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Syndromic hearing loss accounts for approximately 30% of all cases of hearing loss due to genetic causes. Mutation screening in known genes is important because it potentially sheds light on the genetic etiology of hearing loss and helps in genetic counseling of families. In this study, we describe a customized Ion AmpliSeq Panel, specifically designed for the investigation of syndromic hearing loss. The Ion AmpliSeq Panel was customized to cover the coding sequences of 52 genes. Twenty-four patients were recruited: 17 patients with a clinical diagnosis of a known syndrome, and seven whose clinical signs did not allow identification of a syndrome. Of 24 patients sequenced, potentially causative mutations were found in nine, all of which belonged to the group with a previous clinical diagnostic and none in the group not clinically diagnosed. We were able to provide conclusive molecular diagnosis to six patients, constituting a diagnostic rate of 25% (6/24). In the group of patients with a suspected clinical diagnosis, the diagnostic rate was 35% (6/17). Of the nine different mutations identified, three are novel, and were found in patients with Waardenburg, Treacher Collins and CHARGE syndromes. Since all patients with a conclusive molecular diagnosis through this panel had a previous suspected clinical diagnosis, our results suggest that this panel was more effective in diagnosing this group of patients. Therefore, the panel demonstrated effectiveness in molecular diagnosis when compared to others in the literature, especially for patients with a defined clinical diagnosis.

Duplications of the long arm of chromosome 1 are rare. Distal duplications are the most common and have been reported as either pure trisomy or unbalanced translocations. The paucity of cases with pure distal 1q duplications has made it difficult to delineate a partial distal trisomy 1q syndrome. Here, we report 2 patients with overlapping 1q duplications detected by G-banding. Array CGH and FISH were performed to characterize the duplicated segments, exclude the involvement of other chromosomes and determine the orientation of the duplication. Patient 1 presents with a mild phenotype and carries a 22.5-Mb 1q41q43 duplication. Patient 2 presents with a pure 1q42.13qter inverted duplication of 21.5 Mb, one of the smallest distal 1q duplications ever described and one of the few cases characterized by array CGH, thus contributing to a better characterization of distal 1q duplication syndrome.

It has been reported that patients with Down syndrome (DS) frequently develop transient myeloproliferative disorder (TMD) and less commonly myeloid leukemia in DS (ML-DS). We examined the pathogenetic relationship of these conditions with somatic mutations of the GATA1 gene in children with both TMD and ML-DS. To determine the incidence of GATA1 mutations in a cohort of DS patients and the applicability of these mutations as a clonal marker to detect minimal residual disease, we screened 198 samples of 169 patients with DS for mutations in GATA1 exon 2 by direct sequencing. Novel mutations were detected in four of the 169 DS patients (2 with TMD and 2 with ML-DS). We examined spontaneous remission and response to therapy in TMD and ML-DS patients and concluded that these mutations can be used as stable markers in PCR analysis to monitor these events.

The TBL1XR1 gene product is a nuclear protein ubiquitously produced. The protein is a component of SMRT/N-CoR co-repressor complexes and participates in the molecular switch of specific gene transcription. Deletions of the TBL1XR1 gene have been described in two families to date, both presenting intellectual disability and dysmorphisms. Rare recurrent chromosomal micro-rearrangements, particularly those involving single genes, represent a challenge for clinicians to ensure correlation with phenotype due to the paucity of previously described cases. Here we present a patient harbouring a TBL1XR1 gene deletion detected by chromosome microarray analysis. In addition to intellectual disability, the patient presents dysmorphic features and multiple cardiac malformations, together with brain malformation, thus contributing to the phenotypic characterization of this rare microdeletion and to the TBL1XR1 gene function.

Deletions in the short arm of chromosome 12 are the rarest subtelomeric imbalances. Less than 20 patients have been reported to date, and their microdeletions were identified either by FISH or array-CGH without SNP data. Here, we report a patient with a 12p13.32pter mosaic deletion detected by chromosome microarray analysis with loss of heterozygosity (LOH) of the deleted segment in addition to the adjacent distal segment. LOH is indicative of a complex rearrangement, suggestive of mitotic microhomology-mediated break-induced replication.

