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

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.

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.

Formação de um residente de Medicina de Família e Comunidade no contexto da Política Nacional de Atenção Integral às Pessoas com Doenças Raras / Training of a Family and Community Medicine resident in the context of the National Policy of Comprehensive Care for People with Rare Diseases / Formación de un residente de Medicina Familiar y Comunitaria en el contexto de la Política Nacional de Atención Integral a Personas con Enfermedades Raras

Problema: Mudanças no perfil de morbimortalidade brasileiro têm evidenciado a importância das doenças genéticas, porém os dados epidemiológicos ainda são limitados. Desde 2014, a Política Nacional de Atenção Integral às Pessoas com Doenças Raras visa fomentar a assistência integral no Sistema Único de Saúde (SUS). Entretanto, os profissionais da atenção primária ainda não são suficientemente capacitados para a abordagem das doenças genéticas e raras. O objetivo do estudo é apresentar a experiência adquirida por um médico residente em Medicina de Família e Comunidade em um serviço de referência em doenças genéticas e raras. Método: Trata-se de um relato de experiência de estágio eletivo desenvolvido durante oito semanas no Serviço de Genética Médica do Hospital Universitário Professor Edgard Santos da Universidade Federal da Bahia (HUPES-UFBA). O estágio foi composto de rotações em ambulatórios, laboratório, enfermaria e participação em aulas teóricas. Resultados: O residente teve contato com conhecimentos e ferramentas de genética que são úteis à sua prática como médico de família e comunidade, auxiliando na atenção às pessoas com doenças genéticas e raras. Também identificou como ferramentas e princípios da atenção primária à saúde potencializam o cuidado em genética médica. Conclusão: A experiência situou o residente quanto ao seu papel na linha de cuidado em doenças raras, reforçando a responsabilidade do profissional da atenção primária na assistência integral.

Problem: Changes in the Brazilian morbidity and mortality profile have highlighted the importance of genetic diseases, but epidemiological data are still limited. Since 2014, the National Policy for Comprehensive Care of People with Rare Diseases aims to foster comprehensive care in The Brazilian Unified Health System (Sistema Único de Saúde ­ SUS). However, primary care professionals are not yet sufficiently trained to deal with genetic and rare diseases. The objective of the study was to present the experience gained by a Family and Community Medicine resident in a reference service in genetic and rare diseases. Methods: This is an experience report of an elective internship developed during eight weeks at the Medical Genetics Service at Hospital Universitário Professor Edgard Santos of Universidade Federal da Bahia (HUPES-UFBA). The internship consisted of rotations in outpatient clinics, laboratory, infirmary, and participation in theoretical classes. Results: Residents had contact with genetics knowledge and tools that are useful to their practice as a family physician, assisting in the care of people with genetic and rare diseases. They also identified how primary health care tools and principles enhance care in Medical Genetics. Conclusion: The experience gave the residents a better understanding of their role within the line of care for rare diseases, reinforcing the primary care professionals' responsibility for comprehensive care.

Problema: Los cambios en el perfil de morbilidad y mortalidad brasileño han puesto en atención la importancia de las enfermedades genéticas, pero los datos epidemiológicos aún son limitados. Desde 2014, la Política Nacional de Atención Integral a Personas con Enfermedades Raras tiene como objetivo fomentar la atención integral en el Sistema Único de Salud (SUS). Sin embargo, los profesionales de atención primaria aún no están lo suficientemente capacitados para hacer frente a las enfermedades genéticas y raras. El objetivo del estudio es presentar la experiencia adquirida por un médico residente en Medicina Familiar y Comunitaria en un servicio de referencia en genética y enfermedades raras. Método: Se trata de un informe de experiencia de estancia electiva desarrollada durante ocho semanas en el Servicio de Genética Médica de HUPES-UFBA. La estancia consistió en rotaciones en consultas externas, laboratorio, enfermería y participación en clases teóricas. Resultados: El residente tuvo contacto con conocimientos y herramientas genéticas que le son útiles para su práctica como médico de familia y comunitario, ayudando a atender a personas con enfermedades genéticas y raras. También identificó cómo las herramientas y los principios de la atención primaria de salud mejoran la atención en Genética Médica. Conclusión: La experiencia colocó al residente en su rol dentro de la línea de atención en enfermedades raras, reforzando la responsabilidad del profesional de atención primaria en la atención integral.

