The newborn screening tests in Brazil: regional and socioeconomic prevalence and inequalities in 2013 and 2019

Abstract Objective: To analyze the prevalence evolution of Guthrie, hearing, and eye screening testing among newborns in Brazil, between 2013 and 2019, according to demographic and socioeconomic characteristics. Methods: This is a cross-sectional study with data from 5231 infants from the Pesquisa Nacional de Saude (PNS), in 2013, and 6637 infants, in 2019, for the Guthrie test, hearing, and red reflex tests. The authors analyzed the outcomes according to the region of residence, self-reported color/race, having health insurance, and per capita household income. By using bivariate and multivariate Poisson regression models, the prevalence ratios and their respective 95 % Confidence Intervals (CI95%) were calculated for each year. Results: In 2013, Guthrie test, hearing, and red reflex tests were performed in 96.5 % (95%CI 95,8;97,0), 65.8 % (95%CI 63,9;67,7), and 60.4 % (95%CI 58,5;62,3) of infants, respectively. In 2019, the prevalence was 97.8 % (95%CI 97,3;98,2) in the Guthrie test, 81.6 % (95%CI 80,3;82,9) in the hearing test, and 78.6 % (95%CI 77,1;79,9) in the red reflex test. The testing frequency was higher among residents of the Southeast and South regions of Brazil, among infants whose mother or guardian was white, had health insurance, and was in the higher income strata; and the most evident differences were in the eye and hearing testing. Conclusions: The coverage inequalities according to the region of residence, income, and having health insurance highlight the need to use strategies that enable exams to be carried out, with more information about their importance, encompassing actions from primary care, prenatal care to the puerperium, aiming at universal access and equity.

Controles de calidad externos en el diagnóstico molecular de enfermedades genéticas. Impacto sobre la calidad de los estudios genéticos / External quality controls in the molecular diagnosis of genetic diseases. Impact on the quality of the genetic studies / Controles de qualidade externos no diagnóstico molecular de doenças genéticas. Impacto na qualidade dos estudos genéticos

Resumen La participación en programas de evaluación externa de la calidad (PEEC) dirigidos al diagnóstico de enfermedades genéticas permite obtener una medida objetiva del desempeño técnico y analítico de los laboratorios y es un requisito para la acreditación de los laboratorios clínicos bajo la norma ISO 15189. El objetivo de este estudio fue evaluar retrospectivamente el desempeño en los esquemas EMQN (European Molecular Genetics Quality Network) y CF Network (Cystic Fibrosis European Network) en el período 2014-2022. Se participó en un total de 88 esquemas. Se recolectó la información de nuestros puntajes y las medias de los laboratorios participantes en las categorías genotipificación, interpretación y exactitud de la información del paciente/informe. Se informó en forma completa el 90,9% (n=80) de los esquemas. El desempeño en genotipificación mostró puntajes superiores a la media en el 89,3% de los esquemas; 0,8% de los informes correspondieron a falsos negativos. En interpretación, el 66,7% de los esquemas evidenció un desempeño superior a la media y el 33,3% debajo de la media. La exactitud de la información del paciente/informe presentó puntajes superiores a la media en el 97,6% de los esquemas. Se observó una diferencia estadísticamente significativa en el porcentaje de esquemas con puntaje por encima de la media en el año 2022 (10/12 esquemas) respecto al año 2014 (1/6 esquemas) en la categoría interpretación (p=0,0128). En conclusión, la participación regular en PEEC tuvo impacto positivo en la calidad de los estudios y permite realizar mejoras continuas a partir de las recomendaciones sugeridas por estos programas.

