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PubMed2002

Presumptive monosomy 21 with neuronal migration disorder re-diagnosed as de novo unbalanced translocation t(18p;21q) by fluorescence in situ hybridisation.

We present clinical and cytogenetic data of a one year old boy with partial monosomy for both 21q and 18p, resulting from a de novo unbalanced translocation. The initial diagnosis of a seemingly full monosomy 21 was revised after fluorescence in situ hybridisation (FISH) with whole chromosome painting probes and a locus-specific chromosome 21 probe. The karyotype was reinterpreted as 45,XY,der(18)t(18;21)(p11.2;q22.1),-21. This karyotype, to our knowledge, has not been previously described. The boy presented with a spectrum of clinical features previously described for (partial) monosomy 18p only, for monosomy 21q only, or for both of these aneusomies. The radiological finding of a neuronal migration disorder with localised polymicrogyria (cortical dysplasia) has not been described for either monosomy before.

Abnormalities, Multiple↗
PubMed2003

Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities.

Uveal melanoma is the most common intraocular malignancy. About 50% of patients die of metastases, which almost exclusively originate from primary tumors that have lost one chromosome 3 (monosomy 3). To gain insight into the biological mechanisms that underlie the various metastasizing potential of uveal melanoma, we have determined gene expression levels in 20 primary tumors using oligonucleotide microarrays containing 12500 probe sets. The expression measurements of those 7902 genes that were expressed in more than 10% of tumors were analyzed using two different statistical approaches. We used a modified Wilcoxon rank-sum test to identify genes differentially expressed between tumors with and without monosomy 3. Seven genes showed complete loss of expression in tumors with monosomy 3 but were expressed in tumors with disomy 3. Two of them, CHL1 and fls485, are located within or close to the uveal melanoma susceptibility locus UVM2 at 3p25. However, mutation analysis of both genes in eight tumors with monosomy 3 did not reveal structural or epigenetic alteration. To identify tumor classes, we performed unsupervised hierarchical cluster analysis; this approach separated uveal melanomas into two groups. We found that this classification is strikingly robust because, when tested by "resampling," the same grouping is obtained from 47 of 50 subsamples of genes. In clusterings of the three remaining subsamples, the grouping of only one tumor does not conform with the original classification. Excluding this tumor, cluster analyses of subsamples containing as few as 300 randomly chosen genes consistently result in the same classification, thus indicating that the difference between the two tumor classes is pervasive. Interestingly, all of the tumors in one of the groups have disomy 3, whereas all of the others have monosomy 3. Our findings suggest that there are two distinct entities of uveal melanoma that were previously unrecognized because they are not obviously distinguishable by clinicopathological features.

Chromosomes, Human, Pair 3↗
PubMed1988

Monocytic involvement by monosomy 7 preceded acute myelomonocytic leukemia in a patient with myelodysplastic syndrome.

Novel techniques were used to detect which cell lineages were affected by monosomy 7 in a patient who had myelodysplastic syndrome and later developed acute leukemia. The patient had had paroxysmal nocturnal hemoglobinuria for 20 years before developing refractory anemia with excess of blasts. Cytogenetic analysis at the myelodysplastic stage disclosed monosomy 7 in bone marrow mitoses. Restriction fragment length polymorphism analysis of fractionated white blood cells with the chromosome 7-specific probes MetH and MetD revealed that blood monocytes and most bone marrow erythroblasts but not blood granulocytes or lymphocytes were affected by monosomy 7. The patient later developed acute myelomonocytic leukemia with blast cells positive for markers of the myelomonocytic lineage but negative for granulocytic markers in a standard surface marker analysis. The leukemic blast cells had monosomy 7 as determined by direct cytogenetic investigation. Thus, the monocytes were found to be affected by monosomy 7 in this patient 8 months before her myelodysplastic syndrome progressed to acute myelomonocytic leukemia, and the affected cells had the same biologic markers at both stages of the disease.

Anemia, Refractory, with Excess of Blasts↗
PubMed2002

Double partial monosomies (10p- and Xp-) in a female baby with choanal atresia.

