Comparative study between primary and secondary antiphospholipid syndrome: clinic and laboratorial characteristics of 149 patients

OBJETIVOS: O presente estudo tem como objetivo analisar as características clínicas, laboratoriais e imunológicas dos pacientes com síndrome antifosfolípide (SAF) e comparar indivíduos portadores da síndrome primária com portadores da secundária. PACIENTES E MÉTODOS: Foi analisado o banco de dados de 149 pacientes com SAF do Serviço de Reumatologia do HC-FMUSP que satisfaziam os critérios de classificação para SAF. RESULTADOS: A amostra consistiu de 140 (94%) mulheres e 9 (6%) homens, com média de idade de 39,7 ± 11,6 anos. A SAF primária perfez o total de 50 (33,8%) pacientes. As tromboses arteriais foram mais significativamente freqüentes no grupo de SAF primária em relação à secundária (56% versus 35,7%, p = 0,02), mais especificamente a presença da síndrome de Sneddon (8% versus 0, p = 0,012) e isquemia de extremidades (18% versus 5%, p = 0,017). Com exceção de catarata, que foi mais freqüente no grupo associado ao LES (10% versus 0, p = 0,017), não se observou diferenças significativas em relação às outras comorbidades. Em relação aos auto-anticorpos, o grupo de SAF secundária apresentou significativamente maior prevalência de FAN (99% versus 60%, p < 0,0001), anti-ENA (45,9% versus 22%, p = 0,007) e anti-Ro/SS-A (43% versus 8%, p < 0,0001). Com exceção da anticardiolipina IgG que foi mais freqüentemente observada no grupo de SAF secundária (84,7% versus 60%, p = 0,0018), os outros anticorpos antifosfolípides (anticardiolipina IgM e anticoagulante lúpico) não diferiram entre os grupos. CONCLUSÕES: O presente estudo identificou população de SAF primária que apresenta maior freqüência de fenômenos trombóticos arteriais, mais especificamente a síndrome de Sneddon e isquemia de extremidades, em relação aos pacientes com SAF secundária. Reforçou, também, o papel de auto-anticorpos na identificação de subgrupos de SAF associada ao LES.OBJECTIVES: The aim of this study was to analyze the prevalence and characteristics of the main clinical, immunologic and laboratorial features of antiphospholipid syndrome (APS), and to perform a comparison between primary and secondary forms of APS. PATIENTS AND METHODS: A data base of 149 patients from HCFMUSP who met the preliminary criteria for the classification of APS was analyzed. RESULTS: The pattern consisted of 140 (94%) female and 9 (6%) male patients with a mean age of 39.7 ± 11.6years. Primary APS was present in 50 (33.8%) of the patients. Arterial thrombosis were more found in primary APS compared to secondary APS (56% vs. 35.7%, p = 0.02), more specifically the presence of Sneddon's syndrome (56% vs. 35,7%, p = 0.02) and limbs ischaemia (18% vs. 5%, p = 0.017) were more prevalent in the first group. Except cataract that was more frequently observed in secondary APS group (10% vs. 0, p = 0.017), no other significant difference was found regarding comorbidities. In relation to autoantibodies, the secondary APS patients had a more significant prevalence of ANA (99% vs. 60%, p < 0.0001), anti-ENA (45.9% vs. 22%, p = 0.007) e anti-Ro/SS-A (43% vs. 8%, p < 0.0001). Antiphospholipid antibodies (IgM anticardiolipin and lupus anticoagulant) did not differ between the groups, except IgG anticardiolipin that was more found in secondary APS group (84.7% vs. 60%, p = 0.0018), CONCLUSIONS: the present study showed that primary APS had more arterial thrombotic events, more specifically Sneddon's syndrome and limbs ischemia, than secondary APS. It was also reinforced the role of autoantibodies to identify patients with APS associated to SLE

