis of data: A total of 44 articles were included to make the following recommendations. Individuals with IEMs need to be up to date with their immunizations. Regarding which vaccines should be offered, children and adults should follow the routine immunization schedules locally available, including the COVID-19 vaccines. The only exception is the rotavirus vaccine for hereditary fructose intolerance. The benefit of immunization outweighs the very low risk of metabolic decompensation. Since not all patients will have an adequate immune response, measuring antibody conversion and titers is recommended Conclusions: All patients should receive age-appropriate immunizations in their respective schedules without delays. The only situation when vaccination may be contraindicated is with oral rotavirus vaccine in hereditary fructose intolerance. Monitoring the levels of antibodies should be done to detect any immune dysfunction or the necessity for boosters. A personalized immunization schedule is ideal for patients with IEMs. The reference organizations could improve their recommendations to address all IEMs, not only some of them.

Disease spectrum and genetic profiles of neonatal inborn errors of metabolism in selected areas of Nanning city / 中国新生儿科杂志

Objective:To study disease spectrum and genetic profiles of inborn errors of metabolism (IEM) among newborns in selected areas of Nanning city.Methods:From July 2019 to December 2021, neonates born and received IEM screening in our hospital were prospectively enrolled. Heel blood samples were tested using tandem mass spectrometry as IEM screening. Neonates with positive results were called back for recheck. Whole exome sequencing was used to detect possible pathogenic genes in suspected cases and IEM was diagnosed combining clinical manifestations. Sanger sequencing method was used for the diagnosed neonates and their parents to confirm the diagnoses.Results:A total of 16 207 live-birth neonates were enrolled. For initial IEM screening, 1 423 neonates were positive (8.8%) and 1 311 were called back (92.1%). 15 cases were suspected with IEM and 8 were diagnosed. The overall detection rate was 1∶2 026. Among 8 confirmed cases, 4 cases had amino acid metabolism disorders (2 cases of phenylketonuria, 1 case of Citrin deficiency and 1 case of tyrosinemia), 2 cases had organic acid metabolism disorders (1 case of methylmalonic acidemia and 1 case of glutaric acidemia) and 2 cases had fatty acid oxidation disorders (1 case of carnitine palmitotransferaseⅡdeficiency and 1 case of primary carnitine deficiency). 5 cases had homozygous genetic variants (2 in PAH, and 1 in SLC25A13, SLC22A5 and FAH, respectively) and 3 had heterozygous genetic variants (1 in CPT2, MUT, and GCDH, respectively). During follow-up, all 8 cases had normal growth and developmental outcomes after standardized treatment.Conclusions:The overall detection rate of IEM is high, with varied genetic profiles in selected areas of Nanning. Timely genetic testing may lead to early diagnosis and treatment and improve the quality of life of neonates.

Research progress on renal calculus associate with inborn error of metabolism / 浙江大学学报·医学版

Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.

Compounded drugs as an alternative to the therapeutical gaps of inborn errors of metabolism

Abstract Inborn errors of metabolism are rare disorders with few therapeutic options for their treatments, which can make patients suffer with complications. Therefore, compounded drugs might be a promising option given that they have the ability of meeting the patient's specific needs, (i) identification of the main drugs described in the literature; (ii) proposal of compounding systems and (iii) calculation of the budgetary addition for the inclusion of these drugs into the Brazilian Unified Health System. The research conducted a literature review and used management data as well as data obtained from official Federal District government websites. The study identified 31 drugs for the treatment of inborn errors of metabolism. Fifty eight percent (58%) (18) of the medicines had their current demand identified, which are currently unmet by the local Health System. The estimated budget for the production of compounded drugs was of R$363,16.98 per year for approximately 300 patients. This estimated cost represents a budgetary addition of only 0.17% from the total of expenditures planned for drug acquirement. There is a therapeutic gap for inborn errors of metabolism and compounding pharmacies show potential in ensuring access to medicine therapy with a low-cost investment.

Dental anomalies in syndromes displaying hypertrichosis in the clinical spectrum

Abstract Hypertrichosis and dental anomalies may occur alone or in combination in the spectrum of many syndromes. To identify genetic entities characterized by hypertrichosis and dental anomalies, a search was performed in the Mendelian Inheritance in Man database with the terms "hypertrichosis" or "hirsutism" and "tooth" or "dental abnormalities." Nondependent androgen metabolism disturbances were classified as hypertrichosis. Genetic entities with hypertrichosis and dental anomalies were included in the study. Additional searches were performed in the PubMed and Orphanet databases, when necessary, in order to include data from scientific articles. An integrative analysis of the genes associated with the identified syndromes was conducted using STRING to characterize biological processes, pathways, and interactive networks. The p-values were subjected to the false discovery rate for the correction of multiple tests. Thirty-nine syndromes were identified, and dental agenesis was the most frequent dental anomaly present in 41.02% (n = 16) of the syndromes. Causative genes were identified in 33 out of 39 genetic syndromes. Among them, 39 genes were identified, and 38 were analyzed by STRING, which showed 148 biological processes and three pathways that were statistically significant. The most significant biological processes were the disassembly of the nucleosome (GO:0006337, p = 1.09e-06), chromosomal organization (GO:0051276, p = 1.09e-06) and remodeling of the chromatin (GO: 0006338, p = 7.86e-06), and the pathways were hepatocellular carcinoma (hsa05225, p = 5.77e-05), thermogenesis (hsa04714, p = 0.00019), and cell cycle (hsa04110, p = 0.0433). Our results showed that the identification of hypertrichosis and dental anomalies may raise the suspicion of one of the thirty-nine syndromes with both phenotypes.

Dificuldades alimentares em pacientes com Fenilcetonúria / Feeding difficulties in patients with Phenylketonuria

RESUMO Objetivo analisar os resultados de um instrumento que se propõe a auxiliar na identificação das dificuldades alimentares em crianças com Fenilcetonúria (PKU), em comparação a crianças sem a doença. Método estudo transversal, controlado, com amostra de conveniência composta por pacientes com PKU e por indivíduos hígidos, equiparados por idade e sexo. O convite para participação no estudo foi feito por meio de divulgação da pesquisa nas redes sociais. As respostas foram fornecidas pelos responsáveis, sendo que 46 controles e 28 pacientes participaram. Além desses, 13 responsáveis por pacientes em acompanhamento em um Ambulatório de Tratamento de Erros Inatos do Metabolismo foram convidados por ligação telefônica, sendo que 12 aceitaram o convite. Todos os participantes responderam a Escala Brasileira de Alimentação Infantil (EBAI) de forma eletrônica. Resultados foram incluídos no estudo 86 participantes, sendo 40 pacientes (mediana de idade, 2 anos; intervalo interquartil (IQR) = 2 - 4) e 46 controles (mediana de idade, 3,5 anos; IQR = 2 - 5,25). Dez (25%) pacientes e 13 (28,3%) controles apresentaram resultados compatíveis com dificuldades alimentares, demonstrando uma frequência semelhante entre os grupos. O estudo observou que os pacientes com PKU apresentaram menos autonomia alimentar (p = 0,005), foram menos amamentados (p = 0,002) e usaram mais mamadeira que os controles (p = 0,028). Conclusão a frequência de dificuldades alimentares referidas pelos cuidadores foi semelhante entre os grupos, porém as crianças com PKU demonstraram menos autonomia para se alimentar, foram menos amamentadas e usaram mais mamadeira quando comparadas com as crianças sem a doença.

ABSTRACT Purpose to analyze the results of an instrument that aims to assist in the identification of feeding difficulties in children with Phenylketonuria (PKU), compared to children without the disease. Methods cross-sectional, controlled study with a convenience sample composed of patients with PKU and healthy individuals, matched for age and sex. The invitation to participate in the study was made through the dissemination of the research on social networks. The answers were provided by the guardians, 46 controls and 28 patients agreed to participate. In addition to these, 13 guardians of patients being followed up at an Outpatient Clinic for the Treatment of Inborn Errors of Metabolism were invited by phone call, and 12 accepted the invitation. All participants answered the Brazilian Infant Feeding Scale (in Portuguese Escala Brasileira de Alimentação Infantil (EBAI)) electronically. Results the study included 86 participants, 40 patients (median of age = 2 years; interquartile range (IQR) = 2 - 4) and 46 controls (median of age = 3.5 years; IQR = 2 - 5.25). Ten (25%) patients and 13 (28.3%) controls had suspicion of feeding difficulties, demonstrating a similar frequency of feeding difficulties between groups. The study found that PKU patients had less feed autonomy (p = 0.005), were less breastfed (p = 0.002) and used more baby's bottle than controls (p = 0.028). Conclusion the frequency of feeding difficulties reported by caregivers was similar between the comparison groups, but children with PKU had less feed autonomy, were less breastfed and used more baby's bottles when compared to children without the disease.