Abstract Participation in external quality assessment programmes focused on rare genetic diseases makes it possible to assess the laboratory technical and analytical performance and it is a prerequisite for accreditation according to ISO 15189. The objective of this study was to perform a retrospective evaluation of our performance in the EMQN (European Molecular Genetics Quality Network) and the CF Network (Cystic Fibrosis European Network) programmes in the 2014-2022 period. The laboratory performance on genotyping, interpretation and clerical accuracy and patient identifiers in a total of 88 schemes were assessed. The information of our scores and the mean scores of all participating laboratories in the three categories were collected. A total of 90.9% of the schemes were fully completed. The performance in genotyping showed scores above the mean scores in 89.3% of the schemes; 0.8% of the reports correspond to false negative results. Regarding interpretation category, 66.7% of the schemes presented scores above the mean scores and 33.3% below the mean scores. The clerical accuracy and patient identifiers were above the mean scores in 97.6% of the schemes. A statistically significant difference in the percentage of schemes with a score above the mean for the interpretation category in the year 2022 (10/12 schemes) was observed compared to the year 2014 (1/6 schemes) (p=0.0128). In conclusion, regular participation in external quality assessment programmes had a positive impact on the quality of the studies and allows for continuous improvements based on the recommendations suggested by these programmes.

Resumo A participação em programas de avaliação externa da qualidade (PEECs) voltados para o diagnóstico de doenças genéticas permite obter uma mensuração objetiva do desempenho técnico e analítico dos laboratórios e é requisito para a acreditação dos laboratórios clínicos sob a norma ISO 15189. O objetivo desse estudo foi avaliar retrospectivamente o desempenho nos esquemas EMQN (European Molecular Genetics Quality Network) e CF Network (Cystic Fibrosis European Network) no período 2014-2022. Participou-se em um total de 88 esquemas. Foram coletadas informações de nossos escores e das médias dos laboratórios participantes nas categorias genotipagem, interpretação e precisão da informação do paciente/laudo. 90,9% (n=80) dos esquemas foram informados em sua totalidade. O desempenho na genotipagem apresentou escores acima da média em 89,3% dos esquemas; 0,8% dos laudos corresponderam a falsos negativos. Na interpretação, 66,7% dos esquemas apresentaram desempenho acima da média e 33,3% abaixo da média. A precisão das informações do paciente/laudo apresentou escores acima da média em 97,6% dos esquemas. Observou-se diferença estatisticamente significativa no percentual de esquemas com pontuação acima da média no ano de 2022 (10/12 esquemas) em relação ao ano de 2014 (1/6 esquemas) na categoria interpretação (p=0,0128). Em conclusão, a participação regular em PEECs teve um impacto positivo na qualidade dos estudos e permite fazer melhorias contínuas com base nas recomendações sugeridas por esses programas.

Borderline ovarian tumors: a review of its biology, molecular profile, and management / Tumores borderline de ovário: uma revisão de sua biologia, perfil molecular e manejo

Borderline ovarian tumors typically exhibit indolent behavior and boast a favorable prognosis; however, a subset of patients experiences disease recurrence and progression to low-grade ovarian carcinoma. The complex biology underlying these phenomena has been illuminated through molecular analyses. KRAS and BRAF mutations have emerged as recurrent ?ndings in borderline ovarian tumors. Speci?cally, KRAS mutations have been linked to a higher risk of recurrence and progression to low-grade ovarian carcinoma, while BRAF mutations seem to confer a protective e?ect, inducing a senescent state that mitigates the likelihood of progression. In this comprehensive review, we explore the biology and the molecular pro?le of borderline ovarian tumors, shedding light on recent discoveries that have enriched our comprehension. Additionally, we discuss the current state of borderline ovarian tumors management. Surgery remains the cornerstone of treatment. While cytotoxic therapies role is limited so far, molecular characterization emphasizes the imminent potential for personalized therapeutic approaches.

Os tumores borderline de ovário geralmente exibem comportamento indolente e apresentam prognóstico favorável; no entanto, um subconjunto de pacientes apresenta recorrência da doença e progressão para carcinoma de ovário de baixo grau. A biologia complexa subjacente a estes fenômenos foi iluminada através de análises moleculares. Mutações KRAS e BRAF surgiram como achados recorrentes em tumores borderline de ovário. Especificamente, as mutações KRAS têm sido associadas a um maior risco de recorrência e progressão para carcinoma de ovário de baixo grau, enquanto as mutações BRAF parecem conferir um efeito protetor, induzindo um estado senescente que mitiga a probabilidade de progressão. Nesta revisão abrangente, exploramos a biologia e o perfil molecular dos tumores borderline de ovário, lançando luz sobre descobertas recentes que enriqueceram nossa compreensão. Além disso, discutimos o estado atual do manejo de tumores borderline de ovário. A cirurgia continua sendo o pilar de tratamento. Embora o papel das terapias citotóxicas seja limitado até o momento, a caracterização molecular enfatiza o potencial iminente para abordagens terapêuticas personalizadas.

