Tatiana Ferreira de Almeida

Further evidence of the importance of RIT1 in Noonan syndrome

Noonan syndrome (NS) is an autosomal dominant disorder consisting of short stature, short and/or webbed neck, distinctive facial features, cardiac abnormalities, cryptorchidism, and coagulation defects. NS exhibits genetic heterogeneity, associated with mutated genes that participate in RAS‐mitogen‐activated protein kinase signal transduction. Recently, a new gene (RIT1) was discovered as the causative gene in 17 of 180 Japanese individuals who were negative for the previously known genes for NS and were studied using exome sequencing (four patients), followed by Sanger sequencing (13 patients). The present study used the same technique in 70 Brazilian patients with NS and identified six with RIT1 missense mutations. Thus, we confirm that RIT1 is responsible for approximately 10% of the patients negative for mutations in the previously known genes. The phenotype includes a high frequency of high birth weight, relative macrocephaly, left ventricular hypertrophy, and ectodermal findings, such as curly hair, hyperpigmentation, and wrinkled palms and soles. Short stature and pectus deformity were less frequent. The majority of patients with a RIT1 mutation did not show apparent intellectual disability. Because of the relatively high frequency of mutations in RIT1 among patients with NS and its occurrence in different populations, we suggest that it should be added to the list of genes included in panels for the molecular diagnosis of NS through targeted next‐generation sequencing.

The use of different doses of metamizol for post-operative analgesia in dogs.

OBJECTIVE To evaluate the post-operative analgesic effect of metamizol (dipyrone) administered intravenously at three different doses (15 mg kg(-1), 25 mg kg(-1) and 35 mg kg(-1)) compared to placebo in dogs undergoing ovariohysterectomy. STUDY DESIGN Prospective, comparative, randomized, blinded trial. ANIMALS Forty healthy bitches, aged 1-6 years, weighing 10-35 kg METHODS The animals were randomly divided into four groups and received their respective treatments immediately after surgery: placebo group (0.9% saline solution), D15 group (metamizol 15 mg kg(-1) IV), D25 group (metamizol 25 mg kg(-1) IV), D35 group (metamizol 35 mg kg(-1) IV). The following variables were measured: sedation, pulse rate (PR), respiratory rate (f(R)), arterial blood pressure (ABP), plasma catecholamines, serum cortisol, blood urea nitrogen (BUN) and creatinine metabolites, albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), hemogram, platelet counts and level of analgesia which was assessed by visual analog (VAS), descriptive and behavioral scales. Patients were monitored for 48 hours after the administration of the analgesic agent. Rescue analgesia (tramadol, 2 mg kg(-1), intramuscularly) was provided for animals with pain scores ≥4, as determined by the VAS or descriptive scale. RESULTS The D25 and D35 groups showed equivalent post-operative analgesia, as shown by decreased pain scores, according to the three different pain scales, and fewer animals that required rescue analgesia. Significantly lower serum cortisol concentrations were observed in the D25 and D35 groups when compared to the placebo and D15 groups. No hematologic, renal, hepatic or clinical adverse effects were observed during the treatment. CONCLUSIONS AND CLINICAL RELEVANCE Metamizol administered intravenously at 25 or 35 mg kg(-1) can provide adequate post-operative analgesia in bitches undergoing ovariohysterectomy.

Exomic variants of an elderly cohort of Brazilians in the ABraOM database

Brazilians are highly admixed with ancestry from Europe, Africa, America, and Asia and yet still underrepresented in genomic databanks. We hereby present a collection of exomic variants from 609 elderly Brazilians in a census‐based cohort (SABE609) with comprehensive phenotyping. Variants were deposited in ABraOM (Online Archive of Brazilian Mutations), a Web‐based public database. Population representative phenotype and genotype repositories are essential for variant interpretation through allele frequency filtering; since elderly individuals are less likely to harbor pathogenic mutations for early‐ and adult‐onset diseases, such variant databases are of great interest. Among the over 2.3 million variants from the present cohort, 1,282,008 were high‐confidence calls. Importantly, 207,621 variants were absent from major public databases. We found 9,791 potential loss‐of‐function variants with about 300 mutations per individual. Pathogenic variants on clinically relevant genes (ACMG) were observed in 1.15% of the individuals and were correlated with clinical phenotype. We conducted incidence estimation for prevalent recessive disorders based upon heterozygous frequency and concluded that it relies on appropriate pathogenicity assertion. These observations illustrate the relevance of collecting demographic data from diverse, poorly characterized populations. Census‐based datasets of aged individuals with comprehensive phenotyping are an invaluable resource toward the improved understanding of variant pathogenicity.

Mutations in PCYT1A Cause Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy

Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare autosomal-recessive disorder characterized by severe short stature, progressive lower-limb bowing, flattened vertebral bodies, metaphyseal involvement, and visual impairment caused by cone-rod dystrophy. Whole-exome sequencing of four individuals affected by this disorder from two Brazilian families identified two previously unreported homozygous mutations in PCYT1A. This gene encodes the alpha isoform of the phosphate cytidylyltransferase 1 choline enzyme, which is responsible for converting phosphocholine into cytidine diphosphate-choline, a key intermediate step in the phosphatidylcholine biosynthesis pathway. A different enzymatic defect in this pathway has been previously associated with a muscular dystrophy with mitochondrial structural abnormalities that does not have cartilage and/or bone or retinal involvement. Thus, the deregulation of the phosphatidylcholine pathway may play a role in multiple genetic diseases in humans, and further studies are necessary to uncover its precise pathogenic mechanisms and the entirety of its phenotypic spectrum.

Comparison of epidural and systemic tramadol for analgesia following ovariohysterectomy.

The objective of the study was to compare epidural and systemic tramadol for postoperative analgesia in bitches undergoing ovariohysterectomy. Twenty animals, randomly divided into two groups, received either epidural (EPI) or intramuscular (IM) tramadol (2 mg/kg) 30 min before anesthetic induction. Analgesia, sedation, cardiorespiratory parameters, end-tidal isoflurane, blood catecholamines and cortisol, and arterial blood gases were measured at different time points up to 24 hr after agent administration. There were no differences between the two groups regarding cardiorespiratory parameters, end-tidal isoflurane, and pain scores. Two dogs in the IM and one in the EPI group required supplemental analgesia. Cortisol was increased (P<0.05) at 120 min (3.59 μg/dL and 3.27 μg/dL in the IM and EPI groups, respectively) and 240 min (2.45 μg/dL and 2.54 μg/dL in the IM and EPI groups, respectively) compared to baseline. Norepinephrine was also increased (P<0.05) at 120 min in both groups compared to baseline values. Epinephrine values were higher (P<0.05) in the IM group compared with the EPI group at 50 min, 120 min, and 1,440 min after tramadol administration. Epidural tramadol is a safe analgesic, but does not appear to have improved analgesic effects compared with IM administration.

Origem e dispersão dos Tupiguarani: o que diz a morfologia craniana?

Resumo: A origem e a dispersao dos povos Tupiguarani tem sido intensamente debatidas entre arqueologos e linguistas nas ultimas cinco decadas. Em resumo, pode-se dizer que a ideia de que esses povos, que ocuparam grande parte do territorio brasileiro e parte da Bolivia, do Paraguai, do Uruguai e da Argentina, tiveram sua etnogenese na Amazonia e dali partiram para o leste e para o sul, por volta de 2.500 anos antes do presente, e bastante aceita entre os especialistas, embora uma dispersao no sentido oposto, isto e, do sul para o norte, com origem na bacia do Tiete-Parana, nao seja completamente descartada. Entre os arqueologos que consideram a Amazonia como berco desses povos, alguns acreditam que esse surgimento se deu na Amazonia central. Outros acreditam que a etnogenese Tupiguarani ocorreu no sudoeste da Amazonia, onde hoje se concentra a maior diversidade linguistica do tronco Tupi. Neste trabalho, a morfologia de 19 crânios associados a cerâmica Tupiguarani ou etnograficamente classificados como tais foram comparados a varias series cranianas pre-historicas e etnograficas brasileiras por meio de estatisticas multivariadas. Duas tecnicas multivariadas foram empregadas: Analise de Componentes Principais, aplicada sobre os centroides de cada serie, e Distâncias de Mahalanobis, aplicadas aos dados individuais. Os resultados obtidos sugerem uma origem amazonica para os povos Tupiguarani, sobretudo pela forte associacao encontrada entre crânios Tupi e Guarani do sudeste e do sul brasileiro e dos Tupi do norte do Brasil, com os especimes provenientes da ilha de Marajo incluidos no estudo. Palavras-chave: Analise multivariada. Craniometria. Nativos americanos.

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).

Microdeletion 11q13.1.q13.2 in a patient presenting with developmental delay, facial dysmorphism, and esophageal atresia: Possible role of the GSTP1 gene in esophagus malformation

BACKGROUND Esophageal atresia is a major congenital malformation characterized by a complete interruption of the esophageal continuity. It is frequently observed in associations and syndromes. As an isolated finding, it has a multifactorial etiology whose genetic factors are poorly known. Recently, the GST family, especially the GSTM1 null genotype (but not the GSTP1 polymorphism I105V), has been associated with esophageal atresia. These enzymes play a role in phase II detoxification of xenobiotics. Here we present the clinical and molecular findings observed in a patient suggesting that the loss of the GSTP1 allele might predispose to this malformation. CASE We describe a patient presenting with esophageal atresia associated with developmental delay and facial dysmorphism, whose mother used tobacco and alcohol during the first 2 months of her pregnancy. Microdeletion/microduplication analysis was performed using comparative genomic hybridization and a 180K Agilent array. It detected a de novo 2 Mb chromosome 11q13.1.q13.2 deletion. CONCLUSION The deleted chromosomal segment includes the GSTP1 gene. We hypothesize that the deletion of one GSTP1 allele (an isoform highly expressed in embryonic tissues), associated with specific environmental factors, such as tobacco and alcohol, could cause the esophageal atresia observed in our patient.

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.

Origin and dispersion of the Tupiguarani: what does cranial morphology say?

Resumo: A origem e a dispersao dos povos Tupiguarani tem sido intensamente debatidas entre arqueologos e linguistas nas ultimas cinco decadas. Em resumo, pode-se dizer que a ideia de que esses povos, que ocuparam grande parte do territorio brasileiro e parte da Bolivia, do Paraguai, do Uruguai e da Argentina, tiveram sua etnogenese na Amazonia e dali partiram para o leste e para o sul, por volta de 2.500 anos antes do presente, e bastante aceita entre os especialistas, embora uma dispersao no sentido oposto, isto e, do sul para o norte, com origem na bacia do Tiete-Parana, nao seja completamente descartada. Entre os arqueologos que consideram a Amazonia como berco desses povos, alguns acreditam que esse surgimento se deu na Amazonia central. Outros acreditam que a etnogenese Tupiguarani ocorreu no sudoeste da Amazonia, onde hoje se concentra a maior diversidade linguistica do tronco Tupi. Neste trabalho, a morfologia de 19 crânios associados a cerâmica Tupiguarani ou etnograficamente classificados como tais foram comparados a varias series cranianas pre-historicas e etnograficas brasileiras por meio de estatisticas multivariadas. Duas tecnicas multivariadas foram empregadas: Analise de Componentes Principais, aplicada sobre os centroides de cada serie, e Distâncias de Mahalanobis, aplicadas aos dados individuais. Os resultados obtidos sugerem uma origem amazonica para os povos Tupiguarani, sobretudo pela forte associacao encontrada entre crânios Tupi e Guarani do sudeste e do sul brasileiro e dos Tupi do norte do Brasil, com os especimes provenientes da ilha de Marajo incluidos no estudo. Palavras-chave: Analise multivariada. Craniometria. Nativos americanos.