Prevalence of Café-au-Lait Spots in children with solid tumors.

Cafe-au-lait maculae (CALM) are frequently observed in humans, and usually are present as a solitary spot. Multiple CALMs are present in a smaller fraction of the population and are usually associated with other congenital anomalies as part of many syndromes. Most of these syndromes carry an increased risk of cancer development. Previous studies have indicated that minor congenital anomalies may be more prevalent in children with cancer. We investigated the prevalence of CALMs in two samples of Brazilian patients with childhood solid tumors, totaling 307 individuals. Additionally, 176 school children without diagnosis of cancer, or of a cancer predisposing syndrome, were investigated for the presence of CALMs. The prevalence of solitary CALM was similar in both study groups (18% and 19%) and also in the group of children without cancer. Multiple CALMs were more frequently observed in one of the study groups (Z = 2.1). However, when both groups were analyzed together, the significance disappeared (Z = 1.5). The additional morphological abnormalities in children with multiple CALMs were analyzed and compared to the findings observed in the literature. The nosologic entities associated with CALMs are reviewed.

Large germline copy number variations as predisposing factor in childhood neoplasms.

AIMS: Constitutive genetic factors are believed to predispose to cancer in children. This study investigated the role of rare germline copy number variations (CNVs) in pediatric cancer predisposition. PATIENTS & METHODS: A total of 54 patients who developed cancer in infancy were screened by array-CGH for germline CNVs. RESULTS: In total, 12 rare CNVs were detected, including a Xq27.2 triplication, and two >1.8 Mb deletions: one of them at 13q31, containing only RNA genes, and another at 3q26.33-q27.1, in a patient with congenital malformations. Detected rare CNVs are significantly larger than those identified in controls, and encompass genes never implicated in cancer predisposition. CONCLUSION: Our results suggest that constitutive CNVs contribute to the etiology of pediatric neoplasms, revealing new candidate genes for tumorigenesis.

A de novo em ~1.3 Mb microdeletion at 17q11.2 associated with Neurofibromatosis-Noonan syndrome

Introduction: Neurofibromatosis-Noonan syndrome is a clinical entity considered an extended Neurofibromatosis phenotype generally caused by different types of intragenic mutations at the NF1 gene. About 5%-10% of patients with neurofibromatosis diagnosis carry chromosomal microdeletions involving NF1, often presenting with a more severe phenotype than that observedin the patients carrying intragenic mutations; however, anticipating the presence of a deletion based only in the phenotype is not straightforward. Patient and Methods: Here we investigated by oligoarray-CGH (aCGH) the presence of a submicroscopic genomic rearrangement in a patientwith a clinical picture of Neurofibromatosis, and other characteristics compatible with Noonansyndrome. Results: The aCGH analysis revealed a germline de novo ~1.3 Mb microdeletion at 17q11.2 encompassing other coding genes besides the NF1 gene. Discussion: Up to now, thenumber of reported patients with Neurofibromatosis-Noonan syndrome carrying NF1 microdeletions is quite small. The continuous identification of patients carrying 17q11.2 deletions canhelp to establish a reliable genotype-phenotype relationship in this syndrome

A rare case of trisomy 15pter-q21.2 due to a de novo marker chromosome.

Supernumerary marker chromosomes (sSMC) may or may not be associated with an abnormal phenotype, depending on the presence of euchromatin, on their chromosomal origin and whether they are inherited. Over 80% of sSMCs are derived from acrocentric chromosomes and half of them include the short arm of chromosome 15. Generally, they appear as bisatellited isodicentric marker chromosomes, most of them are symmetric. These chromosomes are normally originated de novo and are associated with mild to severe intellectual disability but not with physical abnormalities. We report on a patient with an SMC studied using classical and molecular cytogenetic procedures (G and C banding, NOR staining, painting and centromeric fluorescent in situ hybridization (FISH), BAC-FISH, and SKY). The MLPA technique and DNA polymorphic markers were used in order to identify its parental origin. The marker chromosome, monosatellited and monocentric, was found to be derived from a maternal chromosome 15 and was defined as 15pter-q21.2. This is the report of the largest de novo monosatellited 15q marker chromosome ever published presenting detailed cytogenetic and clinical data. It was associated with a phenotype including cardiac defect, absence of septum pellucidum, and dysplasia of the corpus callosum.