Immediate adverse events to intravenous immunoglobulin in pediatric patients with inborn errors of immunity: A longitudinal study with a pre-infusion protocol

Introduction Immunoglobulin represents the main therapy for patients with inborn errors of immunity (IEI) and it is a safe procedure, but adverse events (AEs) can occur with variable frequencies. Objective To evaluate the frequency of immediate AEs to intravenous immunoglobulin (IVIG) regular therapy in a pediatric cohort with IEI after a pre-IVIG infusion protocol. Methods This was a longitudinal study from 2011 to 2019 at a tertiary pediatric hospital in Brazil. Results A total of 1736 infusions were studied in 70 patients with IEI, 46 (65.7%) of whom were males and whose median age was 5.8 years old (range: 6 mo - 18 yo). Seven different brands of IVIG were used with the median loading dose of 0.57g/kg (range: 0.23 - 0.88g/Kg). According to the protocol, pre-medication and step-up infusion rate, were performed in 1305 (75.2%) infusions. Immediate AEs were noted in 10 children (14.3%) and in 22 (1.2%) infusions. Skin reactions (rash or urticaria) were the most common AE with 14 episodes (0.8% of all infusions). Almost all AEs were mild (19/86.4%), with no severe ones being observed. The majority of the AEs (81.8%) was identified at a 0.04ml/kg/min infusion rate. Gender, age at first infusion, presence of infection on the infusion day and change of the IVIG brand were evaluated and none of them were associated with AEs. Conclusion The low frequency of immediate AEs in children with IEI highlights the safety and tolerability of intravenous immunoglobulin replacement with the procedures established at our center.

Patient care in cystic fibrosis centers: a real-world analysis in Brazil / Assistência ao paciente em centros de fibrose cística: análise do mundo real no Brasil

ABSTRACT Objective: To analyze the characteristics of cystic fibrosis (CF) care centers (CFCCs) in Brazil. Methods: A questionnaire was sent to the coordinators of all 51 registered CFCCs between May and September of 2021. Results: The response rate was 100%. Southeastern Brazil is the region where most of the CFCCs in the country are located (21 centers; 41%), followed by the southern and northeastern regions (11 centers each; 21.5%), the central-western region (6; 12%), and the northern region (2; 4%). A total of 4,371 patients with CF were cared for in Brazil during the study period, ranging from 7 to 240 patients per center (mean, 86 patients/center; median, 75 patients/center); 2,197 patients (50%) were cared for in centers in the southeastern region of the country, particularly in the state of São Paulo (33%), the remaining patients being treated in southern Brazil (1,014 patients, 23%), northeastern Brazil (665 patients, 15%), central-western Brazil (354 patients, 8%), and northern Brazil (141 patients, 4%). Overall, 47 centers (92%) reported having an incomplete multidisciplinary team; 4 (8%) lacked essential team members; 6 (12%) lacked a physical therapist; 5 (10%) lacked a dietitian; 17 (33%) lacked outpatient nursing care; 13 (25%) lacked outpatient social work services; 14 (27%) lacked a psychologist; and 32 (63%) lacked a clinical pharmacist. Seven CFCCs (14%) in the northern and northeastern regions of Brazil reported that the quality of newborn screening for CF was poor. All centers reported having difficulties in accessing CF medications. Conclusions: Brazilian CFCCs experience multiple problems, including inadequate staffing, infrastructure, testing, and medication supply. There is an urgent need to regulate the implementation of CF referral centers and an appropriate network structure for the diagnosis and follow-up of CF patients using optimal treatment recommendations.