Chromosomal abnormalities involving double partial monosomies are very rare. A female infant with non-mosaic monosomy 10p13-->10pter along with monosomy Xp11.4-->Xpter which arose de novo is described. The clinical manifestations of this patient included microcephaly, mild synophrys, short and down-slanted palpebral fissures, ptosis of the left eye, long eyelashes, a depressed nasal bridge, dysplastic ears, micrognathia, a short neck. sensorineural hearing impairment, and severe growth retardation. Left choanal atresia and laryngomalacia were detected by flexible fibroscopy. No signs of hypoparathyroidism or defective cellular immunity could be found. Fluorescence in situ hybridization (FISH) with whole-chromosome painting probes for chromosomes 10 and X was performed, which excluded the possibility of cryptic translocations of the involved chromosome segments. No submicroscopic chromosome 22q11 deletion could be found by FISH. Thus this very rare coexistence of double independent partial monosomies was confirmed. There are no previous reports of such concurrent double partial monosomies.

Choanal Atresia↗
PubMed1982

The development of monosomy 19 mouse embryos.

In general, autosomal monosomy is lethal much earlier in mammalian development than autosomal trisomy. In an attempt to understand why monosomy is so deleterious, we have begun to characterize the development of mouse embryos monosomic for chromosome 19. A dramatic loss of monosomy 19 embryos was found to occur between days 3 and 4 of development. This loss occurred both in vivo and in vitro and with intact blastocysts or isolated inner cell masses. Experiments with inbred strains showed that this loss was not due to the expression of recessive lethal genes. While monosomic embryos were found to have fewer cells than normal and trisomic litter-mates beginning at the early morula stage, the ability to form blastocysts is not interfered with. Electron microscopy revealed no difference in the cellular ultrastructure of monosomic when compared with diploid embryos. Furthermore, two-dimensional gel electrophoresis did not reveal any differences in the proteins synthesized by monosomic, trisomic or diploid litter-mates when examined at day 3 of development. These results indicate a lack of gross genomic disturbances in monosomic embryos. When monosomy in equilibrium diploid chimaeras were made, viable monosomic cells were found in day-9 post-implantation embryos, well past the lethal period. Thus, in chimaeric embryos, the normal cells appear to be able to provide whatever is lacking, suggesting that monosomy 19 is not a cell lethal. Instead, death may be due to a dosage alteration in specific gene products needed during early development.

Aneuploidy↗
PubMed1999

Loss of maternal allele in a child with myelodysplastic syndrome and monosomy 7.

Monosomy 7 or partial deletion of the long arm of chromosome 7 is frequently described in children with myelodysplastic syndrome and acute myeloblastic leukemia. Parental origin of chromosome 7 in children with sporadic monosomy 7 has been examined very rarely. To investigate if monosomy 7 shows parent-of-origin, we have studied a female child with monosomy 7 and de novo myelodysplastic syndrome by a series of polymorphic polymerase chain reaction markers. We found loss of maternal allele and discussed the results with the previous reports.

Alleles↗
PubMed1999

Transient monosomy 7: a case series in children and review of the literature.

BACKGROUND: Monosomy 7 and deletions of the long arm of chromosome 7 [del (7q)] are recurrent, nonrandom chromosomal abnormalities associated with both de novo and therapy-related myelodysplastic syndromes (MDS). The overall prognosis for children and adults with these chromosomal abnormalities is poor. In the current report, the authors present five children with MDS associated with monosomy 7/del(7q) who achieved spontaneous hematologic disease remission as well as a review of the literature. METHODS: Five children with either de novo or treatment-related MDS who achieved spontaneous hematologic disease remission are presented. Relevant clinical, cytogenetic, and fluorescent in situ hybridization data are included. RESULTS: All patients were boys. Three had de novo MDS whereas two others previously had received chemotherapy for another malignancy. Four patients achieved spontaneous and durable hematologic disease remission that was associated with cytogenetic disease remission in all three patients tested. The fifth patient developed a disease recurrence and died with evidence of clonal evolution after a long interval of hematologic and cytogenetic remission. CONCLUSIONS: A subset of children who develop MDS associated with monosomy 7 or del(7q) achieve spontaneous hematologic and cytogenetic improvement. Although this appears to be uncommon, further data are needed to determine the percentage of patients who improve without therapy and to define clinical characteristics that may predict this clinical outcome. These findings suggest that monosomy 7/del(7q) is insufficient to produce full leukemic transformation.

Adolescent↗
PubMed1997

Full monosomy 21, prenatally diagnosed by fluorescent in situ hybridization.