Two new Brazilian patients with Gómez-López-Hernández syndrome: reviewing the expanded phenotype with molecular insights.

Gómez-López-Hernández (GLH) syndrome or cerebello-trigeminal dysplasia is a neurocutaneous syndrome whose etiology is unknown at the present time. We report two additional Brazilian patients, including the oldest one known to date (age 29). Here, we review the expanded phenotype in four patients with new clinical, psychiatric, radiological, and molecular investigations. One patient may have hypomania within the bipolar spectrum disorder with onset in childhood and adolescence. Primary growth hormone (GH) deficiency was ruled out in all patients, although one of them might have developed secondary GH deficiency due to partial hypopituitarism following severe hydrocephalus. Brain magnetic resonance angiography disclosed no azygous anterior cerebral artery (ACA) but only normal variants. Molecular analysis of the lysosomal acid phosphatase gene (ACP2) was performed, but no pathogenic mutations were identified. We present an overview of the phenotypic features of all patients described to date. There are currently 12 unrelated patients reported in the literature, 5 of whom are Brazilian. We discuss new molecular insights and speculate about the pathogenesis of GLH syndrome.

Avaliação da prevalência de defeitos congênitos, doenças genéticas e alterações dismórficas em crianças com câncer / Determination of prevalence of birth defects, genetic disease and dismorphic features in childhood malignancy

As características específicas das neoplasias da criança tem sugerido que uma grande parte pode ser atribuída a mutações genéticas ou predisposições genéticas. Estudos mostram a presença de associações entre defeitos congênitos e neoplasia na infância, postulando que alterações em vias moleculares do desenvolvimento estariam tambem, de maneira análoga, envolvidas na tumorigênese em crianças. As anomalias menores parecem ser indicadores importantes, pois estudos mostram uma prevalência aumentada destes nas crianças portadores de câncer. Esses achados dismorfológicos são indentificáveis ao exame físico externo, constituindo informações clínicas valiosas e potencialmente úteis em possível rastreamento de neoplasia nas crianças. Esse estudo visa determinar a prevalência de variações comuns, anomalias menores e defeitos congênitos em crianças portadoras de câncer e descrever associações entre estes achados dismórficos e grupos específicos de neoplasias. O estudo é transversal com casuística constituída por crianças portadoras de câncer atendidas em regime ambulatorial do Departamento de Pediatria do Hospital do Câncer A.C. Camargo. O exame clínico foi realizado por médico geneticista que preencheu um protocolo padronizado constituído por lista integral de achados físicos. O atendimento genético-clínico consistiu na obtenção por anamnese dos antecedentes obstétricos e perinatais do paciente, da história familial com realização de heredograma e o exame físico dismorfológico externo. As variáveis estudadas consistem em dados clínico-epidemiológicos, antecedentes materno-obstétricos e perinatais, dados do tumor (tipo histológico e tratamento) além de uma lista de achados dismorfológico constituídos por anomalias maiores e menores. Os dados coletados a partir do protocolo clínico foram tabulados em planilha do programa SPSS versão 11.0. Foram examinados 122 crianças portadoras de câncer. Todos os pacientes apresentaram variações fenotípicas. As prevalências de anomalias menores e defeitos congênitos corresponderam respectivamente a 76,2% e 20,5%. As síndromes genéticas encontradas consistiam em um caso de síndrome de Down, um caso de hemihipertrofia isolada e três casos de neurofibromatose do tipo 1. Não houve prevalência aumentada significativa de anomalias menores e maiores em um determinado tipo de neoplasia. O grupo dos tumores embrionários mostrou prevalência significativamente maior de anomalias menores comparado com os demais grupos de tumores. Há uma alta prevalência de anomalias menores e defeitos congênitos na população estudada de crianças com câncer. Portanto, a investigação de achados dismórficos criança com câncer infantil pode prover importantes indícios referentes à heterogeneidade clínica e biológica da doença e sugerir localização de genes que podem ter um papel importante no desenvolvimento neoplásico.

