A case of presumptive monosomy 21 re-diagnosed as unbalanced t(5p;21q) by FISH and review of literature

By using fluorescence in situ hybridization (FISH), we demonstrate a case of monosomy 21 to result from an unbalanced translocation involving the short arm of chromosome 5 and the long arm of chromosome 21. Our case is compared to 3 similar cases of t(5p;21q) reported recently, which were also originally diagnosed as monosomy 21. The breakpoint on chromosome 5 in these cases occurred in the p13–p15 region, whereas the breakpoint on chromosome 21 was in the q21–q22 region. Comparison of the clinical findings in these patients demonstrated great similarities. Furthermore, a strong correlation between the clinical manifestations of these patients with cridu-chat syndrome patients was also noted. We suggest that cases with unbalanced t(5p;21q) represent a distinct syndrome which can be grouped under a new category of “5p/21q deletion syndrome.” Am. J. Med. Genet. 70:174–178, 1997. © 1997 Wiley-Liss, Inc.     

Central diabetes insipidus and inv(3)(q21q26) and monosomy 7 in acute myeloid leukemia

Chromosomal anomalies involving region 3q21q26 have been reported associated with thrombocytosis in various hematological malignancies, such as chronic myeloid leukemia, myelodysplastic syndrome, and acute myeloid leukemia (AML). Recent reports described the association of central diabetes insipidus with AML and chromosomal anomalies involving region 3q21q26. We review the database in our institution and report five cases of inv(3)(q21q26) in consecutive cytogenetic studies of AML and myelodysplastic syndromes from 1992 to 2000, two cases presented as sole abnormalities and three cases were associated with monosomy 7. Only one case was associated with central diabetes insipidus. The literature of 3q21q26 syndrome and central diabetes insipidus in myeloid leukemia is reviewed.     

A cytogenetic study of nonpolymalformed patients with mental retardation of clinically undefined etiology: application of a high resolution banding technique

We performed a cytogenetic study on 140 nonpolymalformed patients with mental retardation of clinically undefined origin, using a high resolution banding technique, to determine how much chromosome abnormalities contribute to the etiology of this condition. A total of 15 patients (10.7%) were found to have autosomal or sex chromosomal abnormalities. Autosomal abnormalities included partial monosomy (5 cases), reciprocal translocation (one case), 13/14 robertsonian translocation (3 cases), unbalanced translocation (one case), inverted duplication of 15q (one case) and mosaic trisomy 21 (one case). Sex chromosomal abnormalities comprised structural rearrangement of the short arm of the X chromosome (one case) and 47, XXY in a pure or mosaic form (two cases). It should be noted that four out of the 5 cases of partial monosomy had subtle interstitial deletions, which might have been unidentified by the conventional G-banding method alone. In one case of the robertsonian translocation 46,XY,t(13;14)/45,XY,t(13;14), a small deletion was thought to have occurred in the cells with a chromosome number of 45. Comparison of clinical features of the 15 chromosomally abnormal patients with those of patients with normal karyotypes did not show any clinical parameter indicative of chromosome imbalance. These results suggest that a subtle chromosomal deletion is specific to mental retardation associated with few malformations. We believe that diagnostic evaluation of mentally retarded patients, even if nonmalformed, should include chromosome analysis using a high resolution banding technique.     

Monosomy 21 syndrome: Further delineation including clinical, neuropathological, cytogenetic and biochemical studies

Only six cases of living newborns with apparently complete monosomy 21 have been reported. All the previous cases with the exception of the present case died between 3 weeks and 20 months. Only one of these cases had a postmortem examination. The subject of this report was previously described at the age of 6 years (Davis et al. 1976). He survived until 11 years old and is the oldest known case of complete monosomy 21. We report here the clinical presentation over 11 years, results of gene dosage studies, cytogenetic analysis, and the neuropathological postmortem examination.     