RESUMO Objetivo: Analisar as características dos centros de tratamento de fibrose cística (CTFC) no Brasil. Métodos: Entre maio e setembro de 2021, um questionário foi enviado aos coordenadores de todos os 51 CTFC registrados. Resultados: A taxa de resposta foi de 100%. O Sudeste do Brasil é a região onde está a maioria dos CTFC do país (21 centros; 41%), seguida pelas regiões Sul e Nordeste (11 centros cada; 21,5%), Centro-Oeste (6; 12%) e Norte (2; 4%). No total, 4.371 pacientes com fibrose cística (FC) foram atendidos no Brasil durante o período do estudo, variando de 7 a 240 pacientes por centro (média de 86 pacientes/centro; mediana de 75 pacientes/centro); 2.197 pacientes (50%) foram atendidos em centros da região Sudeste, particularmente no estado de São Paulo (33%), e os demais receberam atendimento nas regiões Sul (1.014 pacientes, 23%), Nordeste (665 pacientes, 15%), Centro-Oeste (354 pacientes, 8%) e Norte (141 pacientes, 4%). Do total de CTFC, 47 (92%) relataram que a equipe multidisciplinar estava incompleta; em 4 centros (8%), as equipes multidisciplinares careciam de membros essenciais; 6 centros (12%) careciam de fisioterapeuta; 5 (10%) careciam de dietista; 17 (33%) careciam de cuidados ambulatoriais de enfermagem; 13 (25%) careciam de serviços ambulatoriais de assistência social; 14 (27%) careciam de psicólogo e 32 (63%) careciam de farmacêutico clínico. Sete CTFC (14%) nas regiões Norte e Nordeste relataram que a qualidade da triagem neonatal de FC era ruim. Todos os centros relataram dificuldades de acesso a medicamentos para FC. Conclusões: Os CTFC brasileiros enfrentam múltiplos problemas: pessoal inadequado, infraestrutura inadequada, testes inadequados e fornecimento inadequado de medicamentos. Há uma necessidade urgente de regulamentar a implantação de centros de referência em FC e de uma rede adequada para o diagnóstico e acompanhamento de pacientes com FC com base nas recomendações para o tratamento ideal da doença.

Advances in genetics and prevention of monogenic global developmental delay and intellectual disability / 中华围产医学杂志

Global developmental delay/intellectual disability (GDD/ID) is an enormous group of neurodevelopmental disorders with diverse clinical and genetic heterogeneity. The estimated prevalence of GDD/ID was 1%-3%, affecting about 150 million people. GDD/ID is one of the leading causes of disability in children worldwide. The causes of GDD/ID are complex, comprising genetic and environmental factors. It is often co-morbid with a variety of psychiatric behavioral disorders, such as autism spectrum disorder and attention deficit hyperactivity disorder. Owing to the improvement of genetic technology, monogenic GDD/ID has been one of the hot-spot research in genomic era, and the relevant preventive measures deserve extensive attention. In this review, we summarized the advances in genetics and prevention of monogenic GDD/ID.

Lethal mitochondrial trifunctional protein deficiency caused by HADHB gene variation: a case report / 中华围产医学杂志

This article reported a male neonate with lethal mitochondrial trifunctional protein deficiency (MTPD) caused by compound heterozygous variations in the HADHB gene. The patient presented with poor milk intake complicated by abnormal myocardial enzymes within 24 h after birth and was transferred to the Children's Hospital of Nanjing Medical University on day 4. Physical examination revealed no obvious abnormalities on admission. Laboratory examination showed increased creatine kinase isoenzyme and cardiac troponin levels, and electrocardiogram suggested sinus tachycardia and low QRS voltage in limb leads. Blood screening for metabolic abnormalities showed high levels of tetradecenyl carnitine and various 3-hydroxycarnitines. Heterozygous mutations of c.739C>T(p.Arg247Cys) and c.607C>T(p.Arg203Ter,272) were detected in the HADHB gene in the boy, which were pathogenic variants included in the Human Gene Mutation Database. Followed up to three months of age, the boy was readmitted to hospital due to poor milk intake for one week and poor response for 2 d after catching a cold. After admission, he quickly developed multiple organs dysfunction such as heart failure and respiratory failure, and then died. Lethal MTPD is rare with no effective treatment and poor prognosis. Lethal MTPD should be highly suspected when unexplained cardiomyopathy, hypoglycemia, acidosis and other metabolic abnormalities appear in the neonatal period, and an early diagnosis could be confirmed with genetic testing in the neonatal period.