Clusters of rare disorders and congenital anomalies in South America / Conglomerados de trastornos y malformaciones congénitas poco frecuentes en América del Sur / Agrupamentos de doenças raras e anomalias congênitas na América do Sul

ABSTRACT Objective. To map geographic clusters of rare disorders and congenital anomalies reported in South America. Methods. Qualitative systematic review conducted in Medline/PubMed, Lilacs, and Scielo electronic databases to identify studies meeting eligibility criteria. The strategy resulted in 1 672 unique articles, from which 164 were selected for full reading by a pair of reviewers. Results. Fifty-five articles reported at least one cluster of genetic disorders or congenital anomalies in South American territory. From these papers, 122 clusters were identified, of which half (61) were related to autosomal recessive disorders. Sixty-five (53.3%) of the clusters were located in Brazil. Conclusions. The results of the review reinforce that rare diseases and congenital anomalies can occur in a non-random way in space, which is discussed in the perspective of the complex history of formation, social organization, and genetic structure of the South American population. Mapping clusters in population medical genetics can be an important public health tool, given that such places concentrate cases of rare diseases that frequently require multiprofessional, specialized care. Therefore, these results can support important agendas in public health related to rare diseases and congenital anomalies, such as health promotion and surveillance.

RESUMEN Objetivo. Trazar los conglomerados geográficos de los trastornos y las malformaciones congénitas poco frecuentes notificados en América del Sur. Métodos. Se realizó una revisión sistemática cualitativa en las bases de datos electrónicas Medline/PubMed, Lilacs y Scielo para encontrar los estudios que cumplieran con los criterios de selección. Se encontraron 1672 artículos originales, de los que se seleccionaron 164 para su lectura completa por un par de revisores. Resultados. En 55 artículos se informó de al menos un conglomerado de trastornos genéticos o malformaciones congénitas en América del Sur. A partir de estos artículos, se encontraron 122 conglomerados, de los cuales la mitad (61) se asociaron con trastornos autosómicos recesivos. Sesenta y cinco (53,3%) de los conglomerados se ubicaron en Brasil. Conclusiones. Los resultados de la revisión confirman que las enfermedades raras y las malformaciones congénitas pueden presentarse de una forma no aleatoria en el espacio, lo que se comenta desde la perspectiva de la complejidad histórica del proceso de formación, organización social y estructura genética de la población de América del Sur. Definir geográficamente los conglomerados en la genética médica poblacional puede ser una importante herramienta de salud pública, ya que en esos lugares se concentran casos de enfermedades raras que suelen requerir una atención especializada y multidisciplinaria. Por lo tanto, estos resultados pueden servir de apoyo a importantes programas de salud pública relacionados con las enfermedades raras y las malformaciones congénitas como, por ejemplo, la promoción de la salud y la vigilancia.

RESUMO Objetivo. Mapear agrupamentos geográficos de doenças raras e anomalias congênitas relatados na América do Sul. Métodos. Revisão sistemática qualitativa realizada nas bases de dados eletrônicos Medline/PubMed, Lilacs e Scielo para identificar estudos que atendessem aos critérios de elegibilidade. A estratégia resultou em 1.672 artigos únicos, dos quais 164 foram selecionados para leitura completa por uma dupla de revisores. Resultados. Cinquenta e cinco artigos relataram pelo menos um agrupamento de distúrbios genéticos ou anomalias congênitas no território sul-americano. A partir desses artigos, foram identificados 122 agrupamentos, dos quais metade (61) estava relacionada a doenças autossômicas recessivas. Sessenta e cinco (53,3%) dos agrupamentos estavam localizados no Brasil. Conclusões. Os resultados da revisão reforçam a observação de que doenças raras e anomalias congênitas podem ocorrer de forma não aleatória no espaço, o que é discutido na perspectiva da complexa história de formação, organização social e estrutura genética da população sul-americana. O mapeamento de agrupamentos em genética médica populacional pode ser uma importante ferramenta de saúde pública, visto que esses locais concentram casos de doenças raras que frequentemente requerem atendimento multiprofissional especializado. Portanto, esses resultados podem apoiar importantes agendas de saúde pública relacionadas a doenças raras e anomalias congênitas, como a vigilância e a promoção da saúde.