Acquired cystic disease-associated renal cell carcinoma: an immunohistochemical and fluorescence in situ hybridization study

Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) has been recently identified. However, there are only a few genetic studies to date. In this article, we performed an immunohistochemical and fluorescence in situ hybridization (FISH) study for six cases including one case with sarcomatoid change. As a result, we observed frequent immunohistochemical expression of AMACR. FISH of chromosome 3 showed trisomy for three cases, monosomy for two cases, and disomy for one case. Additionally, FISH of chromosome 16 showed trisomy for three cases, monosomy for two cases, and both trisomy and monosomy for one case. Furthermore, both the carcinomatous area and the sarcomatoid area of one ACD-associated RCC with sarcomatoid change revealed monosomy of chromosomes 3, 9, and 16 but showed disomy of chromosome 14. In conclusion, the numerical abnormalities of chromosomes 3 and 16, irrespective of gain or loss, may be characteristic of ACD-associated RCC.     

"Compensatory" uniparental disomy of chromosome 21 in two cases.

Two cases of growth failure, microcephaly, facial dysmorphism, muscular hypertonia, and severe psychomotor retardation are described. At birth, both cases had cytogenetic mosaicism in lymphocytes and skin fibroblasts, in case 1 ring chromosome 21 and monosomy 21 and in case 2, deletion of chromosome 21 and monosomy 21. At a later age the lymphocyte karyotype changed almost completely to 46,XX, but the fibroblast karyotype remained as before. DNA polymorphism analysis described elsewhere indicated that the 46,XX lymphocytes contained two identical chromosomes 21 (isodisomy), in case 1 inherited from the father and in case 2 from the mother. The isodisomy was the result of duplication of a chromosome in mitosis after the loss of the homologous abnormal chromosome ("compensatory isodisomy"). We report here that this cytogenetic mechanism can result in false normal cytogenetic findings. The phenotypes were attributed to the cells with monosomy 21 in case 1 and to the deletion and monosomy of chromosome 21 in case 2.     

Mantle cell lymphoma with in situ or mantle zone growth pattern: a study of five cases and review of literature

We present two rare cases of in situ mantle cell lymphoma (“in situ MCL”) and three cases of MCL with mantle zone growth pattern (MCL-MZGP). The patients include four males and one female, with a median age of 66 years (range, 52 to 86 years). Two present with isolated lymphadenopathy and three with multiple lymphadenopathy. At presentation, the complete blood count (CBC) and serum lactate dehydrogenase (LDH) are normal in all cases. Histologic examination reveals an in situ pattern in two cases and a mantle zone growth pattern in three cases. The staging bone marrow biopsies show minimal involvement by lymphoma in one case and no morphologic evidence of lymphoma in four cases. All cases are positive for cyclin D1, including two with typical MCL phenotype and three with CD5-negativity. Four out of five cases express kappa light chain. FISH study for t(11;14) is performed in three cases, of which one is positive and two are inconclusive. For four patients with a median follow-up of 38 months, three are in clinical remission and one has persistent disease. In conclusion, the “in situ MCL” is associated with incidental finding, indolent clinical course and lower tumor burden. The predominant usage of kappa light chain and frequent CD5-negativity observed in our cases are unusual. We review the clinical and laboratory features of “in situ MCL” cases in the literature.     

De novo supernumerary ring chromosome 7: first report of a non-mosaic patient and review of the literature

The present authors report the case of a 12-year-old-boy with a de novo, non-mosaic supernumerary ring chromosome 7 associated with significant developmental delay and speech difficulty. A review of the literature identified a total of 18 cases with ring chromosomes 7 who can be classified into two groups: (1) patients with a cell line that has 47 chromosomes with a small supernumerary ring chromosome 7 resulting in partial trisomy; and (2) individuals had a cell line with a large ring chromosome replacing one of the normal chromosomes 7 resulting in partial monosomy. A comparison of clinical features in the two groups of patients showed several common features such as growth and mental retardation, and facial dysmorphism, including, ear and eye anomalies. However, patients with partial trisomy have speech difficulty as a distinguishing feature, while patients with partial monosomy have skin lesions as a cardinal feature. All the published cases of ring chromosome 7, irrespective whether they are supernumerary or normal modal number, are mosaics except for one. The present subject is the first case of a de novo, non-mosaic supernumerary ring chromosome 7.     

Clonal abnormalities in patients with Waldenström's macroglobulinemia with special reference to a Burkitt-type t(8;14)

Clonal chromosome changes have been found in two patients with Waldenström's macroglobulinemia (WM). In one, the changes were only numerical: trisomy 3, trisomy 18, and monosomy 21. In the other, both numerical and structural changes were observed, among which t(8;14) with breakpoints (q24;q32), similar to those found in Burkitt's lymphoma, was the most relevant.This association between a new lymphoproliferative process and the Burkitt-type t(8;14) is stressed.     