Curry-Jones syndrome: the first case reported in China / 中华皮肤科杂志

A 3-year-6-month-old boy presented with multiple asymptomatic banded white macules at birth, which expanded in proportion to his body, and deformity of his right thumb with slight dyskinesia. The patient showed difficulty in communication and concentration compared with children of the same age. The family history was unremarkable. The child had clear consciousness, passable spirits, and poor language ability. Physical examination revealed a special face and slight macrodactyly of the right thumb joints, and the heart, lung, and abdominal examination was otherwise normal. Skin examination showed multiple banded or confluent irregular white macules of varying sizes and slightly elevated plaques distributed along the Blaschko′s lines on the right chest, the flexor aspect of the right upper limb, the median line of the lower abdomen, and the right lower limbs, and banded brown macules on the palmar side of the right hand and radial aspect of the right thumb. Histopathological findings of the while macule on the lower limb were consistent with basaloid follicular hamartoma. Cranial magnetic resonance imaging revealed agenesis of the corpus callosum. Whole-exome sequencing of the lesional tissue showed a mutation c.1234C>T (p.L412F) in the SMO gene, which was not found in his parents. A diagnosis of Curry-Jones syndrome was made based on the skin lesions, and pathological and genetic findings. The mutation c.1234C>T (p.L412F) in the SMO gene may contribute to the disease. The patient continued functional exercises to improve the mobility of his right thumb, and underwent a close follow-up.

Córnea plana congénita y error innato del metabolismo en un niño

Introducción: La córnea plana congénita es una rara anomalía de herencia autosómica dominante o recesiva. Los defectos del ciclo de la urea son errores innatos del metabolismo que puede producir encefalopatía progresiva. Objetivo: Describir las características clínicas de un paciente con diagnósticos de córnea plana congénita y error innato del metabolismo. Presentación del caso: Paciente masculino de 7 años de edad, miembro de la cuarta generación de una familia con diagnóstico de córnea plana congénita. Al examen oftalmológico se observó en ambos ojos esclerización superior del limbo, aplanamiento corneal generalizado y cámaras anteriores estrechas. La topografía corneal mostró patrones esféricos y aplanamiento corneal más prominente en la media y extrema periferia. A la edad de 5 años comenzó a presentar ataxia recurrente, crisis epilépticas de inicio focal motoras clónicas en el hemicuerpo derecho y vómitos. Ingresó en estado de coma en la unidad de cuidados intensivos pediátricos del Hospital Pediátrico Universitario "William Soler". Se planteó encefalopatía progresiva por trastorno en el ciclo de la urea luego de constatarse hiperamonemia (error congénito del metabolismo), sin acidosis metabólica. Conclusiones: La córnea plana congénita es una enfermedad caracterizada por aplanamiento corneal generalizado con repercusión en la calidad visual. Los errores innatos del metabolismo debidos a trastornos en el ciclo de la urea se caracterizan por manifestaciones neurológicas graves con peligro potencial para la vida. Resulta novedosa la presentación de estas dos enfermedades infrecuentes en un mismo paciente, asociación que no aparece publicada con anterioridad.

Introduction: Congenital flat cornea is a rare anomaly of dominant or recessive autosomal inheritance. Urea cycle defects are inborn errors of metabolism that can lead to progressive encephalopathy. Objective: To describe the clinical characteristics of a patient with diagnoses of congenital flat cornea and inborn error of metabolism. Case Presentation: A 7-year-old male patient, member of the fourth generation of a family diagnosed with congenital flat cornea. Ophthalmological examination showed upper limbal sclerization, generalized corneal flattening and narrow anterior chambers in both eyes. Corneal topography showed more prominent spherical patterns and corneal flattening in the middle and extreme periphery. At the age of 5 years, he began to present recurrent ataxia, focal onset epileptic seizures of clonic motor in the right hemibody and vomiting. He was admitted in a coma in the pediatric intensive care unit of "William Soler" University Pediatric Hospital. Progressive encephalopathy was stated due to disorder in the urea cycle after hyperammonemia (congenital error of metabolism) was observed, without metabolic acidosis. Conclusions: Congenital flat cornea is a disease characterized by generalized corneal flattening with an impact on visual quality. Inborn errors of metabolism due to disorders in the urea cycle are characterized by severe neurological manifestations with potential danger to life. The presentation of these two rare diseases in the same patient is novel; an association that has not been published previously.