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.

Combined superior mesenteric artery syndrome and nutcraker syndrome presenting as acute pancreatitis: a case report / Síndrome da artéria mesentérica superior em combinação com síndrome de quebra-nozes manifestando-se como pancreatite aguda: relato de caso

Abstract Superior mesenteric artery syndrome designates compression of the third part of the duodenum between the superior mesenteric artery and the aorta. This condition has a low incidence, being more common in thin young women. Nutcracker syndrome is compression of the left renal vein between the superior mesenteric artery and the aorta. Both entities are rare, and their coexistence has been reported in a few cases. Conservative treatment targeting weight gain is sufficient in most cases. An association between the superior mesenteric artery syndrome and acute pancreatitis has rarely been reported. We intend to describe the case of an 18-year-old girl who was admitted to the emergency room with epigastric pain and emesis. Our investigation revealed acute acalculous pancreatitis. During work-up, we discovered superior mesenteric artery syndrome and a compressed left renal vein. The patient is on conservative treatment, and her symptoms have improved.

Resumo A síndrome da artéria mesentérica superior designa compressão da terceira parte do duodeno pela artéria mesentérica superior e a aorta. Essa condição tem uma baixa incidência, sendo mais comum em mulheres jovens magras. A síndrome de quebra-nozes resulta da compressão da veia renal esquerda pela artéria mesentérica superior e a aorta. Ambas as entidades são raras, e a sua coexistência foi descrita em poucos casos. Tratamento conservador com o objetivo de ganho ponderal é suficiente na maioria dos casos. A associação entre a síndrome da artéria mesentérica superior e a pancreatite aguda foi raramente relatada. Pretendemos descrever o caso de uma jovem de 18 anos que recorreu ao serviço de urgência com epigastralgia e vômitos. A investigação realizada revelou pancreatite aguda alitiásica. Durante o estudo complementar, foi identificada a síndrome da artéria mesentérica superior, bem como uma veia renal esquerda comprimida. A paciente encontra-se em tratamento conservador, apresentando melhora clínica.

Juvenile scoliosis as the first manifestation of syringomyelia associated with Chiari malformation type I / Escoliosis juvenil como primera manifestación de siringomielia asociada con malformación de Chiari tipo I

Abstract Background: Scoliosis is a spinal deformity that usually manifests as a structural curve determining a variable deformity of the trunk. According to some published series, 4 to 26% of scoliosis initially classified as idiopathic show neurological alterations when studied with nuclear magnetic resonance, such as syringomyelia and Chiari malformation, among the most frequent. Chiari malformations are characterized by descending herniation of the cerebellar tonsils, brainstem, and IV ventricle into the spinal canal. Case report: We present the case of a patient whose first symptomatic manifestation was early-onset scoliosis. The overlapping of some physical examination signs, such as postural lateralization and scoliosis, reinforced the active suspicion of neuroaxis alterations. Conclusions: Early childhood-onset scoliosis should raise a high degree of suspicion for association with neuro-spinal diseases. Although the frequency of Chiari malformation is low, its early approach could reduce the progression of associated comorbidities. An early detection could change the prognosis of the disease.

Resumen Introducción: La escoliosis es una deformidad de la columna que usualmente se manifiesta como una curva estructural que determina una deformidad variable del tronco. Las malformaciones de Chiari se caracterizan por la herniación descendente de las amígdalas cerebelosas, tronco encefálico y IV ventrículo hacia el canal espinal. Según algunas series publicadas, del 4 al 26% de las escoliosis inicialmente catalogadas como idiopáticas muestran alteraciones neurológicas al ser estudiadas con resonancia magnética nuclear, como la siringomielia y malformación de Chiari, dentro de las más frecuentes. Caso clínico: Se presenta el caso de un paciente cuya primera manifestación sintomática fue escoliosis de comienzo temprano. El solapamiento de algunos signos del examen físico, como la lateralización de la postura y la escoliosis, reforzaron la sospecha activa de alteraciones del neuroeje. Conclusiones: La escoliosis de inicio temprano en la infancia debe despertar un alto grado de sospecha de asociación con enfermedades neuro-espinales. Dentro de este contexto, aunque malformación Chiari es de baja frecuencia, su abordaje precoz permitiría disminuir la progresión de comorbilidades asociadas. La detección temprana podría cambiar el pronóstico de la enfermedad.

Enfermedades raras en la infancia. Visión gastroenterológica

Introducción: Las enfermedades raras conforman las afecciones de baja prevalencia que asociadas a los medicamentos huérfanos representan un problema sanitario y social mundial. Objetivo: Revisar los aspectos más sobresalientes relacionados con las enfermedades raras, con una visión gastroenterológica, y su repercusión en la infancia. Métodos: Se realizaron búsquedas no estructuradas de publicaciones en español e inglés en PubMed, Google Scholar, Scimago, SciELO, desde enero 2010 hasta agosto 2021. Se usaron los términos: enfermedades raras, conceptualización, prevalencia, epidemiología, medicamentos huérfanos y ética. Análisis y síntesis de la información: Se revisaron las enfermedades raras en la infancia, criterios conceptuales, epidemiología global, enfermedades más reconocidas con énfasis en gastroenterología. Se destacó la prevalencia, vínculo genético, importancia social, dilema diagnóstico y categorías; repercusión de los tratamientos con medicamentos huérfanos, sus costos y problemas éticos. Se resaltó la incidencia de enfermedades digestivas y el valor de la endoscopia y la biopsia en el diagnóstico. Conclusiones: Se documentaron las enfermedades raras en la infancia, y se analizaron como problema mundial, sanitario y social. El desarrollo de la técnica y de la ciencia, resultaron contribuciones decisivas que variaron criterios sobre diferentes afecciones catalogadas como raras.

Introduction: Rare diseases are the conditions of low prevalence associated with orphan drugs and they represent a global health and social problem. Objective: To review the most outstanding aspects related to rare diseases, with a gastroenterological view, and their impact on childhood. Methods: Unstructured searches for publications in Spanish and English in PubMed, Google Scholar, Scimago, SciELO were conducted, from January 2010 to August 2021. The terms rare diseases, conceptualization, prevalence, epidemiology, orphan drugs and ethics were used. Analysis and synthesis of information: Rare diseases in childhood, conceptual criteria, global epidemiology, and the most well-known diseases with emphasis on gastroenterology were reviewed. Prevalence, genetic link, social importance, diagnostic dilemma and categories, also the impact of orphan drug treatments, their costs and ethical problems were highlighted. The incidence of digestive diseases and the value of endoscopy and biopsy in diagnosis were highlighted. Conclusions: Rare diseases in childhood were documented and analyzed as a global health and social problem. The development of technique and science were decisive contributions that varied criteria on different conditions classified as rare.

Dental anomalies in individuals with osteogenesis imperfecta: a systematic review and meta-analysis of prevalence and comparative studies

Abstract Background Osteogenesis imperfecta (OI) is a rare genetic disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. OI is also known as brittle bone disease. Objective This study aims to describe the prevalence of dental anomalies (except dentinogenesis imperfecta) in individuals with OI, and compare the prevalence of dental anomalies between individuals with and without OI and between individuals with different types of OI. Search methods Searches in PubMed, Web of Science, Scopus, Ovid, and gray literature were performed in October 2022. Selection criteria Observational studies (with or without a comparison group) that evaluated the prevalence of dental anomalies in individuals with OI. Data collection and analysis: Data items were extracted by two authors. Quality assessment employing the Joanna Briggs Institute checklists and meta-analyses was conducted. Results were provided in prevalence values and odds ratio (OR) / 95% confidence interval (CI). Strength of evidence was determined. Results Eighteen studies were included. Most prevalent dental anomalies in individuals with OI included pulp obliteration (46.4%), dental impaction (33.5%), dental impaction of second molars (27%), and tooth agenesis (23.9%). Individuals with OI type III/IV had 20.16-fold greater chance of exhibiting tooth discoloration in comparison with individuals with OI type I (CI: 1.10-370.98). In comparison with the group without OI, the individuals with OI had 6.90-fold greater chance of exhibiting dental impaction (CI: 1.54-31.00). High methodological quality was found in 47% of the studies. Strength of evidence was low or very low. Conclusions Pulp obliteration, dental impaction, and tooth agenesis were the most prevalent dental anomalies in the OI group. Individuals with OI were more likely to have dental impaction than individuals without OI. Individuals with OI type III/IV (severe-moderate) are more likely to have tooth discoloration than individuals with OI type I (mild).