A clinical follow-up of 35 Brazilian patients with Prader-Willi Syndrome

OBJECTIVE: Prader-Willi Syndrome is a common etiology of syndromic obesity that is typically caused by either a paternal microdeletion of a region in chromosome 15 (microdeletions) or a maternal uniparental disomy of this chromosome. The purpose of this study was to describe the most significant clinical features of 35 Brazilian patients with molecularly confirmed Prader-Willi syndrome and to determine the effects of growth hormone treatment on clinical outcomes. METHODS: A retrospective study was performed based on the medical records of a cohort of 35 patients diagnosed with Prader-Willi syndrome. The main clinical characteristics were compared between the group of patients presenting with microdeletions and the group presenting with maternal uniparental disomy of chromosome 15. Curves for height/length, weight and body mass index were constructed and compared between Prader-Willi syndrome patients treated with and without growth hormone to determine how growth hormone treatment affected body composition. The curves for these patient groups were also compared with curves for the normal population. RESULTS: No significant differences were identified between patients with microdeletions and patients with maternal uniparental disomy for any of the clinical parameters measured. Growth hormone treatment considerably improved the control of weight gain and body mass index for female patients but had no effect on either parameter in male patients. Growth hormone treatment did not affect height/length in either gender. CONCLUSION: The prevalence rates of several clinical features in this study are in agreement with the rates reported in the literature. Additionally, we found modest benefits of growth hormone treatment but failed to demonstrate differences between patients with microdeletions and those with maternal uniparental disomy. The control of weight gain in patients with Prader-Willi syndrome is complex and does not depend exclusively on growth hormone treatment

Tegumentary manifestations of Noonan and Noonan-related syndromes

OBJECTIVES: Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement. METHODS: A standard questionnaire was administered. A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations. The molecular analysis of this cohort included sequencing of the following genes in all patients: PTPN1, SOS1, RAF1, KRAS, SHOC2 and BRAF. RESULTS: The most frequent tegumentary alterations were xeroderma (46%), photosensitivity (29%), excessive hair loss (24%), recurrent oral ulcers (22%), curly hair (20%), nevi (17%), markedly increased palmar and plantar creases (12%), follicular hyperkeratosis (12%), palmoplantar hyperkeratosis (10%), café-au-lait spots (10%) and sparse eyebrows (7%). Patients with mutations in PTPN11 had lower frequencies of palmar and plantar creases and palmar/plantar hyperkeratosis compared with the other patients. CONCLUSIONS: We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades (SOS1, BRAF, KRAS and RAF1) had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades (PTPN11)

Hypopigmented macules associated to seizures must raise avareness for the possibility of the diagnosis of tuberous sclerosis

A esclerose tuberosa (ET) é uma doença multissistêmica de herança autossômica dominante caracterizada pelo desenvolvimento de hamartomas em diversos órgãos, com incidência estimada em 1:10.000 a 1:6.000 nascidos vivos. Sua ocorrência relaciona-se a mutações com perda de função nos genes TSC1 e TSC2, cujos produtos proteicos (respectivamente hamartina e tuberina) formam um heterodímero com importante função na supressão tumoral e no controle do ciclo celular [...

Impact of ERT and follow-up of 17 patients from the same family with a mild form of MPS II

Background: Mucopolysaccharidosis type&nbsp;II, also known as Hunter syndrome, is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme Iduronate-2- Sulfatase (IDS), leading to progressive accumulation of Glycosaminoglycans (GAGs) in several organs. Over the years, Enzyme Replacement Therapy (ERT) has provided significant benefits for patients, retarding the natural progression of the disease. Results: The authors evaluated&nbsp;17&nbsp;patients from the same family with a mild form of MPS type&nbsp;II; the proband had developed acute decompensated heart failure refractory to clinical measurements at&nbsp;23&nbsp;years and needed a rather urgent heart transplant; however, he died from surgical complications shortly after the procedure. Nevertheless, subsequent to his tragic death, 16&nbsp;affected male relatives were detected after biochemical tests identifying the low or absent activity of the IDS enzyme and confirmed by molecular analysis of the IDS gene. Following diagnosis, different options of treatment were chosen: 6&nbsp;patients started ERT with Elaprase® (Idursulfase) soon after, while the other&nbsp;10&nbsp;remained without ERT. Eventually, 4&nbsp;patients in the latter group began ERT with Hunterase® (Idursulfase Beta). None presented adverse effects to either form of the enzyme. Among the&nbsp;6&nbsp;individuals without any ERT, two died of natural causes, after reaching&nbsp;70&nbsp;years. Despite the variable phenotype within the same family (mainly heart dysfunctions and carpal tunnel syndrome), all&nbsp;14&nbsp;remaining patients were alive with an independent lifestyle. Conclusion: Here, the authors report the variable progress of the disease with and without ERT in a large Brazilian family with a slowly progressive form of MPS II, harboring the same missense variant in the IDS gene

EVALUATION OF AGREEMENT BETWEEN C/T-13910 POLYMORPHISM GENOTYPING RESULTS AND LACTOSE TOLERANCE TEST RESULTS: A RETROSPECTIVE POPULATION-BASED STUDY IN BRAZIL

ABSTRACT Background: Lactose tolerant test (LTT) is the most broadly used diagnostic test for lactose intolerance in Brazil, is an indirect, minimally invasive and a low-cost test that is widely available in primary care and useful in clinical practice. The C/T-13910 polymorphism in lactase persistence has been well characterized in Caucasian populations, but there are no studies evaluating the concordance between C/T-13910 polymorphism genotyping results and LTT results in Brazil, where the population is highly mixed. Objective: We aimed to evaluate agreement between presence of C/T-13910 polymorphism genotyping and malabsorption in LTT results. Methods: This is a retrospective analysis of a Brazilian population whose data were collected from a single laboratory database present in several Brazilian states. Results of individuals who underwent both genetic testing for lactose intolerance (C/T-13910 polymorphism genotyping) and an LTT from April 2016 until February 2019 were analysed to evaluate agreement between tests. Groups were classified according to age (<10-year-old (yo), 10-17 yo, ≥18 yo groups) and state of residence (São Paulo or Rio Grande do Sul). Results: Among the 404 patients evaluated, there was agreement between the genotyping and LTT results in 325 (80.4%) patients and discordance in 79 (19.6%) patients (k=0.42 -moderate agreement). Regarding the genotype, 47 patients with genotype C/C (lactase nonpersistence) had normal LTT results, and 32 with genotype C/T or T/T (indicating lactase persistence) had abnormal LTT results. Neither age nor state of residence (Rio Grande do Sul or São Paulo) affected the agreement between test results. Conclusion: Considering the moderate agreement between C/T-13910 polymorphism genotyping and LTT results (κ=0.42) in the Brazilian population, we hypothesize that an analysis of other polymorphisms could be a strategy to improve the agreement between genotyping and established tests and suggest that additional studies should focus on exploring this approach

Discrepant outcomes in two Brazilian patients with Bloom syndrome and Wilms’ tumor: two case reports

Abstract\ud \ud Introduction\ud Bloom syndrome is a rare, autosomal recessive, chromosomal instability disorder caused by mutations in the BLM gene that increase the risk of developing neoplasias, particularly lymphomas and leukemias, at an early age.\ud \ud \ud Case presentation\ud Case 1 was a 10-year-old Brazilian girl, the third child of a non-consanguineous non-Jewish family, who was born at 36 weeks of gestation and presented with severe intrauterine growth restriction. She had Bloom syndrome and was diagnosed with a unilateral Wilms’ tumor at the age of 3.5 years. She responded well to oncological treatment and has remained disease-free for the last 17 years. Case 2 was a 2-year-old Brazilian girl born to non-Jewish first-degree cousins. Her gestation was marked by intrauterine growth restriction. She had Bloom syndrome; a unilateral stage II Wilms’ tumor was diagnosed at the age of 4 years after the evaluation of a sudden onset abdominal mass. Surgical removal, neoadjuvant chemotherapy and radiotherapy were not sufficient to control the neoplasia. The tumor recurred after 8 months and she died from clinical complications.\ud \ud \ud Conclusion\ud Our study reports the importance of rapid diagnostics and clinical follow-up of these patients.CAPE

Discrepant outcomes in two Brazilian patients with Bloom syndrome and Wilms’ tumor: two case reports

Abstract\ud \ud Introduction\ud Bloom syndrome is a rare, autosomal recessive, chromosomal instability disorder caused by mutations in the BLM gene that increase the risk of developing neoplasias, particularly lymphomas and leukemias, at an early age.\ud \ud \ud Case presentation\ud Case 1 was a 10-year-old Brazilian girl, the third child of a non-consanguineous non-Jewish family, who was born at 36 weeks of gestation and presented with severe intrauterine growth restriction. She had Bloom syndrome and was diagnosed with a unilateral Wilms’ tumor at the age of 3.5 years. She responded well to oncological treatment and has remained disease-free for the last 17 years. Case 2 was a 2-year-old Brazilian girl born to non-Jewish first-degree cousins. Her gestation was marked by intrauterine growth restriction. She had Bloom syndrome; a unilateral stage II Wilms’ tumor was diagnosed at the age of 4 years after the evaluation of a sudden onset abdominal mass. Surgical removal, neoadjuvant chemotherapy and radiotherapy were not sufficient to control the neoplasia. The tumor recurred after 8 months and she died from clinical complications.\ud \ud \ud Conclusion\ud Our study reports the importance of rapid diagnostics and clinical follow-up of these patients.CAPE

