Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome.

BACKGROUND: Platelet α-granule biogenesis in precursor megakaryocytes is critically dependent on VPS33B and VPS16B, as demonstrated by the platelet α-granule deficiency seen in the rare multisystem disorder arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome associated with biallelic pathogenic variants in VPS33B and VIPAS39 (encoding VPS16B). VPS33B and VPS16B are ubiquitously expressed proteins that are known to interact and play key roles in protein sorting and trafficking between subcellular locations. However, there remain significant gaps in our knowledge of the nature of these interactions in primary cells from patients with ARC syndrome. OBJECTIVES: To use primary cells from patients with ARC syndrome to better understand the interactions and roles of VPS33B and VPS16B in platelets and precursor megakaryocytes. PATIENTS/METHODS: The proband and his male sibling were clinically suspected to have ARC syndrome. Confirmatory genetic testing and platelet phenotyping, including electron microscopy and protein expression analysis, was performed with consent in a research setting. RESULTS: We describe the first case of ARC syndrome identified in Costa Rica, associated with a novel homozygous nonsense VPS33B variant that is linked with loss of expression of both VPS33B and VPS16B in platelets. CONCLUSION: These results indicate that stable expression of VPS16B in platelets, their precursor megakaryocytes, and other cells is dependent on VPS33B. We suggest that systematic evaluation of primary cells from patients with a range of VPS33B and VIPAS39 variants would help to elucidate the interactions and functions of these proteins.

[Clinical profile of patients with chronic urticaria in a tertiary care hospital of the social security system in Costa Ricas]. / Perfil clínico de los pacientes con urticaria crónica en un hospital de tercer nivel de atención del sistema de seguridad social de Costa Rica.

OBJECTIVE: To describe the medical and laboratory profile of the patients who have been diagnosed with chronic urticaria in the outpatient clinic of a tertiary care hospital of the social security system in Costa Rica. METHODS: All patients over 13 years of age who had been diagnosed with chronic urticaria between January 1st, 2014, and December 31st, 2018 were included. Variables of medical and laboratory data were statistically analyzed, and the treatment of the patients between their first and last medical consultation was compared. RESULTS: This was about 160 patients who had been diagnosed with chronic urticaria; 129 of them were women, 45.7 % between the ages of 30-49 years; in 17.5 % of them (28 patients), inducible urticaria was associated; 54.8 % (46/84) had positive antithyroperoxidase antibodies; 16.9 % (27 patients) maintained a single dose of second-generation anti-H1 antihistamines in the last consultation; 16.3 % (26 patients) no longer required antihistamine treatment in the last consultation. Cyclosporine was used in 8.8 % (14 patients), and omalizumab was used in 2.5 % (four patients). CONCLUSION: Since this is a real-life study in a geographic region with limited publications on this pathology, we trust that the provided information will contribute to the scientific community in order to improve the quality of life of patients with chronic urticaria through a timely diagnosis and an effective and efficient treatment.

Objetivo: Describir el perfil clínico y de laboratorio de los pacientes diagnosticados con urticaria crónica en la consulta externa de alergología en un hospital de tercer nivel de atención del sistema de seguridad social de Costa Rica. Métodos: Se incluyeron todos los pacientes mayores de 13 años diagnosticados con urticaria crónica entre el 1 de enero de 2014 y el 31 de diciembre de 2018. Se analizaron estadísticamente variables de datos clínicos y de laboratorio y se comparó el tratamiento de los pacientes entre la primera y última consulta. Resultados: Se trató de 160 pacientes con diagnóstico de urticaria crónica: 129 del sexo femenino, 45.7 % con edad entre 30 y 49 años, en 17.5 % (28 pacientes) se asoció urticaria inducible, 54.8 % (46/84) presentó anticuerpo antitiroperoxidasa positivo, 16.9 % (27 pacientes) se mantuvo en la última consulta con una dosis de antihistamínicos anti-H1 de segunda generación; 16.3 % (26 pacientes) ya no requería tratamiento antihistamínico en la última consulta. En 8.8 % de los casos (14 pacientes) se utilizó ciclosporina y en 2.5 % (cuatro pacientes), omalizumab. Conclusión: Al tratase de un estudio de vida real en una región geográfica con limitadas publicaciones sobre esta patología, confiamos que la información provista contribuya a la comunidad científica a mejorar la calidad de vida de los pacientes con urticaria crónica mediante un diagnóstico oportuno y un tratamiento eficaz y efectivo.

Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Wilson disease in Costa Rica: Pediatric phenotype and genotype characterization.

INTRODUCTION: The prevalence of Wilson disease (WD) in Costa Rica is among the highest reported in the world, 4.9:100 000. Previous investigators have also described a burden of autosomal recessive conditions in this country. Genetic testing for WD began in 2010 as a strategy for earlier detection due to the country's high prevalence. Here we describe what we have learned about the genotype and phenotype of the Costa Rican pediatric population with WD. METHODS: We completed a retrospective review of medical records from pediatric individuals (<18 years of age) with molecular testing for ATP7B between 2010 and 2015. We documented phenotype and genotype for cases with WD as defined by the international scoring system. RESULTS: Thirty-four WD cases from 28 families were included, 15 female and 19 male patients. The most frequent pathogenic variant in ATP7B was NM_000053:c.3809A>G, p.Asn1270Ser, with 58.8% of affected individuals homozygous for this variant. Age of diagnosis ranged from 1 to 17 years, with an average of 8.8 ± 3.6 years. All individuals who presented with acute liver failure (n = 6) were homozygous for the p.Asn1270Ser variant (Chi-squared, P < .05). DISCUSSION: Molecular testing has facilitated the detection of presymptomatic patients with WD in Costa Rica. We hope that ongoing efforts in the delivery of clinical services lead to optimized molecular screening for WD and other genetic conditions in Costa Rica.

Williams-Beuren syndrome in diverse populations.

Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses.