Browsing by Author "Simão, L."
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- Chromosomal disorders and male infertilityPublication . Simão, L.; Caetano, I.; Pedro, S.; Silva, M.; Ambrósio, P.; Gonçalves, J.; Brito, F.; Marques, B.; Alves, C.; Serafim, S.; Geraldes, M.C.; Correia, H.Male factor infertility is considered a complex disorder with a largely unknown etiology that affects about 7% of men. In general, genetic abnormalities account for 15%-30% of condition and Y chromosome microdeletions are also frequent. The study, based on our casuistic, aimed at contributing to a better understanding of the genetic causes of infertility. A group of 410 idiopathic infertile men with non-obstructive azoospermia, oligozoospermia, or unknown semen quality (based on clinical evaluation and/or sperm counts) was retrospectively selected. Conventional karyotype was performed in all samples; Y microdeletion screen was performed in 247 samples. Forty two abnormal karyotypes (10.2%) were found, indicating an elevated frequency of chromosome abnormalities among the selected infertile men, as compared to that of newborn populations (≈0.4%). This frequency is higher than that reported in most similar studies that pointed to frequencies ranging from 2.2%-14.3%. Klinefelter´s syndrome was the most common chromosome disorder (4.9%). There were 18 cases with 47,XXY karyotype and 2 cases of mosaicism involving lines 47,XXY and 46,XY. Reciprocal translocations were identified in 10 cases (2.4%), particularly in men with unknown semen quality. Overall, reciprocal translocations have been found in approximately 1% of the infertile men and more commonly in azoospermics than in oligozoospermics. However, this type of association was not found in the present study. On the other hand, Y microdeletions were identified in 16/247 cases (6.5%), more frequently in azoospermics (13.3%, corresponding to 8/60 azoospermics). Among these 8 cases, 7 presented deletions at the AZFc region. The marked presence of chromosomal abnormalities and Y microdeletions enphasizes the relevance of studying both factors in infertile men to improve genetic counseling, to allow the development of appropriate therapies, and to expand the knowledge about the ethiology of male infertility.
- Derivative chromosome 7 in a newborn with hypotelorism, cleft palate, agenesis of corpus callosum and semilobar holoprosencephalyPublication . Simão, L.; Serafim, S.; Brito, F.; Ventura, C.; Scortenschi, E.; Santos, V.; Correia, H.Cytogenetically visible unbalanced chromosome rearrangements involving the euchromatic regions most often result in severe phenotypic features. Often, it is not possible at microscopic level to distinguish if a chromosomal anomaly involves one or more than one chromosome. In these cases, the parents study is fundamental and is usually the first line of study. We report a female newborn with multiple anomalies. Ultrasonography at 32+6 weeks of gestation revealed moderate ventricular dilatation, microcephaly and intrauterine growth restriction (IUGR). Delivery was at 35 weeks and microcephaly, hypotelorism, complete medium cleft palate with nasal depression, agenesis of the corpus callosum, thalamic fusion and fusion of the lateral ventricles in the frontal region suggestive of semilobar holoprosencephaly (HPE) was observed. Seizures and nistagmus were described since the eighth day. Hypotonia was present. In addition, diabetes insipidus was diagnosed. Sepsis was developed at day 14 followed by death at day 18 in consequence of seizures and respiratory insuficiency. Cytogenetic analysis revealed an abnormal chromosome 7qter as a result of an unbalanced segregation of a maternal reciprocal translocation t(7;19), with breakpoints at 7q36.1 and 19q13.42. The newborn karyotype is 46,XX,der(7)t(7;19)(q36.1;q13.42)mat. The patient presented a partial trisomy of the region 19q13.42→qter and a partial monosomy of the region 7q36.1→7qter. Partial monosomy of chromosome 7qter has been characterized by a wide phenotypic manifestations, but HPE, microcephaly, midface hypoplasia, maxillary anomalies and sacral agenesis are frequently described. However, is not often reported in newborns. Partial trisomy 19q is a rare and severe condition, and has been described associated with low birth weight, growth retardation, microcephaly, seizures, dysmorphic facial features, short neck, clynodactyly, heart malformations, anomalies of the genitor-urinary and gastrointestinal tract. To our knowledge, there is only one previous case of der(7)t(7q;19q)(q36.1;q13.43) described, in a fetus who presented severe sacral agenesis and IUGR. The case herein reported presents some of the most common features of 7q36 partial monosomy and 19q terminal trisomy, although some of them are present in both conditions. The presence of those two imbalances may complicate the final phenotype but the important matter will be the counseling of the couple and to prevent future imbalances in their offspring.