Let ′Rare Disease′ Been Seen: Delving into the Building up of Resource and Information Service in Medical Libraries for Rare Diseases / 罕见病研究

With the development of the diagnosis and treatment for rare diseases and the promotion of the construction of ′Double First-Class′ Universities in China, the libraries of medical schools have to make full use of their strengths to better face new challenges in discipline construction proactively. This article refers to resource and information service practices related to the rare disease carried out by medical libraries in China and in other countries; explores the possibilities of building up the resource and information in the future, aiming at improving the awareness of rare diseases among medical students, researchers, and the general public. The article also focuses on the need for strengthening the support for teaching and research into rare diseases, hoping to contribute to the overall improvement of the diagnosis, treatment, and educational research in rare diseases in China.

The Research Progress of Visual Snow Syndrome / 罕见病研究

Visual snow syndrome(VSS)is a visual-disturbance disease characterized by continuous flickering tiny dots in the entire visual field, sometimes with visual symptoms like photophobia or nyctalopia and non-visual symptoms such as anxiety and depression.VSS can remain stable or worsen, causing distress to patients′ visual experience and mental state. The pathological mechanism of VSS is still unclear and a hypothesis indicates a relationship between VSS and increased cortical excitability of the visual cortex. Some case reports suggest anti-seizure medications, colored filters and TMS may help eliminate symptoms, but futher studies are required to verify these treatments. This review will systematically introduce what we know about VSS so far.

Advancements in the Diagnosis and Treatment of Rare Kidney Diseases / 罕见病研究

Rare kidney diseases constitute a significant factor leading to kidney failure with many having a hereditary basis. The incidence of inherited disorders contributing to adult chronic kidney disease is lower compared to that in children; however, up to 10% of adult patients with chronic kidney disease are affected by a single-gene pathogenic variant. Over the past decade, sequencing technologies have become widely utilized in clinical settings, undergoing continuous iterations and updates to enhance the diagnosis of rare kidney diseases. Simultaneously, the field confronts numerous challenges, particularly in the development and application of novel therapeutic drugs. In an era crucial development, China is set to publish rare disease catalogs in 2018 and 2023, a move that holds the promise of comprehensively advancing the diagnosis, treatment, and research of rare kidney diseases in the country.

A Case Report of Surgical Resection of Tuberous Sclerosis Complex Related Renal Giant Angiomyolipoma / 罕见病研究

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disease that affects multiple organs and systems throughout the body. TSC-associated kidney disease is the leading cause of death in adult TSC patients. This article retrospectively analyzed the characteristics of one TSC-related renal giant angiomyolipoma(RAML)treated with surgery. The patient, 25 years old, was diagnosed with tuberous sclerosis complex in 2000 due to multiple maculopapular rashes on both cheeks. At a regular follow-up in July 2019, imaging examinations revealed a tumor in the left lower quadrant with a maximum cross-sectional area of 16 cm×7 cm. Genetic testing showed a loss of heterozygosity in the EX18_ 41 of TSC2. After the diagnosis was confirmed, open left partial nephrectomy was performed, during which multiple tumors were found on the kidney surface and the largest one was located on the ventral side with a diameter of approximately 20 cm. After the renal artery was occluded, kidney tumors were completely enucleate. Postoperative pathological confirmed the diagnosis of angiomyolipoma. This case provides a reference for the treatment of TSC-related renal giant hamartoma.

A Case of Dent Disease in Children Presenting with Massive Proteinuria / 罕见病研究

This article reported the diagnosis and treatment of a boy with Dent disease presenting with massive proteinuria.He was 3 years old and found to have massive proteinuria during routine physical examination without hypoalbuminemia, urine protein electrophoresis indicated mainly low molecular weight proteins, with hypercalciuria, and metabolic acidosis, no diabetes, no amino acid urine, and renal ultrasound showed no renal calcium deposition, He had no mental and physical developmental delay and no abnormal family history. Gene detection revealed one missense mutation in exon 15 of the OCRL1 gene, c.1477C > T (p.Arg493Trp). After the diagnosis was confirmed, restrictions in dietary intake of calcium, sodium, and oxalate was restricted and oral potassium citrate and hydrochlorothiazide was prescribed. During two months of follow-up, we observed a decrease in urinary calcium levels and normal renal function. This article aims to improve the understanding of this disease among physicians and provide reference for the diagnosis and treatment of this disease through typical case report and review of previous literatures.