Nueva mutación en el gen KMT2B como causa de distonía generalizada de inicio temprano: reporte de caso / Early-onset generalized dystonia caused by a new mutation in the KMT2B gene: Case report

La distonía por mutación en el gen KMT2B es un subtipo recientemente descrito del inicio focal de la enfermedad en los miembros inferiores que, posteriormente, evoluciona a una forma generalizada con compromiso cervical y orofaríngeo, disartria, trastorno secundario de la deglución y discapacidad intelectual. Se describe el caso de una escolar de 10 años de edad, sin antecedentes de consanguinidad ni historia familiar de enfermedad neurológica, que presentó alteración de la marcha y distonía de inicio focal, de curso progresivo a una forma generalizada que afectó sus músculos orofaciales y bulbares con alteración significativa del lenguaje y la deglución. Los estudios metabólicos y sistémicos, incluidas las neuroimágenes, no evidenciaron anormalidades. Se hizo una secuenciación genómica completa y se identificó una nueva variante, probablemente patogénica heterocigota, en el gen KMT2B, la c.1205delC, p.(Pro402Hisfs*5), que causa desplazamiento en el marco de lectura. Este hallazgo explica el fenotipo de la paciente y la distonía de inicio temprano autosómica dominante. Se reporta una nueva mutación heterocigota del gen KMT2B como causa de distonía generalizada de inicio temprano, no reportada en la literatura especializada hasta el momento. El diagnóstico de esta afección tiene implicaciones en el tratamiento y el pronóstico de los pacientes, porque las estrategias terapéuticas tempranas pueden prevenir su rápido deterioro y un curso más grave de la enfermedad.

Introduction: KMT2B-related dystonia is a recently described subtype of focal-onset dystonia in the lower limbs, evolving into a generalized form with cervical, oropharyngeal involvement, dysarthria, swallowing disorder and intellectual disability. Clinical case: We describe the case of a 10-year-old female patient, without a history of consanguinity or neurological disease. She manifested abnormal gait and dystonia with focal onset and progressive course with evolution into generalized dystonia, affecting orofacial and bulbar muscles, significant alteration of language and swallowing. Metabolic and systemic studies, including neuroimaging, were found to be normal. A complete genomic sequencing study was performed identifying a new, probably pathogenic, heterozygous variant in the KMT2B gene, c.1205delC, p. (Pro402Hisfs*5), causing displacement in the reading frame, a finding that explains the patient's phenotype and it is associated to autosomal dominant childhood-onset dystonia-28. Conclusion: We report a new heterozygous mutation in the KMT2B gene as a cause of generalized early-onset dystonia not reported in the literature until the date. The diagnosis of this pathology has implications for the treatment and prognosis of patients, given that therapeutic strategies implemented early can prevent the fast deterioration and severe course of this disease.

Síndrome de Marfan. Presentación de un caso / Marfan syndrome. A case report

RESUMEN El síndrome de Marfan es una enfermedad genética autosómica dominante del tejido conectivo, caracterizada por una combinación variable de manifestaciones cardiovasculares, músculo-esqueléticas y oftalmológicas. A pesar del descubrimiento de las mutaciones causales, su diagnóstico resulta complejo, al exhibir una gran diversidad en su presentación clínica y carecer de características patognomónicas. El diagnóstico actual de síndrome de Marfan se basa en una serie de criterios clínicos y genéticos denominados Criterios Gante revisados. Se describe el caso de una paciente de 44 años de edad, con antecedentes de luxación del cristalino, miopía y escoliosis, sin antecedentes patológicos familiares y que cumplió con los criterios diagnósticos actuales. Se sugiere la pesquisa etiológica de afecciones como luxación del cristalino y escoliosis, por parte de las especialidades correspondientes, como traducción orgánica de una enfermedad sistémica como el síndrome de Marfan.

ABSTRACT Marfan syndrome is an autosomal dominant genetic disease of connective tissue, characterized by a variable combination of cardiovascular, musculoskeletal, and ophthalmologic manifestations. Despite the discovery of the causal mutations, its diagnosis is complex, as it exhibits great diversity in its clinical presentation and lacks pathognomonic characteristics. The current diagnosis of Marfan syndrome is based on a series of clinical and genetic criteria called the revised Ghent Criteria. The case of a 44-years-old female patient with a history of lens dislocation, myopia and scoliosis, with no family pathological history and who met current diagnostic criteria is described. The etiological investigation of conditions such as lens dislocation and scoliosis is suggested, by the corresponding specialties, as an organic translation of a systemic disease such as Marfan syndrome.