- Diagnóstico pré-natal tardio de uma gestação com anomalias ecográficas e com duplicação da região 7q11.23Publication . Simão, L.; Serafim, S.; Ferreira, C.; Alves, C.; Brito, F.; Silva, M.; Furtado, J.; Viegas, M.; Pedro, S.; Marques, B.; Rodrigues, M.; Sá, J.; Castro, M.J.; Mendes, P.; Vassal, H.; Correia, H.Introdução: O diagnóstico pré-natal (DPN) atempado de anomalias cromossómicas em fetos com anomalias ecográficas é fundamental no prognóstico da gravidez, ou na sua possível interrupção. Assim, a realização das ecografias fetais nas semanas preconizadas é determinante para a gestão dos casos anormais. Descrevemos um caso de uma gravidez mal vigiada, com ecografia fetal realizada às 29 semanas de gestação, onde se identificou uma dilatação pielo-calicial grave no rim esquerdo e dúvida na área cardíaca. Objectivos: Evidenciar que a vigilância atempada das gestações conjuntamente com a análise por microarray aumenta a capacidade de diagnóstico em gestações com anomalias fetais detetadas ecograficamente.
- Interstitial deletion on chromosome 14q in prenatal diagnosisPublication . Simão, L.; Alves, C.; Marques, B.; Pedro, S.; Ferreira, C.; Viegas, M.; Ventura, C.; Furtado, J.; Cruz, J.; Martins, A.; Cohen, A.; Fernandes, R.; Freixo, J.; Correia, J.; Correia, H.A limited number of prenatal diagnosis (PND) cases have reported interstitial deletions of the long arm of chromosome 14 involving the 14q31-32 region. Those cases presented cardiac anomalies, urogenital anomalies, congenital diaphragmatic hernia, and mild pyelectasis. We report the PND of a 33-year-old pregnant woman, who underwent chorionic villus sampling at 12 weeks of gestation after a positive combined 1st trimester screen. The karyotype revealed a 14q interstitial deletion. Amniocentesis was performed at 18 weeks of gestation to confirm the deletion and to exclude a confined placental mosaicism and a microarray analysis was performed in order to accurately define the deletion breakpoints. Cytogenetics analysis revealed a karyotype 46,XY,del(14)(q31q32.2)dn. Microarray analysis allowed to redefined the breakpoints accurate localization and the identification of a ~21Mb deletion (arr[hg19] 14q31.1q32.31(79917376_101568230)x1). At 18 weeks of gestation the fetus presented abnormal fetal biometric parameters (occipitofrontal diameter, cephalic perimeter and abdominal circumference) on ultrasound. After counseling the couple opted for pregnancy termination. The postmorten analysis presented decreased biometry, low weight and low fetal size, facial dysmorphism, clinodactyly, club foot, overlapping fingers and short penis. In internal habitus he presented thymus hypoplasia, bladder hypoplasia, and horseshoe kidneys. The genotype-phenotype correlation in PND pure del(14q) cases is not well established. Furthermore, to our knowledge, del(14q) had not been reported so early in the gestation yet. In this case the positive 1st trimester screen was related to the inverted ductus venosus and low PAPP-A value. The urogenital anomalies (as horseshoe kidneys) and biometry anomalies are described in the literature. However, to our knowledge, some features of the present case were not seen in other reported cases, for instance clinodactyly, club foot, overlapping fingers, thymus hypoplasia and bladder hypoplasia. Other reports described cardiac and cerebral anomalies, diaphragmatic hernia, and also UPD(14)like phenotypes, which are possibly liked to the 14q32 imprinted region. The establishment of a phenotype-genotype correlation is difficult given the size of the deletion, which includes a large number of genes in distinct regions. Nevertheless, this work contributes to a better identification of additional features associated to del(14q) that can be present in PND.