Translocations (5;17) and (7;17) in patients with de novo or therapy-related myelodysplastic syndromes or acute nonlymphocytic leukemia. A possible association with acquired pseudo-Pelger-Hu?t anomaly and small vacuolated granulocytes

Twelve patients [two with de novo myelodysplastic syndrome (MDS), four with secondary MDS, five with de novo acute nonlymphocytic leukemia (ANLL), one with secondary ANLL] showed a 17p deletion resulting from translocations involving 17p: t(5;17)(p11;p11) in four cases, t(7;17)(p11;p11) in six cases, complex (5;17)(q23;p12) translocation with dicentric chromosome in one case, and t(17;?)(p11-12;?) in the remaining patient. All these structural anomalies were observed in hypodiploid clones associated with total or partial monosomy of chromosomes 5 and 7 (12 cases), monosomy 12 (five cases), monosomy 3 (four cases), and monosomy 4 (three cases). Median survival was only 3.3 months (range 3 days to 8 months). Striking features were observed in bone marrow mature granulocytes: all but one case had a pseudo-Pelger-Hu?t anomaly in a significant number of granulocytes, and eight patients had granulocytes with reduced size and clear cytoplasmic vacuoles. Careful cytological review of 51 patients with MDS or ANLL and various cytogenetic anomalies was performed for comparison: vacuolated granulocytes were a very uncommon finding. On the other hand, eight patients had a pseudo-Pelger-Hu?t anomaly, which correlated significantly with total monosomy 17 in these patients. A possible correlation between cytological anomalies and cytogenetic data is discussed, and the role of 17p in the nuclear segmentation of granulocytes is stressed.     

The incidence, type, and subsequent evolution of 14 variant Ph1 translocations in 180 South African patients with Ph1-positive chronic myeloid leukemia

A Philadelphia (Ph1) chromosome translocation was found in 180 of 198 cases of chronic myeloid leukemia (CML). A standard t(9;22) was present in 166 patients, 83 of whom were black, 79 white, and 4 of "mixed" ancestry; whereas a variant Ph1 translocation was detected in 14 patients (7.8%), 11 of whom were black and only 3 white. There was a higher frequency of a variant Ph1 among black patients compared with whites. The significantly higher frequency of a variant among our patients compared with surveys from elsewhere could be due to differing environmental agents. Simple variants were detected in four patients. Complex variants were found in eight cases; in one of these patients, only chromosomes #9 and #22 were involved, but a complex rearrangement of chromosome #9 had occurred. A "masked" Ph1 translocation was detected in two cases, both of which showed monosomy #22 because the Ph1 chromosome was incorporated or interchanged with chromosome #9. Karyotypic evolution of the Ph1-positive cell line was observed more frequently in the variant group (71.4%) than the standard group (29.5%). This difference was significant (p less than 0.005). There was no difference in the type of clonal changes seen in standard and variant groups. The majority of clonal changes were observed during the acute stage in both groups. In the variant group, there was no obvious correlation between the type of variant, type of clonal change, blast morphology, or survival. Their initial survival pattern resembled that of Ph1-negative cases, but those patients who survived longer than 1 year showed a survival trend similar to standard Ph1-positive cases. Possible explanations for the specificity of chromosome #22 involvement and the constancy of the 22q11 breakpoint in all these variant translocations are discussed.     

Fluorescence in situ hybridization for the study of cell lineage involvement in myelodysplastic syndromes with chromosome 5 anomalies

Fluorescence in situ hybridization (FISH) with a locus-specific dual DNA probe (LSI EGR-1SO/D5S23SG) for chromosome 5 was used in combination with morphology to study bone marrow cell lineage involvement of the abnormal chromosomal clone in 13 patients with deletion 5q [del(5q)], either as a sole aberration or as part of a complex karyotype, and in six cases with monosomy 5 by metaphase cytogenetics, all with complex karyotypes including 2-6 marker chromosomes. In the monosomy 5 group, only one case displayed the expected one orange and one green (1O + 1G) FISH pattern in a majority of the cells. The other five patients instead showed 1O + 2G FISH signals in 17-86% of the bone marrow cells, which is the typical pattern for del(5q). In the del(5q) group, 26-98% of the bone marrow cells exhibited 1O + 2G FISH signals. All patients showed clonal involvement of the myeloid cell lineages, including the megakaryocytes in a few cases, whereas lymphoid cells generally exhibited the normal 2O + 2G FISH pattern. No difference was seen between patients with 5q- syndrome, those with del(5q) and a complex karyotype, and the monosomy 5 group. We were thus unable to confirm the recent suggestion that B-cells are a part of the abnormal clone in MDS with del(5q). Furthermore, true monosomy 5 seems to be rare in MDS.     

