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Structural variation is a source of genetic variation that, in some cases, may trigger pathogenicity. Here, we describe two cases, a mother and son, with the same partial inverted duplication of the long arm of chromosome 8 [invdup(8)(q24.21q24.21)] of 17.18 Mb, showing different clinical manifestations: microcephaly, dorsal hypertrichosis, seizures and neuropsychomotor development delay in the child, and a cleft lip/palate, down-slanted palpebral fissures and learning disabilities in the mother. The deleterious outcome, in general, is reflected by the gain or loss of genetic material. However, discrepancies among the clinical manifestations raise some concerns about the genomic configuration within the chromosome and other genetic modifiers. With that in mind, we also performed a literature review of research published in the last 20 years about the duplication of the same, or close, chromosome region, seeking the elucidation of at least some relevant clinical features.

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Cat eye syndrome (CES) is a rare chromosomal disorder that may be evident at birth. A small supernumerary chromosome is present, frequently has 2 centromeres, is bisatellited, and represents an inv dup(22)(q11) in those affected. It's known that the 22q11 region is associated with disorders involving higher and lower gene dosages. Conditions such as CES, 22q11 microduplication syndrome (Dup22q11) and oculoauriculovertebral spectrum phenotype (OAVS) may share genes belonging to this same region, which is known to have a predisposition to chromosomal rearrangements. The conditions, besides being related to chromosome 22, also share similar phenotypes. Here we have added a molecular evaluation update and results found of the first patient described with CES and OAVS phenotype, trying to explain the potential mechanism involved in the occurrence of this association.

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This report describes an adolescent with Mixed Gonadal Dysgenesis and unexpected mosaicism [karyotype 46,X,mar(Y)/ 47,X, mar(Y),+mar(Y)].). Diagnosis with 1 month of age due to atypical genitalia. He presented a right streak gonad, which was removed due to the risk for germ cell tumor, and a left testis with epididymis barely connected and without vas deferens. Left testis maintenance was sufficient for him to undergo spontaneous puberty. The patient was non-responsive to growth hormone. Webbed neck was the only dysmorphic feature. To the best of our knowledge, there were no similar cases reported with spontaneous pubertal progress reported in the literature.

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Chromosomal duplications are associated with a large group of human diseases that arise mainly from dosage imbalance of genes within the rearrangements. Phenotypes range widely but are often associated with global development delay, intellectual disability, autism spectrum disorders, and multiple congenital abnormalities. How different contiguous genes from a duplicated genomic region interact and dynamically affect the expression of each other remains unclear in most cases. Here, we report a genomic comparative delineation of genes located in duplicated chromosomal regions 8q24.13q24.3, 18p11.32p11.21, and Xq22.3q27.2 in three patients followed up at our genetics service who has the intellectual disability (ID) as a common phenotype. We integrated several genomic data levels by identification of gene content within the duplications, protein-protein interactions, and functional analysis on specific tissues. We found functional relationships among genes from three different duplicated chromosomal regions, reflecting interactions of protein-coding genes and their involvement in common cellular subnetworks. Furthermore, the sharing of common significant biological processes associated with ID has been demonstrated between proteins from the different chromosomal regions. Finally, we elaborated a shared model of pathways directly or indirectly related to the central nervous system (CNS), which could perturb cognitive function and lead to ID in the three duplication conditions.

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Microdeletion syndromes (MSs) are a heterogeneous group of genetic diseases that can virtually affect all functions and organs in humans. Although systems biology approaches integrating multiomics and database information into biological networks have expanded our knowledge of genetic disorders, cytogenomic network-based analysis has rarely been applied to study MSs. In this study, we analyzed data of 28 MSs, using network-based approaches, to investigate the associations between the critical chromosome regions and the respective underlying biological network systems. We identified MSs-associated proteins that were organized in a network of linked modules within the human interactome. Certain MSs formed highly interlinked self-contained disease modules. Furthermore, we observed disease modules involving proteins from other disease groups in the MSs interactome. Moreover, analysis of integrated data from 564 genes located in known chromosomal critical regions, including those contributing to topological parameters, shared pathways, and gene-disease associations, indicated that complex biological systems and cellular networks may underlie many genotype to phenotype associations in MSs. In conclusion, we used a network-based analysis to provide resources that may contribute to better understanding of the molecular pathways involved in MSs.

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OBJECTIVE: To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells. CASE DESCRIPTION: In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse. COMMENTS: HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.

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ABSTRACT Objective: To describe the case of a child who presented hemophagocytic lymphohistiocytosis (HLH) associated with acute monocytic leukemia after chemotherapy, with hemophagocytosis caused by leukemic cells. Case description: In a university hospital in Southern Brazil, a 3-year-old female was diagnosed with acute monocytic leukemia with normal karyotype. The chemotherapy regimen was initiated, and she achieved complete remission six months later, relapsing after four months with a complex karyotype involving chromosomes 8p and 16q. The bone marrow showed vacuolated blasts with a monocytic aspect and evidence of hemophagocytosis. The child presented progressive clinical deterioration and died two months after the relapse. Comments: HLH is a rare and aggressive inflammatory condition characterized by cytopenias, hepatosplenomegaly, fever, and hemophagocytosis in the bone marrow, lymph nodes, spleen, and liver. Although rare, malignancy-associated HLH (M-HLH) is fatal. The patient in this case report met five out of the eight established criteria for HLH. The evolution of the patient's karyotype, regardless of the diagnostic profile, seemed secondary to the treatment for acute monocytic leukemia. In this case, the cytogenetic instability might have influenced the abnormal behavior of leukemic cells. This is a rare case of HLH in a child with acute monocytic leukemia.