- Mudanças no diagnóstico pré-natal cromossómico: indicações clínicas, amostras biológicas, metodologias e cromossomopatiasPublication . Simão, L.; Silva, M.; Alves, C.; Brito, F.; Serafim, S.; Ambrósio, P.; Geraldes, M.C.; Marques, B.; Ferreira, C.; Pedro, S.; Furtado, J.; Ventura, C.; Tristão, J.; Ferreira, A.; Correia, J.; Correia, H.Introdução: As mudanças no diagnóstico pré-natal de anomalias cromossómicas (DPN) nos últimos 10-15 anos foram contínuas e significativas. Objetivos: Propômo-nos analisar essa evolução: mudanças nas indicações clínicas; introdução das biópsias de vilosidades coriónicas (BVC); utilização do diagnóstico rápido de aneuploidias (DRA); estudos por microarray; alterações cromossómicas encontradas. Metodologia: Fez-se a avaliação retrospetiva nas gestações com amostras estudadas nos triénios 2004-2006 e 2014-2016. Analisaram-se os parâmetros indicação clínica, tipo de amostra, metodologias utilizadas e resultados. Resultados: Identificaram-se 68 fetos com cariotipo anormal em 2210 cariotipos (3,1%) em 2004-2006 e 208 fetos com cariotipo anormal em 2315 cariotipos (9,0%) em 2014-2016. A maior frequência de anomalias encontrou-se nos casos de rastreios ecográficos e combinados indicativos de risco acrescido de anomalia numérica e de progenitores portadores de alterações cromossómicas. As BVC permitiram respostas precoces nas gestações com anomalias numéricas e, adicionalmente, um aumento desses cariotipos (7.5% das amostras). O DRA permitiu ter uma resposta rápida nas anomalias numéricas mais frequentes (2 dias). As anomalias estruturais foram menos preponderantes nos cariotipos anormais (32,4% em 2004-2006 e 14.4% em 2014-2016). Discussão e conclusões: O DRA reduziu o tempo de resposta e das decisões sobre o futuro das gestações. O microarray permitiu identificar alterações sindromáticas em situações não resolúveis por outras metodologias. A utilização de BVC permite estabelecer uma melhor correlação fenotipo-genotipo em menores idades gestacionais. No entanto, as gestações com anomalias numéricas têm algum risco de perda fetal no primeiro e início do segundo trimestres. Assim, algumas BVC com cariotipos anormais resultariam em perdas espontâneas, o que poderia disponibilizar outros casos para DPN. Por outro lado, o menor número de anomalias estruturais equilibradas encontrado pode reduzir o conhecimento da variação genética nas famílias e na população. Um novo paradigma resulta da implementação dos testes não invasivos no DPN, para os quais ainda não conhecemos todas as limitações e repercussões.
- Prenatal diagnosis of 7q11.23 duplication in a fetus with renal pelvic dilatation and the postnatal outcomePublication . Serafim, S.; Ferreira, C.; Simão, L.; Alves, C.; Brito, F.; Silva, M.; Furtado, J.; Viegas, M.; Pedro, S.; Marques, B.; Rodrigues, M.; Sá, J.; Castro, M.J.; Mendes, P.; Vassal, H.; Correia, H.7q11.23 duplication syndrome is a multisystemic developmental disorder characterized by variable manifestations, such as speech delay, mild craniofacial anomalies with distinctive facial features, and intellectual ability ranging from mental retardation to normal cognitive development. Approximately 30% of individuals with 7q11.23 duplication have one or more congenital anomalies. Penetrance is complete with variable expression of phenotypic features. Prevalence has been estimated at 1:7,500-1:20,000. The 7q11.23 duplication is frequently inherited from a parent. Here we report a 33-year-old woman referred for prenatal diagnosis at 29 weeks of gestation due to fetal renal pelvic dilatation. Chromosomal microarray analysis (CMA) was performed after a normal molecular rapid aneuploidy test result and identified a 1.44 Mb duplication at 7q11.23 - arr [GRCh37] 7q11.23 (72,700,467-74,136,633)x3 - overlapping the 7q11.23 duplication syndrome region, in a female fetus. The gain was inherited from the mother which had no previous clinical evaluation but a later reassessment revealed mild cognitive delay and language impairment. Delivery was at 35 weeks due to a maternal respiratory infection with acute pulmonary edema. Newborn resuscitation was required for neonatal respiratory depression with an Apgar score of 1'-2, 5'-4, 10 '-8. Birth weight and length was 2140g and 43cm respectively, with a head circumference of 32cm. In the neonatal period a transient systolic murmur was identified with no alterations on the echocardiogram. Renal and bladder ultrasound showed pelvic dilatation with no changes of the ureteral tract, suggesting a relation with ureteropelvic junction syndrome. Left pyeloplasty for the ureteropelvic junction syndrome was performed at 14 months of age. Clinical evaluation at the age of 22 months revealed psychomotor development delay with delayed speech, facial features overlapping Williams-Beuren syndrome, and the systolic murmur grade I/VI was still present. Growth and weight were both normal. To the best of our knowledge this is the second prenatal case of 7q11.23 duplication described. Although genitourinary tract abnormalities are not the most common feature in patients with 7q11.23 duplication, congenital anomalies of the urinary tract can occur in 15%-18%, including hydronephrosis and unilateral renal agenesis. This shows that the ultrasound abnormalities not always suggest a specific syndrome but after the identification of a pathogenic CNV made possible by the use of CMA a correlation may be achievable. Additionally the discovery of CNVs in prenatal CMA may go beyond the context of the current pregnancy allowing for the identification of carriers thus having a larger impact in a family's health management and genetic counseling.