We describe a case of full monosomy 21 which was prenatally diagnosed in chorionic villi by fluorescent in situ hybridization (FISH). Because of intrauterine fetal death, a curettage was performed and cytogenetic analysis of skin fibroblasts confirmed the presence of monosomy 21 in fetal cells. DNA investigations showed a paternal origin of the single chromosome 21. Inspection and autopsy of the fetus revealed several congenital malformations. Some of them have been reported in earlier studies of monosomy 21; others concern new observations. Regarding the eye, the following abnormalities were microscopically observed: absence of the anterior and posterior eye chambers, aniridy, a hypoplastic ciliary body, Peter's anomaly, and a double retina with secondary dysplasia. In addition, malformations of the extremities were seen: partial, proximal syndactyly of digits 3 and 4 of the right hand; pes varus position of the right foot; and transverse reduction defect at the tarsals of the left foot. To our knowledge, this is the first case in which full monosomy 21 has been proven.

Abnormalities, Multiple↗
PubMed1995

Monosomy of chromosome 18 detected by fluorescence in situ hybridization in colorectal tumors.

BACKGROUND: At least two different evolutional pathways of colorectal cancer, namely the adenoma-carcinoma sequence and de novo carcinogenesis, have been indicated. However, whether there is a difference between them in affected chromosomes and genes has not yet been elucidated. Chromosomal examination is expected to provide a clue to an answer to this question. In this study, the relation of aberrations in chromosome 18 to type of colorectal cancer was examined. METHODS: Numeric aberrations in chromosome 18 were investigated in 71 colorectal tumors by means of fluorescence in situ hybridization, using an alphoid satellite DNA probe specific for the pericentromeric region on chromosome 18. RESULTS: The loss of one chromosome 18 was found in 33% (6 of 18) of patients with early cancer, excluding those with cancer in an adenoma. The loss was frequent in early colorectal carcinomas without foci of adenoma (four of six patients, 67%), whereas monosomy 18 was not significant in those with foci of adenoma except for patients with a hereditary background. Specimens exhibiting monosomy 18 were macroscopically classified as flat lesions, but the converse was not true. No adenoma showed monosomy 18. It was encountered in 44% of nine cancers with invasion to the muscularis propria. However, no significant subpopulation of monosomy 18 was present in cancers penetrating through the serosa or adventitia in which polysomic populations were often identified alternatively. Furthermore, tetrasomy for this chromosome was exclusive in these advanced cancers. CONCLUSIONS: The loss of chromosome 18 is closely related to colorectal cancers without foci of adenoma.

Adenoma↗
PubMed1990

Gene dosage effect in acquired monosomy 7: distinct behaviour of beta-glucuronidase and phosphoserine phosphatase.

Evidence for gene dosage effect for beta-glucuronidase (GUSB) and phosphoserine phosphatase (PSP), whose genes are mapped on chromosome 7, was searched in a group of 13 patients with myeloproliferative disorders and acquired monosomy 7. The monosomy 7 was the sole anomaly in nine patients and was associated with other chromosome changes in four. A group of 19 patients with similar diseases but with normal karyotype or with anomalies not involving chromosome 7 served as control. beta-galactosidase and arylsulphatase A, whose genes are not on chromosome 7, were tested as control enzymes. We obtained evidence for a gene dosage effect for GUSB, but not for PSP. When all cases with monosomy 7 were compared with controls, no dosage effect was observed for PSP, but when this group was split into two, according to the presence of anomalies additional to the monosomy 7, the values of activity in the group with additional anomalies were significantly lower than in the controls. Thus, in the case of PSP, the loss of one allele is not followed immediately by reduction in activity, and this could be due to the specific importance of PSP in nucleic acid metabolism. We postulate that some regulatory mechanisms are able to keep normal levels of PSP even in the presence of only one allele, and that they are overwhelmed only when additional chromosome changes are present. These changes tend to involve chromosomes carrying genes for enzymes involved in a metabolic pathway closely related to PSP functions, and only then is a gene dosage effect for PSP detectable.

Alleles↗
PubMed1985

The early lethality of autosomal monosomy in the mouse.

Using male mice doubly heterozygous for pairs of Robertsonian translocation chromosomes that have one arm in common, mouse embryos monosomic for 11 of the 19 autosomes have been generated. All of these monosomies result in death prior to or during the implantation period, with only rare survivors being detected 6 days after fertilization. For some of the monosomies the onset of lethality can be detected during the third or fourth day of development, but others do not begin to die until sometime after the late blastocyst stage on day 4. Retardation of development, as revealed by decreased cell numbers, is often detectable prior to or after the onset of the lethal period. The period during which death occurs may spread over several days and does not coincide with any of the developmental landmarks of the pre- or peri-implantation period. Genetic factors that may affect the rate of cellular proliferation or other aspects of embryonic development appear to play an important role in determining exactly when individual monosomies result in death. The universal early lethality of the autosomal monosomies leads to the conclusion that a large number of loci scattered over all of the autosomes are involved in processes that are so concentration dependent that a 50% reduction is sufficient to produce very serious consequences.