Cytogenetic follow-up of patients with nonlymphocytic leukemia. II. Acute nonlymphocytic leukemia

Bone marrow (BM) karyotypes of 86 patients with acute nonlymphocytic leukemia (ANLL) were studied at the time of diagnosis; 39 of them (45%) were normally diploid and 47 (55%) showed acquired abnormalities. The median survival was no longer in the diploid group than in the aneuploid one. Nonrandom aberrations were often found: trisomy 8 (15 times), monosomy 7 (7 times), and t(8;21) (7 times). Two patients with acute promyelocytic leukemia presented with the t(15;17) in BM cells. Serial cytogenetic studies performed in 17 cases showed that karyotypic evolution closely followed the clinical evolution. Complete remission, obtained in 10 cases, was characterized by BM metaphases with a normal karyotype. Relapse after a period of complete remission was documented four times; the BM metaphases then showed the original abnormal karyotype with additional changes that, in three cases, were limited to a new structural aberration.     

Cytogenetic studies in 56 cases with Ph1-positive hematologic disorders

Karyotypes were examined in 56 cases of Ph¹-positive hematologic disorders based on direct examination of bone marrow material and culture of blood for 24 hr without phytohemagglutinin (PHA). Various banding techniques (Q, followed by R or C, where necessary) were used. The series of patients consisted of 21 females and 35 males with the ages ranging from 3 to 72 years. In three cases, the clinical and hematologic picture at the time of diagnosis and karyotyping was not compatible with chronic myeloid leukemia (CML): 1 case had acute myeloblastic leukemia (AML), another acute lymphoblastic leukemia (ALL) and the third subacute myeloid leucosis. The results are as follows: In three cases (two female, one male), no Ph¹ translocation could be demonstrated in any of the metaphases either with Q- or R-banding. In 50 cases (19 female, 31 male), a standard Ph¹ translocation, t(9;22)(q34;q11), was observed. In two of these cases, ages 45 and 47, the Ph¹ translocation was accompanied by loss of the Y chromosome in all the metaphases examined. Finally, in three cases (all male), variant Ph¹-translocations were found: t(7;9)(9;22)(q35?;q31?;q11), t(3;9;22)(p21;q34;q11), and t(1;9)(9;22)(q21;q34;q11).     

Chromosome features of two retinoblastomas

Giemsa-banded chromosomal analysis of two unilateral retinoblastoma tumors from unrelated patients with normal constitutional chromosomes revealed near-diploid karyotypes with multiple structural rearrangements. The two tumors shared aberrations of trisomy 1q, monosomy 16 and 17, and 21p+. Other aberrations were unique to each tumor. One tumor expressed a del(13) and trisomy 6p.     

Cytogenetic and fluorescence in situ hybridization studies in 60 patients with multiple myeloma and plasma cell leukemia

We report cytogenetic results in a series of 60 patients affected with multiple myeloma (MM) and plasma cell leukemia (PCL) and compare the results with those previously reported. In our series, a total of 41% of MM patients and 71% of PCL patients displayed chromosome abnormalities. To evaluate the clinical value of monosomy 18, we obtained fluorescence in situ hybridization results (using centromeric probe for chromosome 18) of 22 MM patients who displayed a normal karyotype. Monosomy 18 was present in 3 of 22 patients (14%). Using conventional cytogenetics, we detected monosomy 18 in one patient affected with PCL. Two of four cases with monosomy 18 followed an aggressive course, with overall survival of 1 and 9 months. The remaining two are in follow-up and remain stable. The association of monosomy 18 with IgA subtype predominance and poor prognosis was not observed in this series of MMs and PCLs. Although these results do not confirm our previous hypothesis, further observations of this group of patients (with monosomy 18) regarding malignant transformation is warranted.     