Presence of pattern of phenotypic abnormalities in children with cancer suggest that constitutional gene defects may be involved in paediatric oncogenesis. A large number of studies have shown birth defects of various origin associated with childhood cancer- Minor anomalies are harmless and easily recognizable morphological abnormalities which may be detected during physical examination. In a well-organized surveillance system, minor anomalies may be considered as potential clues for useful detection of yet unidentified malignancy. This study concerns the relationship between minor anomalies and birth defects in infants with cancer. We aim to describe the frequency of minor anomalies / birth defects and the association between dismorphic features and specific group of malignancy. This transversal study enrolled children with cancer followed in outpatient unit of the Pediatric Department of the Hospital do Cdncer A.C. Camargo. We examined by a careful non-invasive physical examination directed at 683 well-defined phenotypic features in 122 children. Clinical and epidemiological datas, family history and pregnancy history were obtained. All patients present common variants. Prevalence of minor anomalies and birth defects were 76,2% and 20,5%, respectively. Genetic syndrome detected were Down syndrome (1), isolated hemihypertrophy (1) and neurofibromatosis type 1 (3). No significant differences were observed between prevalence of minor anomalies and a specific malignancy. The prevalence or more than three minor anomalies were significantly higher in the embryonal tumor group (p<0.009). Higher prevalence of minor anomalies and birth defects were determined in childhood malignancy. Minor anomalies remain essential to early recognition of several serious malformation syndromes and may be an important predictive value in identification of childhood cancer.

Comparison of embryo implantation in Wistar rats that underwent ovarian stimulation using exogenous gonadotropins associated with cetrorelix acetate or leuprolide acetate.

OBJECTIVE: To compare embryo implantation in Wistar rats submitted to ovarian stimulation using recombinant FSH (rFSH) with cetrorelix acetate or leuprolide acetate. DESIGN: Experimental study. SETTING: Faculty of medicine animal facility. PATIENT(S): Fifty-six female Wistar rats with normal estrus cycles and 30 male. INTERVENTION(S): Ovarian stimulation and laparotomy (by the day 13 of gestation). MAIN OUTCOME MEASURE(S): Embryo implantation. RESULT(S): The female rats were subdivided into four groups: group 1, medicated with rFSH, hCG, and cetrorelix acetate; group 2, medicated with rFSH, hCG, and leuprolide acetate; group 3, medicated with rFSH and hCG; and group 4, in which only saline solution was administered. The female rats were mated with fertile male rats on the day of hCG administration with copulation confirmed through cytologic vaginal analysis. The females were killed on the 13th day of gestation. After laparotomy, comparison and identification was done regarding the numbers of corpora lutea and embryo implantations and gestation rates. Group 1 presented lower numbers of corpora lutea and embryo implantations in comparison to the other groups (P<.05). A difference was not found in the gestation rates between the groups. CONCLUSION(S): The number of embryo implantations in Wistar rats medicated with rFSH and cetrorelix acetate is lower than that of rats medicated with rFSH and leuprolide acetate.

Acute monocytic leukemia and multiple abnormalities in a child with duplication of 1q detected by GTG-banding and SKY.

Patients with 1q duplication have demonstrated a wide range of multiple congenital abnormalities. Alterations involving this chromosomal region have being described in hematopoietic malignancies and a series of candidate genes that may be associated with neoplasias have been mapped in this region. We describe a case of partial trisomy 1q "syndrome" and acute monocytic leukemia. Cytogenetic study of the bone marrow cells by GTG-banding and spectral karyotyping (SKY) showed dup(1)(q23q44) in all cells analyzed. The dismorphological features with the dup(1q) suggest a constitutional chromosome alteration and the first, in our knowledge, association of a trisomy 1q "syndrome" with AML.