Study on the value of pharmaceutical service related to risdiplam based on follow-up data of DTP pharmacy / 中国药房

OBJECTIVE To explore the value of providing pharmaceutical service related to risdiplam in direct-to-patient （DTP） pharmacies. METHODS The follow-up data of spinal muscular atrophy （SMA） patients who purchased and used risdiplam from Shangyao Yunjiankang Yiyao Pharmacy （Shanghai） Co.， Ltd. from May 2021 to January 2023 were collected. The medication information， therapeutic efficacy and the occurrence of adverse events were retrospectively analyzed. RESULTS A total of 42 prescriptions were checked by pharmacists in the DTP pharmacies， and 7 prescriptions were found to be unreasonable （16.7%， 7/42）， which were corrected after the timely intervention. During the follow-up management， pharmacists replied to 4 patients （9.5%， 4/42） regarding medication consultation about medication requirements and adverse events. Two patients with type Ⅰ SMA experienced adverse events： one of them presented with fever and the other presented with skin dryness with darkening. Both of them were grade Ⅰ toxic reactions and generally did not require clinical treatment. Considering that the patient sustained low-grade fever for a long time， the pharmacist suggested symptomatic treatment under the guidance of the doctor. CONCLUSIONS Pharmacists in DTP pharmacies conducting follow-up management of risdiplam use for rare disease SMA patients can help promote rational， standardized medication for patients.

Comments on research status and future of rare diseases in China / 中国热带医学

@#Rare diseases, also known as "orphan diseases", refer to diseases with very low incidence. Countries and regions define rare diseases according to epidemiological standards, economic standards of rare drugs and disease severity. The World Health Organization (WHO) has suggested the prevalence rate of less than 6.5 to 10 per 10 000 people to define rare diseases. In May 2018, "China's First List of Rare Diseases" was released, including 121 rare diseases. Most rare diseases are hereditary diseases with early onset, severe disease, and poor prognosis. About 75% of rare genetic diseases occur in the neonatal period or childhood, which are important part of human birth defects and brings a huge burden to society and families. The effective prevention and treatment of rare diseases is one of the important goals of building a "Healthy China". With the development of molecular biology technology and the continuous research and development of advanced medical products in the field of gene therapy, the level of clinical diagnosis and treatment of rare diseases has risen to a new level, which provides a possibility for the cure of some rare diseases. In China, most rare diseases rely on imported drugs, which cost a lot and bring heavy economic burden to patients. Improving the medical insurance system for rare diseases has become a difficult point in the current medical reform. This paper mainly discusses the definition of rare diseases, the research status, efforts and future development direction of rare diseases in China, in order to deepen the understanding and response of medical workers and the whole society to rare diseases.

Research on the supply guarantee system of orphan drugs in South Korea from the perspective of accessibility and its enlightenment / 中国药房

OBJECTIVE To systematically introduce the supply guarantee system of orphan drugs in South Korea， and to provide reference for improving the accessibility of orphan drugs in China. METHODS The basic characteristics and practical experience of supply guarantee system of orphan drugs in South Korea were summarized by studying the marketing incentive mechanism， reserve supply mechanism and emergency use mechanism. Then， based on the research on the current situation and existing problems of orphan drug supply in China， specific suggestions were put forward to improve the accessibility of orphan drugs in China. RESULTS & CONCLUSIONS South Korea has effectively improved the accessibility of orphan drugs through orphan drug identification channels and supporting incentive policies， relying on the reserve supply mechanism and the import route for emergency use. Therefore， it is suggested that China should guarantee the normal supply of orphan drugs from three aspects： improving the recognition and incentive policy of orphan drugs， building a full-time management department of orphan drugs， and optimizing the temporary import path.