CONTEXTO: Alguns estudos têm demonstrado maior prevalência de doença celíaca entre mulheres com síndrome de Turner, quando comparadas com a população geral. Entretanto, não há registro na literatura desta investigação em pacientes brasileiras. OBJETIVO: Avaliar a prevalência de doença celíaca entre um grupo de pacientes brasileiras com síndrome de Turner. MÉTODOS: Cinquenta e seis pacientes com síndrome de Turner recebendo dieta contendo glúten foram triadas para doença celíaca, utilizando-se ensaios sorológicos com anticorpos imunoglobulina A antiendomísio (IgA-EMA) e imunoglobulina A antitranslgutaminase tecidual (IgA-tTG). Adicionalmente, elas foram genotipadas para os alelos predisponentes para doença celíaca de antígenos leucocitários humanos (doença celíaca-HLA). Às pacientes que mostraram positividade no teste sorológico, propôs-se a realização de biopsia do intestino delgado para confirmação histológica. RESULTADOS: A idade média ao diagnóstico de síndrome de Turner foi 5,5 ± 4,4 anos; idade média durante a triagem da doença celíaca foi 17,0 ± 9,3 anos (abrangendo dos 10 meses de idade aos 52 anos). Duas meninas foram positivas para IgA-EMA e IgA-tTG, apresentaram os alelos predisponentes para doença celíaca HLA-DQ2 e tiveram o diagnóstico de doença celíaca confirmado por biopsia jejunal. CONCLUSÃO: A prevalência de 3,6% de doença celíaca confirmada por biopsia neste grupo de pacientes com síndrome de Turner, foi 10 vezes maior que aquela encontrada entre mulheres da população geral da mesma área geográfica. Este resultado contribui para corroborar a associação entre estas duas doenças e reforça que meninas e mulheres com síndrome de Turner constituem uma população de risco aumentado para desenvolver doença celíaca. CONTEXT: Several studies have demonstrated a higher prevalence of celiac disease (CD) among females with Turner syndrome when compared to the general population. Nevertheless, there is no record in literature concerning this investigation among Brazilian patients. OBJECTIVE: To assess the prevalence of CD among a group of Brazilian patients with Turner syndrome. METHODS: Fifty-six females with Turner syndrome and on gluten-containing diet were screened for CD utilizing immunoglobulin A antiendomysium (IgA-EMA) and immunoglobulin A anti-tissue transglutaminase (IgA-tTG) antibody assays. Additionally, they were genotyped for CD human leukocyte antigen (CD-HLA) predisposing alleles. Patients showing positivity in serological testing were offered to perform small intestine biopsy for histological confirmation. RESULTS: Mean age at diagnosis of Turner syndrome was 5.5 ± 4.4 years; mean age at screening for CD was 17.0 ± 9.3 years (from 10 months of age to 52 years). Two girls were positive for IgA-EMA and IgA-tTG, presented predisposing HLA-DQ2 alleles and both had the diagnosis of CD confirmed by jejunal biopsy. CONCLUSION: The 3.6% prevalence of biopsy-proven CD among this group of females with Turner syndrome is 10 times higher than the one among females from the general population of the same geographical area. This result provides additional support to an association between these two disorders and restates that girls and women with Turner syndrome represent a high risk population for developing CD.

Acute lymphoblastic leukemia (ALL) accounts for approximately 80% of all acute leukemias during childhood. Chromosomal anomalies resulting from gene fusion, which are frequent in leukemias, create hybrid transcripts, the great majority of which encode transcription factors. We analyzed 88 pediatric patients (median age 7.3 years) who had B-lineage acute lymphoblastic leukemia (B-ALL), using reverse transcriptase-polymerase chain reaction, to look for gene fusion transcripts of TEL/AML1, E2A/PBX1, BCR/ABL p190, and MLL/AF4. The frequencies of these transcripts were 21.21, 9.68, 3.03, and 0%, respectively. All positive cases had a common B-ALL immunophenotype. The low frequency of the TEL/AML1 transcript that is found in developing countries, such as Brazil, may be due to the low incidence of leukemia; this would support Greaves' hypothesis.