New Advances in the Use of 18F-FET PET in the Diagnosis and Management of Adult High-Grade Gliomas / 罕见病研究

Gliomas are the most common primary intracranial tumors in adults, among which high-grade glioma patients are characterized by short survival and poor prognosis. The diagnosis, treatment, evaluation of effective treatments, and prognosis prediction of high-grade gliomas are of great significance for improving patient survival. Conventional enhanced magnetic resonance imaging has deficiencies in delineating tumor extent, identifying tumor progression and treatment-related changes. Therefore, there is a broad consensus to incorporate amino acid PET, and 18F-FET PET inparticular, into the diagnostic and therapeutic process of high-grade gliomas. In this article, we review the new research progress of 18F-FET PET in the diagnosis and treatment of adult high-grade glioma in recent years.

Rare Genetic Kidney Diseases: Windows of Precision Nephrology / 罕见病研究

As an important category of rare diseases, rare genetic kidney diseases have many types. In recent years, their diagnosis, treatment, research and management strategies have made great progress. Continuously more new genes and mechanisms have been discovered, giving rise to new technologies and drugs for precision medicine and clinical applications. This article systematically analyzes rare diseases involving the urinary system listed in the catalog of rare diseases in China, gives examples to illustrate the research and management methods for the diagnosis and treatment of rare genetic kidney diseases, promotes clinical applications of new drugs by expanding physiological mechanisms, introduces the application of special blood purification in the field of critical rare diseases, and provides an outlook forward to the future prospects of precise diagnosis and treatment of rare kidney diseases in China.

Consideration of Ethical Protection in Drug Clinical Trials for Rare Diseases in Children / 中国医学伦理学

Children with rare disease belong to a vulnerable group. When China’s current medical security system cannot provide comprehensive health care, they not only face physical and mental torture, but also have a higher risk of children participating in clinical trials than adults. So, adequate protection of children’s safety and rights is the key to ethical review. This paper analyzed the current status of drugs clinical trials for rare disease in children, including trial difficulties and guarantee system; explained the ethical principles that should be followed in clinical trials, such as the principle of informed consent and the principle of no harm; and discussed the path of protecting children’s safety and rights, so as to raise awareness and attention of the importance of ethical review of clinical trials.

Desafíos en el empleo de los medicamentos huérfanos

Las enfermedades raras son aquellas que tienen baja prevalencia y que, por lo tanto, el desarrollo de medicamentos para tratarlas no es rentable para las empresas farmacéuticas debido a la baja demanda. A pesar de que ya se cuenta con diferentes políticas públicas alrededor del mundo para incentivar a las industrias farmacéuticas a investigar estos medicamentos, conocidos como medicamentos huérfanos, su desarrollo conlleva muchas dificultades en las evaluaciones clínicas y el precio final para el público es muy elevado. Si bien en años recientes se ha planteado el uso de tecnología de impresión en 3D para producir estos medicamentos o incluso recurrir a otros medicamentos previamente aprobados para tratar enfermedades raras, existe un historial de mal uso de las legislaciones por parte de las empresas con el fin de generar beneficios comerciales, por lo que estas políticas deben reforzarse para que cumplan su propósito; ayudar a una población muy vulnerable. El objetivo del presente texto es exponer los resultados de una revisión documental sobre el panorama científico y sociopolítico en el que se encuentra el problema de las enfermedades raras y los medicamentos huérfanos, así como las posibles soluciones que se están desplegando para abordarlo. Deriva de un estudio que se desarrolla en el momento actual en la Universidad Autónoma Metropolitana, de Ciudad de México.