Exploration of pharmaceutical service model in multidisciplinary diagnosis and treatment of rare diseases in children / 中国药房

OBJECTIVE To explore the pharmaceutical service model in multidisciplinary diagnosis and treatment （MDT） of rare diseases in children. METHODS Clinical pharmacists of West China Second University Hospital （hereinafter referred to as “our hospital”） participated in the process of MDT of children’s rare diseases. Clinical pharmacists took part in the entire diagnosis and treatment process of children and established the MDT pharmaceutical service model of children’s rare diseases by formulating drug treatment plans based on evidence-based practice， improving the accessibility of drugs， pharmaceutical monitoring and drug treatment management. RESULTS From January 2021 to April 2022， clinical pharmacists of our hospital had participated in a total of 39 cases of rare diseases MDT in children， including 21 hospitalized children with rare diseases and 18 outpatient com children with rare diseases， involving a total of 23 rare diseases. Clinical pharmacists completed 45 pharmaceutical zhanglingli@scu.edu.cn rounds and 26 pharmaceutical consultations for rare diseases inpatients， 25 outpatients’ MDT and 5 pharmaceutical outpatient service for outpatients with rare diseases， 38 medication educations for inpatients and outpatients with rare diseases and 25 follow-up services for out-of-hospital patients. There were 24 cases （61.54%） of off-label drug use， involving 13 rare diseases and 16 therapeutic drugs， among which off-label drug use registration of 11 drugs had been completed or was in progress. The temporary purchase evaluations of 3 drugs had been completed； 268 cases of medical insurance drug and high-value drug prescription had been reviewed. CONCLUSIONS Our hospital have primarily established a loop pharmaceutical service model of MDT for children with rare diseases， which covers inpatients and outpatients. The model improves the availability and standardization of clinical application of therapeutic drugs， and diagnosis and treatment level for children with rare diseases in our hospital.

Study on the strategy of medical security for rare diseases in China from the perspective of public concern and emotion：taking nosinasine as an example / 中国药房

OBJECTIVE To mine the focus and emotional attitude of the public on rare diseases， and to provide decision- making reference for relevant departments to formulate and implement relevant policies， systems and strategies for medical security of rare diseases. METHODS Latent Dirichlet allocation （LDA） topic model and sentiment analysis method were used to analyze the comment text of short videos related to the “nosinasine” medical insurance admission event on the Bilibili video website， mine the theme and sentiment tendency of the text， and put forward relevant strategy suggestions. RESULTS A total of 8 videos with tens of thousands of playback and 7 109 text data were obtained. According to the LDA analysis， online public paid attention to 9 topics related to rare diseases （the price of rare disease drugs， the inclusion of rare disease drugs in medical insurance， the status quo of research and development of rare disease drugs， the scope of medical insurance and the medical security system， the plight of rare disease patients， the prevention and screening of rare diseases， the value of rare disease drugs in medical insurance， the Chinese and western medical methods of rare diseases， and the supply and demand status of rare disease drugs）， which could be summarized into 4 categories according to the objects of concern （rare disease drugs， rare disease medical insurance， rare disease medical and health services and rare disease patient groups）. On the whole， the emotional tendency of the Internet public towards each topic showed a low positive and high negative tendency. CONCLUSIONS The public paid more attention to the price， research and development， supply and demand of rare disease drugs， and was deeply worried about the current medical status of rare diseases in China. To strengthen and improve the medical security for patients with rare diseases， such as actively carrying out public health services for rare diseases， strengthening cooperation in the diagnosis and treatment of rare diseases， and researching rare disease drugs， etc. Chinese medical and health departments can make concerted efforts in medical and health services， drug supply security， medical security and other social security.