Transient myeloproliferative disorder is a form of self-limited leukemia that occurs almost exclusively in neonates with Down syndrome. The authors report an unusual case of a newborn without constitutional trisomy 21 who developed undifferentiated leukemia and subsequently achieved clinical and molecular remission without chemotherapy. Cytogenetics and molecular analysis have shown trisomy 21 and GATA1 mutation restricted to leukemic cells. G-to-T transversion was detected, which is predicted to result in a premature stop codon (c.119G>T; pGlu67X) in diagnosis samples. These findings emphasize that there must be a powerful interaction between GATA1 and trisomy 21 in leukemogenesis process.

Genetic defects resulting in deficiency of thyroid hormone synthesis can be found in about 10% of the patients with permanent congenital hypothyroidism, but the identification of genetic abnormalities in association with the transient form of the disease is extremely rare. We report the case of a boy with transient neonatal hypothyroidism that was undiagnosed in the neonatal screening, associated with extrathyroid malformations and mental retardation. The boy carries an unbalanced translocation t(8;16), and his maternal uncle had a similar phenotype. Chromosomal analysis defined the patient's karyotype as 46,XY,der(8)t(8;16)(q24.3;q22)mat,16qh+. Array-CGH with patient's DNA revealed a ~80 kb terminal deletion on chromosome 8q24.3qter, and a ~21 Mb duplication on chromosome 16q22qter. ZNF252 gene, mapped to the deleted region on patient's chromosome 8, is highly expressed in the thyroid, and may be a candidate gene for our patient's transient neonatal thyroid dysfunction. This is the first report on the association of a chromosomal translocation with the transient form of congenital hypothyroidism. This description creates new hypothesis for the physiopathology of transient congenital hypothyroidism, and may also contribute to the definition of the unbalanced translocation t(8;16)(q24.3;q22) phenotype, which has never been described before. Arq Bras Endocrinol Metab. 2012;56(8):564-9 Defeitos genéticos resultando em deficiência hormonal tireoidiana podem ser encontrados em cerca de 10% dos pacientes com hipotireoidismo congênito permanente, porém a identificação de anormalidades genéticas associadas à forma transitória da doença é extremamente rara. Relatamos o caso de um menino com hipotireoidismo neonatal transitório não diagnosticado no teste de triagem neonatal, associado a malformações extratireoidianas e retardo mental. O paciente é portador de translocação não balanceada t(8;16), e seu tio materno tinha fenótipo similar. A análise cromossômica definiu o cariótipo do paciente como 46,XY,der(8)t(8;16)(q24.3;q22)mat,16qh+. A análise cromossômica array-CGH com o DNA do paciente revelou deleção terminal de ~80 kb no cromossomo 8q24.3qter, e duplicação de ~21 Mb no cromossomo 16q22qter. O gene ZNF252, mapeado na região da deleção no cromossomo 8 do paciente, é altamente expresso na tireoide e pode ser um gene candidato no hipotireoidismo neonatal transitório do paciente. Esse é o primeiro relato de associação de uma translocação cromossômica com a forma transitória do hipotireoidismo congênito. Essa descrição descortina novas hipóteses para a fisiopatologia do hipotireoidismo congênito transitório e também pode contribuir para a definição do fenótipo da translocação não balanceada t(8;16)(q24.3;q22), nunca descrito anteriormente. Arq Bras Endocrinol Metab. 2012;56(8):564-9

Objective To describe oral manifestations in Brazilian individuals with Kabuki syndrome, a multiple congenital anomaly/mental retardation syndrome. Study Design A total of 16 Kabuki syndrome individuals, aged between 8 to 24 years and of both sexes, were referred by the Department of Clinical Genetics for oral treatment and follow-up to the Oral Care Center for Inherited Diseases, University Hospital of Brasília, Brasília, Brazil. Each individual underwent complete physical examination, as well as intraoral and radiographic examinations. Results Craniofacial and dental alterations were observed in all Kabuki syndrome patients examined. In addition, atypical shape of the molars' crowns, occlusal convergence of the premolars' crowns, and root dilaceration were also observed. Enamel diffuse opacities were observed in permanent dentition (n = 10). Conclusion A great clinical heterogeneity was observed in Kabuki syndrome individuals in line with previous studies in the literature. Further clinical and molecular studies are necessary in order to better understand the presence of dental anomalies in this syndrome.