The strange illnesses are those that have low prevalence and that, therefore, the development of medications to treat them is not profitable for the pharmaceutical companies due to the drop demands. Although it is already counted with different political public around the world to motivate to the pharmaceutical industries to investigate these medications, well-known as orphan medications, their development bears many difficulties in the clinical evaluations and the final price for the public it is very high. Although in recent years he/she has thought about the use of impression technology in 3D to produce these medications or even to appeal to other medications previously approved to treat strange illnesses, a record of wrong use of the legislations exists on the part of the companies with the purpose of generating commercial benefits, for what these politicians should be reinforced so that they complete its purpose; to help a very vulnerable population. The objective of the present text is to expose the results of a documental revision on the scientific and sociopolitical panorama in which is the problem of the strange illnesses and the orphan medications, as well as the possible solutions that they are spreading to approach it. It derives of a study that is developed in the current moment in the Metropolitan Autonomous University, of Mexico City.

Enfermedades sin diagnostico y enfermedades raras: avances en neurodesarrollo / Rare diseases and undiagnosed diseases: advances in neurodevelopment

Resumen Las enfermedades raras y enfermedades sin diag nóstico se han posicionado en los últimos años como condiciones clínicas que han permitido avanzar el en tendimiento de las funciones de los genes y el im pacto en el desarrollo del individuo. En esta revisión, presentamos como los esfuerzos individuales hechos por muchos años para entender la fisiopatología de en fermedades comunes, enfermedades raras y otras aún más raras, como las enfermedades sin diagnóstico, que se unen hoy para, de manera cooperativa, avanzar en el conocimiento científico. Estos avances en el conoci miento permiten aplicar los avances obtenidos en un grupo de condiciones clínicas a otras con características fenotípicas similares o viceversa. El trabajo conjunto de equipos multidisciplinarios y la comunicación entre clínicos e investigadores proporcionarán oportunidades para proveer mejores oportunidades de tratamiento para pacientes y familias a lo largo de múltiples diagnósticos comunes o raros.

Abstract Rare diseases and undiagnosed diseases have re cently positioned themselves as clinical entities that provide important opportunities to advance our under standing of gene functions and the impact of them in the individual development. In this review, we present how efforts made over years to understand common diseases, rare diseases and even undiagnosed diseases come together today to cooperatively advances scientific knowledge. These advance in science and new acquired knowledge, make possible to apply the advances ob tained in a group of clinical conditions to others with similar phenotypic characteristics or vice versa. The cooperative work of multidisciplinary teams and the communication between clinicians and researchers have and will provide opportunities for better treatments for patients and families across multiple common and rare diseases.

Síndrome de Klippel-Trenaunay-Weber. Presentación de un caso y revisión de la literatura

El síndrome de Klippel-Trenaunay-Weber es una malformación vascular congénita poco frecuente. Está caracterizada por una triada de manifestaciones clínicas que comprende una malformación vascular venular, linfática y venosa, junto con hipertrofia esquelética; aumento de tejidos blandos de uno o más miembros; y la presencia de fistulas arteriovenosas. Se presenta el caso de una niña de 5 años de edad, a quien se le confirmó por hallazgos clínicos e imagenológicos un síndrome de Klippel-Trenaunay-Weber. Esta es una enfermedad rara, poco frecuente, con un patrón de herencia genética no bien definido, que necesita de un manejo multidisciplinario. El tratamiento de elección es el clínico sintomático, enfocado a evitar la discapacidad, mejorar la capacidad funcional, calidad de vida y prevenir complicaciones. Se presenta el caso por lo poco frecuente del padecimiento para mostrar su seguimiento y además con fines docentes.

Klippel-Trenaunay-Weber syndrome is a rare congenital vascular malformation. Its characterized by a triad of clinical manifestations that includes venular, lymphatic, and venous vascular malformation, together with skeletal hypertrophy, soft tissue enlargement of one or more limbs, and presence of arteriovenous fistulas. We present the case of a 5-year-old girl who was confirmed by clinical and imaging findings to have Klippel-Trenaunay-Weber syndrome. This is a rare, infrequent disease with a not well-defined genetic inheritance pattern that requires multidisciplinary management. The treatment of choice is the symptomatic clinic, focused on avoiding disability, improving functional capacity, quality of life and preventing complications. The case is presented due to the infrequent nature of this condition to show its follow-up and also for teaching purpose

Calidad de vida en pacientes con enfermedad de Pompe: estudio observacional / Quality of Life in Patients with Pompe Disease: Cross-Sectional Study