Molecular findings of rare diseases

As doenças raras são um grupo amplo e diverso de entidades clínicas, 80% das quais apresenta etiologia genética. A elucidação etiológica é fundamental para o manejo clínico adequado, mas o processo diagnóstico pode ser desafiador. O Sequenciamento do Exoma, método de estudo genômico em larga escala, revolucionou o diagnóstico das doenças raras. Este estudo busca entender como o Sequenciamento do Exoma pode auxiliar no diagnóstico de doenças raras e quais são seus impactos clínicos. Os objetivos secundários incluem comparar o rendimento diagnóstico desta técnica com outras metodologias, listar as principais indicações clínicas para investigação etiológica e expandir o conhecimento sobre variantes genéticas raras no Brasil e seus impactos populacionais. Para tanto, foram analisados os dados clínicos e moleculares retrospectivos de 500 indivíduos com doenças raras que realizaram sequenciamento do exoma no laboratório Fleury entre os anos de 2014 e 2020 para investigação etiológica. Observou-se rendimento diagnóstico geral de 31,6% (158/500) com o uso desta metodologia e 15,6% (78/500) desta coorte teve potencial direto de redirecionamento dos cuidados clínicos (terapia-alvo, rastreio para neoplasias, adoção de protocolo de seguimento padronizado, ajuste medicamentoso ou monitorização de complicações específicas). As doenças mais frequentes foram: síndrome de Rett, doenças associadas ao gene POLG, doença de NiemannPick tipo C, síndrome KBG, doenças associadas ao gene DEAF1, síndrome de Cowden e síndrome de Noonan. Foram também observados achados secundários com impacto clínico relevante em 7,4% (n = 37) da coorte. Observou-se, ainda, que 71,9% (230/320) dos indivíduos eram portadores em heterozigose de variantes associadas a doenças autossômicas recessivas. Considerando-se essas frequências de portadores (2pq), a equação de Hardy-Weinberg foi utilizada para estimar de forma aproximada a frequência populacional de doenças recessivas (q2) em 26,39/10.000. Ademais, usando-se dados moleculares, populacionais e estudo de segregação nos genitores, 51 variantes raras foram classificadas como benignas e 211 como provavelmente benignas. Este estudo, pioneiro no Brasil, revelou detalhes importantes sobre achados moleculares de pacientes com doenças raras em uma população pouco representada na literatura científica. O diagnóstico preciso é fundamental para o acolhimento adequado desses indivíduos. O aprofundamento sobre o conhecimento das variantes genéticas raras no Brasil e seus impactos na saúde são importantes alicerces para o planejamento de estratégias para as doenças rarasRare diseases are a broad and diverse group of clinical entities, 80% of which present a genetic etiology. Etiological elucidation is essential for proper clinical management, but the diagnostic process can be challenging. Exome Sequencing, a method of large-scale genomic study, has revolutionized the diagnosis of rare diseases. This study aims to understand how Exome Sequencing can assist in the diagnosis of rare diseases and its clinical impacts. Secondary objectives include comparing the diagnostic yield of this technique with other methodologies, listing the main clinical indications for etiological investigation, and expanding knowledge about rare genetic variants in Brazil and their population impacts. For this purpose, clinical and molecular data from 500 individuals with rare diseases who underwent exome sequencing between 2014 and 2020 for etiological investigation were analyzed. An overall diagnostic yield of 31.6% (158/500) was observed using this methodology, and a significant portion of this cohort (15.6%; 78/500) had direct potential for redirection of clinical care (targeted therapy, screening for neoplasms, adoption of standardized follow-up protocol, medication adjustment, or monitoring of specific complications). The most frequent diseases were Rett syndrome, POLG-associated diseases, Niemann-Pick disease type C, KBG syndrome, DEAF1-associated diseases, Cowden syndrome, and Noonan syndrome. Secondary findings with relevant clinical impact were also observed in 7.4% (37/500) of the cohort. Furthermore, 71.9% (230/320) of individuals were heterozygous carriers of variants associated with autosomal recessive diseases. Considering these carrier frequencies (2pq), the Hardy-Weinberg equation was used to estimate the approximate population frequency of recessive diseases (q2) at 26.39/10,000. Moreover, using molecular and population data, as well as parental segregation studies, 51 rare variants were classified as benign, and 211 as probably benign. This study revealed important details about molecular findings in patients with rare diseases in a population that is poorly represented in the scientific literature. Accurate diagnosis is essential for the proper care of these individuals. Further understanding of rare genetic variants in Brazil and their impacts on health are important foundations for planning strategies for rare disease