Putative monosomy 21 in two patients: clinical findings and investigation using fluorescence in situ hybridization

Complete monosomy 21 is claimed to be a rare chromosomal disorder in which the cytogenetic investigation is bedevilled by technical difficulties. We describe the disparate clinical features in two patients in whom an initial diagnosis of monosomy 21 was made by routine karyotyping. Fluorescence in situ hybridisation (FISH) confirmed a translocation of chromosome 21 material to the short arm of chromosome 5 and to the X chromosome, respectively. The usefulness of FISH in the investigation of subtle chromosomal rearrangements is hereby demonstrated. These findings also cast doubt on the existence of "pure" monosomy 21 as an entity, and suggest that partial monosomy 21 is a more likely occurrence.     

Aplastic anemia evolving into overt myelodysplastic syndrome/acute myeloid leukemia with t(3;5)(p25;q31)

Advances in the treatment of aplastic anemia (AA) have led to the long-term survival of nontransplanted AA patients; however, the issue of subsequent hematological clonal disorders has been raised as some AA patients treated with immunosuppressive therapy or granulocyte-colony stimulating factor (G-CSF) went on to develop myelodysplastic syndromes (MDS) and/or acute myeloid leukemia (AML) with the frequent presentation of monosomy 7. We report a case of AA progressing to overt MDS/AML following 11 years of treatment that included immunosuppressive therapy and G-CSF. The patient's MDS/AML proved refractory to therapy including myeloablative treatment with allogenic peripheral blood stem cell transplantation. Earlier reports and the present case strongly suggest that there is no recurrent chromosomal aberration other than monosomy 7 in cases of AA that progress to MDS/AML. To our knowledge, ours is the first reported case of a t(3;5)(p25;q31) among AA patients that have progressed to MDS/AML.     

Application of molecular and cytogenetic techniques to the detection of a de novo unbalanced t(11q;21q) in a patient previously diagnosed as having monosomy 21

Hertz B, Brandt CA, Petersen MB, Pedersen S, König U, Strømkjær H, Jensen PKA. Application of molecular and cytogenetic techniques to the detection of a de novo unbalanced t(11q;21q) in a patient previously diagnosed as having monosomy 21.
Clin Genet 1993: 44: 89–94. © Munksgaard, 1993
The occurrence of complete autosomal monosomy in man is extremely rare and generally considered to be incompatible with life. Since the introduction of banding techniques in human cytogenetics, several cases of presumptive monosomy for chromosome 21 have nevertheless been reported. However, it has been suggested that most, if not all, of these cases may represent unbalanced translocations or other structural aberrations resulting in only partial monosomy 21. Here we describe a patient in whom full monosomy 21 was initially diagnosed by routine karyotyping. Re-examination with a combination of high resolution banding technique, chromosome painting and DNA polymorphism analysis demonstrated the presence of an unbalanced translocation between the long arms of chromosome 11 and 21, respectively. Consequently, the case was re-classified as a partial monosomy for the proximal long arm of chromosome 21.     

Confirmatory testing illustrates additional risks for structural sex chromosome abnormalities in fetuses with a non‐invasive prenatal screen positive for monosomy X

More and more women rely on non‐invasive prenatal screening (NIPS) to detect fetal sex and risk for aneuploidy. The testing applies massively parallel sequencing or single nucleotide polymorphism (SNP) microarray to circulating cell‐free DNA to determine relative copy number. In addition to trisomies 13, 18, and 21, some labs offer screening for sex chromosome abnormalities as part of their test. In this study, an index neonate screened positive for monosomy X and had discordant postnatal chromosomes indicating an X;autosome translocation. This patient prompted a retrospective chart review for similar cases at a large NIPS testing center. The review found 28 patients with an abnormal NIPS for monosomy X who were eventually diagnosed with additional discrepant structural sex chromosome abnormalities including translocations, isochromosomes, deletions, rings, markers, and uniparental disomy. The majority of these were mosaic with monosomy X, but in seven cases, there was no evidence of mosaicism on confirmatory testing. The identification of multiple sex chromosome aneuploidies in these cases supports the need for additional genetic counseling prior to NIPS testing and following abnormal NIPS results that are positive for monosomy X. This finding broadens our knowledge about the variable outcomes of positive monosomy X NIPS results and emphasizes the importance of confirmatory testing and clinical follow up for these patients.