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Extramedullary hematopoietic effusion (EHE) is one of the extremely rare phenomena associated with extramedullary hematopoiesis, which is caused by serous effusions, including pleural effusion, and may be related to hematologic disorders and neoplasms. Herein, we present the case of an 81-year-old man with EHE accompanying Waldenström's macroglobulinemia (WM). The patient complained of anemia and dyspnea. The chest X-ray and computed tomography showed a massive left pleural effusion, and the aspirates revealed infiltration of the immature myeloid cells and megakaryocytes, in addition to the lymphoma cells. To our knowledge, this is the first report of EHE in WM.

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PURPOSE: Interstitial 6q deletions are associated with rare genetic syndromes characterized by different signs, including developmental delay, dysmorphisms, and Prader-Willi (PWS)-like features. Drug-resistant epilepsy, a relatively rare finding in this condition, is often a challenge in terms of therapeutic approach. Our aim is to present a new case of interstitial 6q deletion and to conduct a systematic review of the literature with an emphasis on the neurophysiological and clinical traits of afflicted individuals. METHODS: We report a patient with an interstitial 6q deletion. Standard electroencephalograms (EEG), video-EEG with polygraphy and MRI features are discussed. We also conducted a literature review of previously described cases. RESULTS: We describe a relatively small interstitial 6q deletion (2 Mb circa), detected by CGH-Array, not encompassing the previously described 6q22 critical region for epilepsy occurrence. The patient, a 12-year-old girl, presented with multiple absence-like episodes and startle-induced epileptic spasms since the age of 11, with partial polytherapy control. Treatment with lamotrigine induced the resolution of startle-induced phenomena. From the literature review, we identified 28 patients with overlapping deletions, often larger than our patient's mutation. Seventeen patients presented with PWS-like features. Epilepsy was reported in 4 patients, and 8 patients presented abnormal EEG findings. In our patient, the deletion included genes MCHR2, SIM1, ASCC3, and GRIK2, but, interestingly, it did not encompass the 6q22 critical region for epilepsy occurrence. The involvement of GRIK2 in the deletion may play a role. CONCLUSION: Literature data are limited, and specific EEG or epileptological phenotypes cannot yet be identified. Epilepsy, although uncommon in the syndrome, deserves a specific diagnostic workup. We speculate on the existence of an additional locus in the 6q16.1-q21 region, different from the already hypothesized q22, promoting the development of epilepsy in affected patients.

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Hypotonia is a symptom of diminished tone of skeletal muscle and can be nongenetic or a part of genetic syndrome. Hypotonia, developmental delay, and facial dysmorphism are nonspecific findings observed in many genetic syndromes mostly in chromosomal microdeletion and duplication. Here we report a case with severe hypotonia and facial dysmorphism, diagnosed with deletion at 6q13q14.3 by array comparative genomic hybridization (CGH) at very early age. Recent genetic diagnostic technologies such as array CGH may enable clinicians to diagnose chromosomal abnormalities earlier and provide appropriate medical management.

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BACKGROUND: Terminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook. The aim of the project is to improve the surveillance of patients with chromosome 6 aberrations and the support for their families by increasing the available information about these rare aberrations. This parent-driven research project makes use of information collected directly from parents via a multilingual online questionnaire. Here, we report our findings on 93 individuals with terminal 6q deletions and 11 individuals with interstitial 6q26q27 deletions, a cohort that includes 38 newly identified individuals. RESULTS: Using this cohort, we can identify a common terminal 6q deletion phenotype that includes microcephaly, dysplastic outer ears, hypertelorism, vision problems, abnormal eye movements, dental abnormalities, feeding problems, recurrent infections, respiratory problems, spinal cord abnormalities, abnormal vertebrae, scoliosis, joint hypermobility, brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), seizures, hypotonia, ataxia, torticollis, balance problems, developmental delay, sleeping problems and hyperactivity. Other frequently reported clinical characteristics are congenital heart defects, kidney problems, abnormalities of the female genitalia, spina bifida, anal abnormalities, positional foot deformities, hypertonia and self-harming behaviour. The phenotypes were comparable up to a deletion size of 7.1 Mb, and most features could be attributed to the terminally located gene DLL1. Larger deletions that include QKI (> 7.1 Mb) lead to a more severe phenotype that includes additional clinical characteristics. CONCLUSIONS: Terminal 6q deletions cause a common but highly variable phenotype. Most clinical characteristics can be linked to the smallest terminal 6q deletions that include the gene DLL1 (> 500 kb). Based on our findings, we provide recommendations for clinical follow-up and surveillance of individuals with terminal 6q deletions.