Introducción: La enfermedad de Pompe es una enfermedad genética multisistémica y rápidamente progresiva, que causa compromiso muscular (esquelético, cardíaco y liso), severa hipotonía y dificultad en la deglución. Debido a la naturaleza de la enfermedad, la calidad de vida de las personas que la padecen puede verse más afectada con respecto a la población general. Método: Se llevó a cabo un estudio descriptivo de corte transversal. Se diseñó un instrumento tipo encuesta con preguntas de caracterización sociodemográfica y referentes a la enfermedad. Para medir la calidad de vida se aplicó el Medical Outcomes Study 36-Item Short Form (SF-36) Questionnaire. Se hizo una comparación entre grupos, con nivel de significancia de 0,05. Resultados: Se obtuvieron encuestas de 27 pacientes de seis países. La edad media fue de 40,52 años, el 59 % fueron mujeres, el 51 % casados, el 63 % activos laboralmente, con edad media de diagnóstico de 30,3 años (SD = 15,557). La dimensión con menor media fue el rol físico (10,2; IC 95 % = 1,5-21,9), mientras que la de mayor media fue la salud mental (65,5; IC 95 % = 56,9-74,0). El 29,7 % (IC 95 % = 11,2-48,0) de los encuestados consideró sentirse en peores condiciones de salud que el año anterior. Discusión: Se evidencia una baja calidad de vida en pacientes con EP, en comparación con la población general, si se tienen en cuenta otros estudios que utilizan el mismo cuestionario. Conclusiones: Se evidencia una baja calidad de vida en los pacientes con enfermedad de Pompe participantes; las dimensiones asociadas con parámetros físicos fueron las de menores puntuaciones.

Introduction: Pompe disease is a rapidly progressive, multisystemic genetic disease that causes muscle involvement (skeletal, cardiac and smooth), severe hypotonia and difficulty in swallowing. Due to the nature of the disease, the quality of life may be more affected compared to the general population. Method: A descriptive cross-sectional study was carried out. A survey-type instrument was designed with questions of sociodemographic characterization and those referring to the disease. To measure Quality of Life, the Medical Outcomes Study 36-Item Short Form (SF-36) questionnaire was applied. A comparison was made between groups with a significance level of 0,05. Results: 27 surveys of patients from six countries were obtained. The mean age 40.52 years, women 59 %, married 51 %, 63 % active in employment, with a mean age of diagnosis of 30.3 years (SD = 15,557). The dimension with the lowest mean was the Physical Role (10.2; 95 % CI = 1.5 - 21.9), while the one with the highest mean was the Mental Health dimension (65.5; 95 % CI = 56.9 - 74.0). 29.7 % (95 % CI = 11.2 - 48.0) of those surveyed considered they felt in worse health conditions than the previous year. Discussion: Low quality of life is evidenced in patients with PD in comparison to the general population described in other studies using the same questionnaire. Conclusions: A low quality of life is evidenced in the study individuals where the dimensions related to the physical area were lower.

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.

Síndrome de Jadassohn-Lewandowsky. Reporte del primer caso pediátrico en Cuba

El síndrome de Jadassohn-Lewandowsky o paquioniquia congénita tipo 1 pertenece al grupo de las enfermedades raras. A nivel mundial se han descrito hasta la fecha menos de mil casos y el que ahora se publica constituye el primer reporte en la edad pediátrica en Cuba. Es un paciente masculino, de siete años de edad ingresado en el Servicio de Clínicas Pediátricas del Hospital Pediátrico Provincial de Holguín con antecedentes de uñas amarillas e hipertróficas desde los nueve meses de edad. Al examen físico se constató la presencia de distrofia ungueal hipertrófica en las 20 uñas, queratosis folicular en codos, manos y miembros inferiores, queratodermia plantar focal y leucoqueratosis oral. Se identificó un patrón de herencia autosómico dominante. Basado en las características fenotípicas y los antecedentes familiares se clasificó el caso presentado como paquioniquia congénita tipo 1, para la cual aún no existe cura y la terapia génica se encuentra en investigación. Por lo poco común de la enfermedad y ser el primer caso en edad pediátrica en Cuba, se decidió su publicación.