Aneuploidy↗
PubMed1988

Cytogenetic evidence for involvement of erythroid and granulocyte/macrophage progenitors in an infant with monosomy 7 syndrome presenting de novo.

Monosomy 7 presenting as a myelodysplastic syndrome following radiation and chemotherapy has been reported to involve a stem cell capable of both erythroid and granulocyte/macrophage differentiation. To determine if monosomy 7 presenting de novo also involves a multipotential stem cell, we examined mitoses from individual colony-forming units (CFU)-GM and burst-forming units (BFU)-E colonies derived from semisolid cultures of marrow from an infant with this disorder. Direct cytogenetic analysis of bone marrow cells disclosed the characteristic 45,XY,-7 karyotype in 32 of 35 abnormal metaphases. Metaphases were obtained from 63 (73%) of 85 CFU-GM and BFU-E colonies (median metaphases per colony = 4, range = 1-21), with well-banded analyzable chromosome spreads available for 15 of the colonies with metaphases. The monosomy 7 karyotype was present in all 14 metaphases from ten BFU-E colonies and in all seven metaphases from five CFU-GM colonies. These results indicate that the monosomy 7 karyotype can originate in haematopoietic stem cells with both erythroid and granulocyte/macrophage differentiative potential.

Chromosome Deletion↗
PubMed1992

A case of congenital leukemia with monosomy 7.

A case of congenital leukemia with monosomy 7 is reported. Immunological study of the blast cells using monoclonal antibodies was suggestive of both myelomegakaryocytic and T-lymphoblastic leukemia. Chromosomal analysis of the bone marrow cells showed monosomy 7. Chemotherapy was initiated with a combination of adriamycin, cytosine arabinoside, 6-mercaptopurine, and prednisolone. The patient obtained complete remission, which has been maintained for 4 years and 1 month. He receives no chemotherapy now. Our case shows that monosomy 7 in congenital leukemia is rare, but the presence of monosomy 7 in congenital leukemia does not necessarily indicate a poor prognosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Prolonged bone marrow failure with monosomy 7 after engraftment failure following bone marrow transplantation.

A patient with acute myelogenous leukemia developed prolonged bone marrow failure along with the monosomy 7 chromosome abnormality. The patient had undergone bone marrow transplantation with CD34+ selection following induction failure. However, she then suffered engraftment failure and long-term pancytopenia. Her white blood cell count gradually increased with supportive therapy including granulocyte colony-stimulating factor (G-CSF), and chromosomal analysis of bone marrow cells revealed an abnormal karyotype. Thirty months after the bone marrow transplantation we observed monosomy 7 together with the existing chromosomal abnormality in the patient's bone marrow cells. It has been reported that some patients with idiopathic and posthepatitis aplastic anemia develop clonal disorders such as myelodysplastic syndrome/acute myelogenous leukemia with monosomy 7. The findings in our case suggest that the appearance of monosomy 7 in patients with aplastic anemia may be caused by prolonged low-level hematopoiesis, with or without G-CSF stimulation.

Adolescent↗
PubMed1999

Clinical relevance of monosomy 22q11.2 in children with pulmonary atresia and ventricular septal defect.

UNLABELLED: The purpose of our study was to describe the prevalence and the clinical spectrum of monosomy 22q11.2 in a population of patients with pulmonary atresia and ventricular septal defect. We examined all 44 patients with this conotruncal cardiac malformation who presented to our institution from January 1994 until December 1997. The type of collateral lung perfusion was recorded including anomalies of the pulmonary arteries as well as facial and immunological abnormalities. Molecular-cytogenetic testing for a 22q11.2 microdeletion was performed using the probes D22S75 and cHKAD26. Statistical differences were evaluated with the Fisher's Exact Test. Monosomy 22q11.2 was present in ten children (23%) with major aortopulmonary collateral arteries (group 1). The remaining 13 children (29%) with major aortopulmonary collateral arteries (group 2) and all 21 children (48%) with ductus arteriosus (group 3) were negative for this microdeletion. All children in group 1 had facial anomalies, six had mild immunological abnormalities including decreased CD 4 + or CD 8 + cells. Anomalies of the pulmonary vascular bed were significantly more frequent in children of group 1 (9/10) than in children of group 2 (4/13) or group 3 (0/21). Due to these pulmonary vascular anomalies, corrective surgery had been accomplished in fewer children with monosomy 22q11.2 (none in group 1) as compared to 7/13 children in group 2 and 14/21 children in group 3. CONCLUSION: In children with pulmonary atresia and ventricular septal defect, monosomy 22q11.2 is preferentially associated with major aortopulmonary collateral arteries. Due to the higher incidence of pulmonary arterial abnormalities, successful surgical repair will require a different therapeutic approach in most patients with this microdeletion.