Genetic epidemiology of rare diseases in San Luis Province, Argentine

Objectives: Genetic epidemiologic studies in populations of the world are scarce and this medical information is of special value for clinical geneticists. The purpose of this work was to know and to implicate the geographical environments with the genetic diseases found in patients attending a genetic consulter, according to the type of work, place of residence, or environment characteristic in the province of San Luis, Argentine. Material and Methods: Clinical genetics consultations during 2014–January 2019 were analyzed for all patients derived to the primary consultation center, and nearby hospitals in San Luis. A total of 448 patients were registered and examined once a week at the Central Hospital of San Luis. The reasons of the derivate medical consultations were divided into major malformations (MMal), neurodevelopment diseases, and genetic counseling. In addition, possible environmental risk factors such as urban or rural origin, the working activity of parents in manufacturing houses or mines, and drug consumption during pregnancy were also considered. The prevalence of genetic diseases was calculated for all eight province departments and compared with the province’s apparent prevalence. Results: In the whole sample (n = 448), the major proportion of patients came from the city. Patients with MMals were the most abundant and significantly higher than the other categories. The prevalence of MMals distributed approximately similarly in all departments of the province, with exception of two of them. No association was found between types of work or drug abuse with MMals in this sample. Conclusion: Of all types of genetic diseases, the most prevalent was the MMals. Regarding its prevalence, except for two departments, each department’s prevalence had a similar distribution. Most of the affected patients with this type of genetic condition were found in the city and not in other regions of supposed risk

Mucopolisacaridosis III. Revisión bibliográfica / Mucopolysaccharidosis III. Bibliographic review

Mucopolisacaridosis de tipo III es una enfermedad rara, con una incidencia de 1 en 70 000 nacidos vivos, es la más frecuente dentro del grupo de Mucopolisacaridosis y se produce por un defecto en la vía del metabolismo del heparan sulfato. Se caracteriza por afectar a mayor profundidad el sistema nervioso central, el paciente tiene un desarrollo normal hasta aproximadamente los 1 a 3 años de edad y posteriormente empieza con deterioro progresivo, cursa con retraso del desarrollo, alteración del comportamiento y trastorno del sueño agregándose déficit motor y cuadros infecciosos, culminando en un estado de postración. La esperanza de vida oscila entre los 20 a 30 años, aunque depende del fenotipo y la principal causa de muerte fue la neumonía. El diagnóstico definitivo se consigue mediante pruebas genómicas y ensayo enzimático. No cuenta con tratamiento curativo, únicamente con paliación y soporte ante las complicaciones que va desarrollando

Mucopolysaccharidosis III is a rare disease, with an incidence of 1 in 70 000 live births, it is the most frequent within the group of Mucopolysaccharidosis and is caused by a defect in the heparan sulfate metabolism pathway. It is characterized by affecting the central nervous system in greater depth, the patient has a normal development until approximately 1 to 3 years of age and later begins with progressive deterioration, courses with developmental delay, behavioral alteration and sleep disorder, adding motor deficits and infectious pictures, culminating in a state of prostration. Life expectancy ranges from 20 to 30 years, although it depends on the phenotype, and the main cause of death is pneumonia. Definitive diagnosis is achieved by genomic tests and enzymatic assay. It does not have curative treatment, only palliation and support in the face of the complications that it develops.

Cutis verticis gyrata. Presentación de un caso y revisión de la literatura

RESUMEN La cutis verticis gyrata es una patología poco frecuente del cuero cabelludo caracterizada por la proliferación del tejido celular subcutáneo e hipertrofia que produce pliegues y surcos que le dan aspecto cerebriforme. Aunque su etiología es aún desconocida, la condición no es exclusivamente congénita, se ha propuesto como teoría la presencia de mutaciones autosómicas dominantes en el receptor de factor de crecimiento de fibroblastos 2. Esta patología es extremadamente rara en pediatría. Se divide en primaria y secundaria. Se presenta el caso de un adolescente de 15 años, de sexo masculino con presencia de cutis verticis gyrata primaria esencial, donde la principal preocupación fue el prurito y la presencia de fetidez. Teniendo en cuenta el carácter benigno de esta condición, se decidió solo manejo sintomático. El caso que se presenta es el primero reportado en la provincia Cienfuegos en edad pediátrica, lo que reafirma la importancia de reconocer esta entidad y su abordaje adecuado para distinguir las formas clínicas de presentación para su mejor tratamiento terapéutico. Dada la rareza de la entidad en edad pediátrica se decide presentar este caso, además de una revisión de la literatura.