- Prenatal diagnosis of idic(9)Publication . Simão, L.; Marques, B.; Cravo, J.; Ventura, C.; Correia, H.; Silva, M.; Mourinha, V.; Furtado, J.; Páramos, A.I.Tetrasomy of the short arm of chromosome 9 is a rare chromosome imbalance that may result from a supernumerary isochromosome 9 with the most recurrent breakpoints being 9p10, 9q12 and 9q13. On ultrasound, it usually presents with intrauterine growth restriction (IUGR), abnormal facial profile and ventriculomegaly. However, few reports establish a correlation between fetal features and the size of isochromosome or the presence of isodicentric 9. We report the clinical case of a 32-year-old pregnant woman, G2P1, underwent amniocentesis at 13 weeks of gestation with fetal increased nuchal translucency (7mm). The fetus also presented IUGR, cystic higroma, generalized subcutaneous edema, cardiac malformations, facial anomalies and fetal death. The karyotype was performed by standard in situ methods. Fluorescence in situ hybridization (FISH) was performed using centromeric probe CEP9. Conventional cytogenetic and FISH analyses revealed a supernumerary chromosome idic(9)(q12) in all cells examined. After counseling the couple opted for termination of pregnancy. The post-mortem analysis revealed a single umbilical arteria, IUGR, cystic higroma, facial dysmorphism with cleft lip and palate, hypertelorism and low set ears. These findings are in accordance with other reports. Nevertheless, the hypertelorism is not commonly described and such an early detection of a cardiac anomaly is uncommon. Additionaly the fetal death occurred early than in the most cases described in literature. Although breakpoint position effect on the severity on the phenotype is not consensual it has proposed that cases presenting with breakpoints on p10, on q12 or on q13 show a similar phenotype. However, cardiac defects seem more frequent on cases in which the abnormality includes 9q material. This work aims to contribute to a better karyotype-phenotype correlation in cases with tetrasomy 9p and isodicentric chromosomes idic(9).
- Prenatal diagnosis of mosaic ring chromosome 16 - a rare event with uncertain prognosisPublication . Brito, F.; M. Silv, M.; Alves, C.; Ferreira, C.; Serafim, S.; Simão, L.; Marques, B.; Pedro, S.; Tarelho, A.; Furtado, J.; Lopes, P.; Silva, N.; Viegas, M.; Fernandes, A.; Teixeira, F.; Gomes, S.; Correia, H.Ring chromosomes are rare cytogenetic findings (prenatal frequency ~ 0.0075%) often associated with an abnormal phenotype, depending of the chromosomal origin, genetic content and the presence of a mosaic. Supernumerary ring chromosome 16 [r(16)] is rarely observed and mosaicism makes the genotype/phenotype correlation difficult. We report a de novo mosaic r(16) detected after prenatal diagnosis in a woman referred for advanced maternal age. Multiplex ligation-dependent probe amplification (MLPA) for aneuploidy testing of chromosomes 13, 18, 21 and X was normal. Karyotype was 47,XX,+r[10]/46,XX[15]. Chromosomal microarray analysis (CMA) on DNA obtained from long-term cultured amniocytes did not detect any alterations. MLPA with a pericentromeric probe kit on an uncultured sample showed a chromosome 16 gain, encompassing 16p11.2 and 16q11.2 regions, including TGFB1I1, AHSP, VPS35 and ORC6 genes, leading to partial characterization of the r(16). Although no phenotype has been correlated with overexpression of these genes, the 16p11.2 region is associated with neurodevelopmental disorders. Nevertheless individuals with microduplication of 16p11.2 and normal development have been described. The lack of a precise definition of genetic content of the r(16) and its mosaic form leads to uncertain prognosis of clinical outcome.