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Objective: To study the clinical and cytogenetic characteristics of patients with multiple myeloma harboring 6q deletion, with the aim to determine the impact of 6q deletion on survival. Methods: This study included the retrospective analysis of 382 newly diagnosed patients with multiple myeloma in our hospital from 2014 to 2017 and compared the clinical and cytogenetic characteristics between patients with and without 6q deletion. The log-rank test and the Cox proportional hazards regression model were used to analyze prognostic factors for progression-free survival (PFS) and overall survival (OS) . Results: Compared to those without 6q, the patients with 6q deletion were older (median age, 63 vs 58 years, P=0.039) , had higher incidence of t (4; 14) (30.4% vs 16.4% , P=0.020) , and higher proportion of complex karyotypes (22.2% vs 5.3% , P=0.001) . Univariate survival analysis using the log-rank test revealed that 6q deletion was associated with shorter PFS. However, by the Cox multivariate proportional hazards regression model, 6q deletion was not an independent prognostic factor and its effect on survival was affected by age, t (4; 14) , and other risk factors. Conclusions: 6q deletion was common in elderly patients with multiple myeloma and was often accompanied by t (4;14) and complex karyotypes. However, 6q deletion was not an independent prognostic factor for multiple myeloma.

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Deletion of the long arm of chromosome 6 (del6q) is the most frequent cytogenetic abnormality in Waldenström macroglobulinaemia (WM), occurring in approximately 50% of patients. Its effect on patient outcome has not been completely established. We used fluorescence in situ hybridisation to analyse the prevalence of del6q in selected CD19+ bone marrow cells of 225 patients with newly diagnosed immunoglobulin M (IgM) monoclonal gammopathies. Del6q was identified in one of 27 (4%) cases of IgM-monoclonal gammopathy of undetermined significance, nine of 105 (9%) of asymptomatic WM (aWM), and 28/93 (30%) of symptomatic WM (sWM), and was associated with adverse prognostic features and higher International Prognostic Scoring System for WM (IPSSWM) score. Asymptomatic patients with del6q ultimately required therapy more often and had a shorter time to transformation (TT) to symptomatic disease (median TT, 30 months vs. 199 months, respectively, P < 0·001). When treatment was required, 6q-deleted patients had shorter progression-free survival (median 20 vs. 47 months, P < 0·001). The presence of del6q translated into shorter overall survival (OS), irrespective of the initial diagnosis, with a median OS of 90 compared with 131 months in non-del6q patients (P = 0·01). In summary, our study shows that del6q in IgM gammopathy is associated with symptomatic disease, need for treatment and poorer clinical outcomes.

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BACKGROUND: Non-acrocentric satellited chromosomes mostly result from familial balanced insertions or translocations with p12 or p13 of any acrocentric. Although all non-acrocentrics have been involved, only 12 instances of chromosome 6 involvement are known. CASE PRESENTATION: A female infant exhibited clinical features typical of 6qter deletions and also generalized hypertrichosis and synophrys, traits seldom reported in patients with similar imbalances or haploinsufficiency of ARID1B located in 6q25.3. She had a paternal derivative satellited 6q of a t(6;22)(q25.3;p12)pat entailing a 6q terminal deletion, karyotype 46,XX,der(6)t(6;22)(q25.3;p12)pat [16].ish del 6q subtel-. CONCLUSION: Male and female carriers of reciprocal translocations or insertions between chromosome 6 and the short arm of any acrocentric have few unbalanced offspring mostly by adjacent-1 segregation. In addition, spontaneous abortions or male infertility was present in 7/13 instances of satellited chromosome 6.