RESUMO Objetivo: Descrever um caso de um paciente pediátrico que apresentou linfo-histiocitose hemofagocítica (LHH) associada à leucemia monocítica aguda pós-quimioterapia, com hemofagocitose causada pelas próprias células leucêmicas. Descrição do caso: Em um hospital universitário do Sul do Brasil, uma menina de três anos foi diagnosticada com leucemia monocítica aguda com cariótipo normal. Após receber protocolo quimioterápico, atingiu remissão seis meses depois do início do tratamento, recaíndo quatro meses após com um cariótipo complexo envolvendo ambos os cromossomos, 8p e 16q. A medula óssea mostrava-se infiltrada por células blásticas vacuolizadas com aspecto monocítico, com evidências de hemofagocitose. A criança apresentou um declínio clínico progressivo e dois meses após a recaída foi a óbito. Comentários: A LHH é uma condição inflamatória rara e agressiva caracterizada por citopenias, hepatoesplenomegalia, febre e hemofagocitose na medula óssea, linfonodos, baço e fígado. A LHH associada a doenças malignas, embora seja uma condição rara, é potencialmente fatal. A paciente deste caso apresentou cinco dos oito critérios estabelecidos para o diagnóstico de LHH. A evolução do cariótipo do paciente, independentemente do perfil do diagnóstico, pareceu ser secundária ao tratamento da leucemia monocítica aguda, sendo que a instabilidade citogenética pode ter influenciado o comportamento atípico observado nas células leucêmicas. Este é um dos raros casos de LHH em uma criança com leucemia monocítica aguda.

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In this report, we present a patient with brain alterations and dysmorphic features associated with chromosome duplication seen in 4p16.3 region and chromosomal deletion in a critical region responsible for Cri-du-chat syndrome (CdCS). Chromosomal microarray analysis (CMA) revealed a 41.1 Mb duplication encompassing the band region 4p16.3-p13, and a 14.7 Mb deletion located between the bands 5p15.33 and p15.1. The patient's clinical findings overlap with previously reported cases of chromosome 4p duplication syndrome and CdCS. The patient's symptoms are notably similar to those of CdCS patients as she presented with a weak, high-pitched voice and showed a similar pathogenicity observed in the brain MRI. These contiguous gene syndromes present with distinct clinical manifestations. However, the phenotypic and cytogenetic variability in affected individuals, such as the low frequency and the large genomic regions that can be altered, make it challenging to identify candidate genes that contribute to the pathogenesis of these syndromes. Therefore, systems biology and CMA techniques were used to investigate the extent of chromosome rearrangement on critical regions in our patient's phenotype. We identified the candidate genes PPARGC1A, CTBP1, TRIO, TERT, and CCT5 that are associated with the neuropsychomotor delay, microcephaly, and neurological alterations found in our patient. Through investigating pathways that associate with essential nodes in the protein interaction network, we discovered proteins involved in cellular differentiation and proliferation, as well as proteins involved in the formation and disposition of the cytoskeleton. The combination of our cytogenomic and bioinformatic analysis provided these possible explanations for the unique clinical phenotype, which has not yet been described in scientific literature.

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Ring chromosome 20 (r20) is characterized by intellectual impairment, behavioral disorders, and refractory epilepsy. We report a patient presenting nonmosaic ring chromosome 20 followed by duplication and deletion in 20q13.33 with seizures, delayed neuropsychomotor development and language, mild hypotonia, low weight gain, and cognitive deficit. Chromosomal microarray analysis (CMA) enabled us to restrict a chromosomal segment and thus integrate clinical and molecular data with systems biology. With this approach, we were able to identify candidate genes that may help to explain the consequences of deletions in 20q13.33. In our analysis, we observed five hubs (ARFGAP1, HELZ2, COL9A3, PTK6, and EEF1A2), seven bottlenecks (CHRNA4, ARFRP1, GID8, COL9A3, PTK6, ZBTB46, and SRMS), and two H-B nodes (PTK6 and COL9A3). The candidate genes may play an important role in the developmental delay and seizures observed in r20 patients. Gene ontology included microtubule-based movement, nucleosome assembly, DNA repair, and cholinergic synaptic transmission. Defects in these bioprocesses are associated with the development of neurological diseases, intellectual disability, neuropathies, and seizures. Therefore, in this study, we can explore molecular cytogenetic data, identify proteins through network analysis of protein-protein interactions, and identify new candidate genes associated with the main clinical findings in patients with 20q13.33 deletions.

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GM1 gangliosidosis is a lysosomal storage disorder caused by ß-galactosidase deficiency. To date, prospective studies for GM1 gangliosidosis are not available, and only a few have focused on the adult form. This retrospective cross-sectional study focused on clinical findings in Brazilian patients with the adult form of GM1 gangliosidosis collected over 2 years. Ten subjects were included in the study. Eight were males and two females, with median age at diagnosis of 11.5 years (IQR, 4-34 years). Short stature and weight below normal were seen in five out of the six patients with data available. Radiological findings revealed that the most frequent skeletal abnormalities were beaked vertebrae, followed by hip dysplasia, and platyspondyly. Neurological examination revealed that dystonia and swallowing problems were the most frequently reported. None of the patients presented hyperkinesia, truncal hypertonia, Parkinsonism, or spinal cord compression. Clinical evaluation revealed impairment in activities of cognitive/intellectual development and behavioral/psychiatric disorders in all nine subjects with data available. Language/speech impairment (dysarthria) was found in 8/9 patients, fine motor and gross motor impairments were reported in 7/9 and 5/9 patients, respectively. Impairment of cognition and daily life activities were seen in 7/9 individuals. Our findings failed to clearly identify typical early or late alterations presented in GM1 gangliosidosis patients, which confirms that it is a very heterogeneous condition with wide phenotypic variability. This should be taken into account in the evaluation of future therapies for this challenging condition.