Jadassohn-Lewandowsky syndrome or congenital pachyonychia type 1 belongs to the rare diseases' group. Worldwide, less than a thousand cases have been described to date and the one that is now published constitutes the first pediatric age report in Cuba. A seven-years-old male patient admitted to the Pediatric Clinic Service at the Holguín Provincial Pediatric Hospital with a history of yellow and hypertrophic nails since he was nine months old. The physical examination confirmed the presence of hypertrophic nail dystrophy in all 20 nails, keratosis follicularis on the elbows, hands and lower limbs, focal plantar keratoderma and oral leukokeratosis. An autosomal dominant inheritance pattern was identified. Based on the phenotypic characteristics and family history, the case presented was classified as congenital pachyonychia type 1, for which there is still no cure and gene therapy is under investigation. Due to the rareness of the disease and being the first pediatric age case in Cuba, its publication was decided.

Innovative mechanisms of pre-marketing authorization access for rare diseases in Brazil: a case study of pabinafusp-alfa for mucopolysaccharidosis type II / Mecanismos inovadores de acesso pré-comercialização a tecnologias para doenças raras no Brasil: um estudo de caso de alfapabinafuspe para mucopolissacaridose tipo II

Patients with rare diseases frequently face unmet medical needs due to the high costs, lengthy development times, and slow approval processes for new treatments. This case study discusses innovative access alternatives for rare diseases in Brazil, focusing on early access to pabinafusp-alfa for mucopolysaccharidosis type II (MPS-II), a rare genetic lysosomal storage disease characterized by a deficiency of the enzyme iduronate-2-sulfatase. From September 2018 to March 2023, 20 Brazilian MPS-II patients received pabinafusp-alfa through a clinical research protocol. This enzyme replacement therapy (ERT) crosses the blood-brain barrier to address central nervous system manifestations unmet by existing treatments. Patients' participation in the clinical study resulted in an estimated BRL 65 million in cost savings for the public healthcare system compared to conventional ERT with idursulfase-alfa and potentially better clinical outcomes. The case study underscores the importance of innovative mechanisms in addressing patients' medical needs. Early access alternatives include: a) clinical study access, with execution/development aligned with healthcare managers and linked to future access strategies; b) regulatory-level risk-sharing, considering effectiveness uncertainties and the possibility of market withdrawal and/or reimbursement in case of negative results; and c) drug pre-delivery, with payment contingent on positive phase III clinical study outcomes. Although public-private partnerships in clinical research are underused, they could benefit all stakeholders by accelerating drug development, facilitating early patient access to innovative medicines, and generating healthcare system savings, particularly for rare diseases.

Pacientes com doenças raras frequentemente enfrentam necessidades médicas não atendidas devido aos altos custos, longos tempos de desenvolvimento e processos de aprovação lentos para novos tratamentos. Este estudo de caso discute alternativas inovadoras de acesso para doenças raras no Brasil, com foco no acesso precoce ao alfapabinafuspe para mucopolissacaridose tipo II (MPS-II), uma doença lisossômica de armazenamento genético rara, caracterizada por uma deficiência da enzima iduronato-2-sulfatase. De setembro de 2018 a março de 2023, 20 pacientes brasileiros com MPS-II receberam alfapabinafuspe por meio de pesquisa clínica. Essa terapia de reposição enzimática (TRE) atravessa a barreira hematoencefálica para tratar manifestações do sistema nervoso central não atendidas pelos tratamentos existentes. A participação dos pacientes no estudo clínico resultou em uma economia estimada de 65 milhões de reais para o sistema público de saúde, em comparação com a TRE convencional com idursulfase alfa, além de potencialmente melhores resultados clínicos. O estudo de caso destaca a importância de mecanismos inovadores no atendimento das necessidades médicas dos pacientes. As alternativas de acesso precoce incluem: a) acesso por meio de estudos clínicos, com execução/desenvolvimento alinhada aos gestores de saúde e vinculada a estratégias futuras de acesso; b) compartilhamento de risco em nível regulatório, considerando as incertezas de eficácia e a possibilidade de retirada do mercado e reembolso em caso de resultados negativos; e c) pré-entrega do medicamento, com pagamento condicionado aos resultados positivos do estudo clínico de fase III. Embora as parcerias público-privadas em pesquisa clínica sejam subutilizadas, elas poderiam beneficiar todas as partes interessadas ao acelerar o desenvolvimento de medicamentos, facilitar o acesso precoce dos pacientes a medicamentos inovadores e gerar economias para o sistema de saúde, especialmente para doenças raras.