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Waldenström macroglobulinemia (WM) is a rare low-grade B-cell lymphoma. This report focuses on WM in Japan. Regarding epidemiology, per the 2016 registry data by the Japanese Society of Hematology, WM and lymphoplasmacytic lymphoma (LPL) cases were 229 and 125, respectively (1.97% of 17,957 mature lymphoid malignancies), with the annual incidence of WM/LPL in Japan 2.8 per million. In addition, 6q deletion (6q del) is the leading aberration and one of the poor prognostic factors in WM. Our findings suggested that the serum IgM level was higher in WM with 6q del compared with those without, and the B-cell receptor signaling pathway and IL-21 receptor expression were activated in WM with 6q del. Hence, these findings might be attributed to the aggressiveness of the WM with 6q del. Regarding treatment, recent studies investigating the epidemiological treatment pattern for WM have reported rituximab (R) monotherapy and alkylating regimen (±R) as the leading initial treatment. Nevertheless, ideal treatment algorithm in Japan warrants further investigation.

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Cancer heterogeneity represents a challenge for the analysis of prognostic molecular markers but can be used to study the evolution of molecular events in tumors. To assess the degree of heterogeneity of 5q21 deletions and their relationship with TMPRSS2:ERG status and 6q15 deletions in prostate cancer, a heterogeneity tissue microarray including 10 tissue spots from 10 different areas of 317 cancers was analyzed by fluorescence in situ hybridization for 5q21 deletion. Data on 6q and ERG were available from earlier studies. Deletions of 5q21 were found in 23% of 265 interpretable cancers and showed marked intratumoral heterogeneity. In the subset of 246 cancers with at least 3 interpretable spots, 23% had a 5q21 deletion. Heterogeneous 5q21 deletions were found in 71% and homogeneous in 29% of these cancers. The likelihood of 5q21 deletion was twice as high in ERG-negative (28%) than in ERG-positive cancers (16%, P = .024). In all 21 cases harboring both alterations, the tumor area containing a 5q21 deletion was smaller or equally large than the ERG-positive area but never larger. Deletions of 5q and 6q were significantly linked. However, the analysis of 32 tumors harboring both deletions did not suggest a specific order of appearance of these deletions. The 5q21 deletion preceded 6q15 in 10 tumors and 6q15 preceded 5q21 in 14 tumors. In summary, our study identifies 5q21 deletion as a highly heterogeneous aberration in prostate cancer that usually occurs late during cancer progression. This is a severe limitation for using 5q21 testing as a prognostic tool.

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The pathogenesis of necrotizing enterocolitis (NEC) remains poorly understood but is thought to be multifactorial. There are no specific recurring chromosomal abnormalities previously associated with NEC. We report 3 cases of intestinal necrosis associated with large chromosome 6 deletions. The first patient was found to have a 7.9-Mb deletion of chromosome 6 encompassing over 40 genes, arr[GRCh37] 6q25.3q26(155699183_163554531)×1. The second patient had a 19.5-Mb deletion of chromosome 6 generated by an unbalanced translocation with chromosome 18, 46,XY,der(6)t (6;18)(q25.1;p11.23), arr[GRCh37] 6q25.1q27(151639526_ 171115067)×1, 18p11.32p11.23(131700_7694199)×3, which included the whole 7.9-Mb region deleted in the first patient. The third patient was the younger sibling of the second patient with an identical derivative chromosome 6. The shared abnormal chromosome 6 region includes multiple genes of interest, particularly EZR. Mouse models have demonstrated that Ezr is expressed in microvillar epithelium and helps regulate cell-cell adhesion in the gut. We hypothesize that deletion of this shared region of 6q leads to gastrointestinal vulnerability which may predispose patients to intestinal necrosis.

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Terminal deletion of chromosome 6q is a rare chromosomal abnormality associated with variable phenotype spectrum. Although intellectual disability, facial dysmorphism, seizures and brain abnormalities are typical features of this syndrome, genotype-phenotype correlation needs to be better understood. We report the case of a 6-year-old Caucasian boy with a clinical diagnosis of intellectual disability, delayed language development and dyspraxia who carries an approximately 8 Mb de novo heterozygous microdeletion in the 6q26-q27 locus identified by karyotype and defined by high-resolution SNP-array analysis. This patient has no significant structural brain or other organ malformation, and he shows a very mild phenotype compared to similar 6q26-qter deletion. The patient phenotype also suggests that a dyspraxia susceptibility gene is located among the deleted genes.