Adolescent↗
PubMed1998

Microphthalmia with linear skin defects syndrome in a mosaic female infant with monosomy for the Xp22 region: molecular analysis of the Xp22 breakpoint and the X-inactivation pattern.

This paper describes a female infant with microphthalmia with linear skin defects syndrome (MLS) and monosomy for the Xp22 region. Her clinical features included right microphthalmia and sclerocornea, left corneal opacity, linear red rash and scar-like skin lesion on the nose and cheeks, and absence of the corpus callosum. Cytogenetic studies revealed a 45,X[18]/46,X,r(X)(p22q21) [24]/46,X,del(X)(p22)[58] karyotype. Fluorescence in situ hybridization analysis showed that the ring X chromosome was positive for DXZ1 and XIST and negative for the Xp and Xq telomeric regions, whereas the deleted X chromosome was positive for DXZI, XIST, and the Xq telomeric region and negative for the Xp telomeric region. Microsatellite analysis for 19 loci at the X-differential region of Xp22 disclosed monosomy for Xp22 involving the critical region for the MLS gene, with the breakpoint between DXS1053 and DXS418. X-inactivation analysis for the methylation status of the PGK gene indicated the presence of inactive normal X chromosomes. The Xp22 deletion of our patient is the largest in MLS patients with molecularly defined Xp22 monosomy. Nevertheless, the result of X-inactivation analysis implies that the normal X chromosomes in the 46,X,del(X)(p22) cell lineage were more or less subject to X-inactivation, because normal X chromosomes in the 45,X and 46,X,r(X)(p22q21) cell lineages are unlikely to undergo X-inactivation. This supports the notion that functional absence of the MLS gene caused by inactivation of the normal X chromosome plays a pivotal role in the development of MLS in patients with Xp22 monosomy.

Chromosome Mapping↗
PubMed1995

Possible co-existence of RAS activation and monosomy 7 in the leukaemic transformation of myelodysplastic syndromes.

The frequency of RAS activation was studied in 48 patients with acute myeloid leukaemia (AML) or with myelodysplastic syndromes (MDS), in order to address the question of whether patients possessing monosomy 7 or other alterations of chromosome 7 have a higher incidence of RAS activation than those lacking chromosome 7 abnormalities. Samples were screened for oncogenic point mutation by DNA amplification followed by oligonucleotide hybridization analysis at codons 12, 13 and 61 of N-RAS and codons 12 and 13 of K-RAS. Two additional samples were considered to have activated RAS due to additional karyotypic abnormalities t(5;12) or loss of both copies of chromosome 17 and hence, the neurofibromatosis (NF1) loci. The group of chronic myelomonocytic leukaemia (CMML) patients had activated RAS in 4/11 cases and inclusion of two CMMLt patients (with monosomy 7) brings this incidence to 5/13. No change in frequency of RAS activation was seen between groups containing de novo AML samples with or without chromosome 7 abnormalities (1/5 and 2/12, respectively). However, assessment of MDS samples in the process of, or subsequent to, leukaemic progression showed a difference between the two groups. The frequency of RAS activation in samples with monosomy 7 was 4/9 samples while none of the seven samples without chromosome 7 changes showed RAS activation. The co-existence of RAS activation and monosomy 7 in MDS indicates that these lesions can co-operate in the multistep process of leukemogenesis.

Base Sequence↗
PubMed1995

Monosomy 1p is correlated with enhanced in vivo glucose metabolism in meningiomas.

The 2-[18F]fluoro-2-deoxy-D-glucose (FDG) uptake of 25 human meningiomas was preoperatively evaluated in vivo by positron-emission tomography (PET). After surgery, meningioma biopsies were analyzed cytogenetically. Five meningiomas showed partial monosomy for chromosome 1p additional to other typical chromosome aberrations. This aberrant karyotype was correlated with increased FDG uptake. Three of five meningiomas with monosomy 1p were classified as grade II according to WHO, while only one of 20 tumors without monosomy 1p was classified as grade II. Thus, monosomy 1p and elevated FDG uptake in PET are to be regarded as cytogenetic and metabolic parameters for the aggressiveness of meningiomas.

Adult↗