ABSTRACT Cutis verticis gyrata is a rare pathology of the scalp characterized by the proliferation of subcutaneous cellular tissue and hypertrophy that produces folds and furrows that give it a cerebriform appearance. Although its etiology is still unknown, the condition is not exclusively congenital, the presence of autosomal dominant mutations in the fibroblast growth factor receptor 2 has been proposed as a theory. This pathology is extremely rare in pediatrics. It is divided into primary and secondary. The case of a 15-year-old male adolescent with the presence of essential primary cutis verticis gyrata, where the main concern was pruritus and the presence of fetidity is presented. Taking into account the benign nature of this condition, only symptomatic management was decided. The case presented is the first reported in Cienfuegos province in pediatric age, which reaffirms the importance of recognizing this entity and its adequate approach to distinguish the clinical forms of presentation for its best therapeutic treatment. Once the oddity of the entity in pediatric age was given this case, in addition to a revision of literature decides to show up.

Acesso a medicamentos para doenças raras no pós-estudo: revisão integrativa / Post-trial access to drugs for rare diseases: an integrative review / Acceso a medicamentos para enfermedades raras en el posestudio: una revisión integradora

Resumo A fim de analisar a produção científica acerca do acesso a medicamentos no pós-estudo por participantes de ensaios clínicos com doenças raras, realizou-se revisão integrativa da literatura nas bases Biblioteca Virtual em Saúde, Embase, PubMed, SciELO, Scopus e Web of Science, abrangendo 21 estudos. No processo analítico, surgiram duas categorias: pesquisa clínica com drogas órfãs e regulação do mercado; e acesso a drogas órfãs: história, globalização e direito à saúde. A primeira analisa questões relativas à quantidade de pacientes com doenças raras, à eficácia e à segurança dessas pesquisas e aos custos e preços dos medicamentos. A segunda trata do panorama histórico do acesso pós-estudo, da globalização dos ensaios clínicos e das dificuldades para efetivar o direito ao acesso a drogas órfãs no pós-estudo. Poucos artigos abordaram o acesso ao medicamento no pós-estudo por participantes com doenças raras como questão central, o que aponta a importância de mais estudos sobre esse tema.

Abstract This study is an integrative literature review to analyze the scientific production about post-trial drug access by participants of clinical trials for rare diseases. The search was carried out in the Virtual Health Library, Embase, PubMed, SciELO, Scopus and Web of Science databases, covering 21 studies. Two categories emerged from the analysis: clinical research with orphan drugs and market regulation; and access to orphan drugs: background, globalization and the right to health. The first analyzes issues related to the number of patients with rare diseases, the efficacy and safety of these studies and the cost and price of medications. The second addresses the historical background of post-trial access, the globalization of clinical trials and the difficulties to ensure the right to post-trial access to orphan drugs. Few articles addressed post-trial drug access by participants with rare diseases as a central issue, which points to the importance of further studies on this subject.

Resumen Se pretende analizar la producción científica sobre el acceso a medicamentos para enfermedades raras en el posestudio a partir de una revisión integradora en las bases de datos Biblioteca Virtual en Salud, Embase, PubMed, SciELO, Scopus y Web of Science, que encontraron 21 estudios. Surgieron dos categorías en el análisis: investigación clínica con medicamentos huérfanos y regulación del mercado; y acceso a medicamentos huérfanos: historia, globalización y derecho a la salud. La primera examina el número de pacientes con enfermedades raras, la eficacia y seguridad de los estudios, así como los costes y precios de los medicamentos. La segunda aborda el panorama histórico del acceso posestudio, la globalización de los ensayos clínicos y las dificultades para materializar el derecho al acceso a medicamentos huérfanos en el posestudio. Pocos estudios plantean el acceso a estos medicamentos en el posestudio, y son necesarios más estudios sobre el tema.