Primer caso de esclerosis múltiple primaria progresiva tratada con ocrelizumab en el Perú / First case of Primary Progressive Multiple Sclerosis treated with Ocrelizumab in Peru

RESUMEN La esclerosis múltiple es una enfermedad crónica, inflamatoria, desmielinizante, de etiología autoinmune que afecta al sistema nervioso central. Es la causa más común de discapacidad neurológica no traumática en adultos jóvenes. El 10 % de pacientes con esta enfermedad son diagnosticados con la forma esclerosis múltiple primaria progresiva (EMPP) que, hasta la aparición del anticuerpo monoclonal anti-CD20 ocrelizumab, no tenía una terapia específica. Se presenta el primer caso de EMPP tratado con ocrelizumab en el sistema público peruano. El paciente presentó una tolerabilidad aceptable y una respuesta clínica adecuada, medida con la Escala Expandida del Estado de Discapacidad (EDSS). Se destaca que, en la legislación peruana, la esclerosis múltiple es considerada una enfermedad rara que requiere una evaluación ad hoc para la autorización de financiamiento público para terapias específicas.

ABSTRACT Multiple Sclerosis is a chronic, demyelinating, autoimmune, neuroinflammatory disease. Known as the most common cause of non-traumatic neurological disability in young adults. Ten per cent of patients with Multiple Sclerosis are diagnosed with the Primary Progressive form (PPMS) which, until the emergence of the anti-CD20 monoclonal antibody Ocrelizumab, had no specific therapy. The first case treated with Ocrelizumab in the Peruvian public healthcare system is reported. The patient presented an acceptable tolerability and an adequate clinical response, as measured by the EDSS scale. Of note, under Peruvian legislation, Multiple Sclerosis is considered a rare disease and, therefore, requires an ad hoc evaluation for the authorization of public funding for specific therapies.

Mastocitosis crónica. Presentación de un caso y revisión de la literatura

La mastocitosis cutánea crónica es una genodermatosis de etiología desconocida y que se encuentra dentro del grupo de enfermedades raras o poco frecuentes. Se caracterizan por el crecimiento y acumulación de causa desconocida de mastocitos en piel y otros órganos y se manifiesta como una urticaria pigmentosa. Se presenta el caso de un paciente de sexo masculino, con lesiones eritematopapulosas en región de las manos que fue extendiéndose a todo el cuerpo y cuero cabelludo que al desaparecer quedaban manchas hipercrómicas con signo de Darier positivo. Se confirmó el diagnóstico de urticaria pigmentosa mediante biopsia de la piel. Es una enfermedad rara con una baja incidencia, la forma cutánea tiene un pronóstico favorable, por lo que resulta de vital importancia conocer y diagnosticar de forma precoz esta entidad con un manejo multidisciplinario para prevenir las manifestaciones sistémicas que aparecen. Llevar un tratamiento sintomático permitirá una mejor calidad de vida en los infantes. Se presenta el caso porque al considerarse la mastocitosis una enfermedad rara la prevalencia e incidencia de estos casos es muy baja.

Chronic cutaneous mastocytosis is a genodermatosis of unknown etiology and that is within the group of rare or infrequent diseases. They are characterized by the growth and accumulation of mast cells in the skin and other organs of unknown cause and manifest as urticaria pigmentosa. The case of a male patient is presented, with erythematopapular lesions in the region of the hands that spread to the entire body and scalp that, when they disappeared, left hyperchromic spots with Darier's sign: positive. The diagnosis of urticaria pigmentosa was confirmed by skin biopsy. It is a rare disease with a low incidence, the cutaneous form has a favorable prognosis, so it is of vital importance to know and diagnose this entity early with a multidisciplinary management to prevent the systemic manifestations that appear. Taking a symptomatic treatment will allow a better quality of life in infants. The case is presented because mastocytosis is considered a rare disease, the prevalence and incidence of these cases is very low.