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We present a patient with a 17.31 MB interstitial deletion of 6q16.3-6q22.31, who demonstrates a unique constellation of 6q- features. Among 6q- patients, he has limb reduction among the most severe reported, he is the second patient with duodenal atresia, and is the first documented case of diaphragmatic eventration.

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Prostate cancer is notorious for its heterogeneity, which poses a problem for the applicability of diagnostic molecular markers. However, heterogeneity analysis can provide valuable information on the chronology in which molecular alterations arise. Here, we constructed a heterogeneity tissue microarray (TMA) comprising samples from 10 different tumor areas of 189 prostate cancers each in order to study the sequence of two frequent molecular alterations, i.e. 6q15 deletion and TMPRSS2:ERG fusion. Previous work shows a marked inverse relationship between these alterations, suggesting that presence of one of these alterations might impact development of the other. 6q15 deletion was analyzed by fluorescence in situ hybridization and ERG-expression by immunohistochemistry. Only 6.6% of 334 ERG-positive but 28.4% of 440 ERG-negative TMA spots showed 6q15 deletions (p < 0.0001). A breakdown of these data to the level of tumor foci revealed 6q deletions in 138 tumor foci that were large enough to have at least 3 analyzable TMA spots. These included 42 tumor foci with homogeneous ERG positivity and 16 with homogeneous 6q15 deletions. Remarkably, six of the 42 homogeneously ERG-positive tumor foci (14.3%) harbored small 6q15-deleted areas, but none of the 34 6q15-deleted foci showed areas of ERG positivity (p = 0.022). In conclusion, our data suggest that ERG-fusion can precede 6q15 deletion, but not vice versa. The complete absence of ERG-positive tumor areas in 6q15-deleted tumor foci further suggest that the functional consequences of 6q15 deletions may prevent the development of TMPRSS2:ERG fusions.

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Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6-year-old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre- and post-natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girl's phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6-7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girl's congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity).

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Here we report a case of two siblings with reciprocal aberrations, one presenting with a deletion and the other carrying two novel duplications at 6q13q16.1. Interestingly, both alterations were inherited from a healthy mother carrying a non-reciprocal translocation of 6q13q16 to 15q11. Deletions at 6q13q16.1 have been previously described; however this is the first characterisation of a 6q13q16.1 duplication. In this report we provide a comprehensive molecular and phenotypical characterisation of the affected siblings and discuss the profiles of previously identified patients carrying 6q deletions.

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There are a number of reports of interstitial deletions of the long arm of chromosome 6 that have developmental delay and obesity suggesting that this is a distinct phenotype almost like Prader-Willi syndrome. Here we report a patient with a similar deletion but a strikingly different phenotype, one more in keeping with Marfan syndrome, although he does not fulfil the criteria for that syndrome. Array comparative genomic hybridization was performed to investigate a patient with a striking phenotype. This revealed an interstitial deletion of 6q14.1q15. Parental FISH studies were normal, indicating that this is a de novo deletion. Our patient has a completely different phenotype compared to other patients reported to have similar deletions. The common feature is developmental delay, but the body features are quite different in that our patient is tall, strikingly thin with pectus excavatum, scoliosis, skin striae, arachnodactyly, pes planus, cataracts, and a high-arched palate. This contrasts with other patients who have a similar deletion but have short stature and obesity. 6q14.1q15 interstitial deletions can have a very variable phenotype and do not necessarily conform to a clinical recognizable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in that region as proposed by others.

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Deletions of 6q chromosome are rare. Although 60 cases of deletions of the long arm of chromosome 6 have been reported in the literature, there was no reported case in Korea. We report a 9 year old boy with a deletion 46,XY,del(6)(q16), who presented growth and developmental delay, brachycephaly, minor facial dysmorphism, low-set ear, short 5th finger with clinodactyly, abnormal palmar creases, cryptorchidism and small feet. Brain MRI showed arachnoid cyst on the temporal lobe with mass effect and dilatation of the lateral ventricle which are consistent with brain atropy. Clinical data were analyzed in comparison with patients reported in the literature.

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