Williams-Beuren syndrome: phenotypic variability and deletions of chromosomes 7, 11, and 22 in a series of 52 patients.

Fluorescence in situ hybridisation (FISH) and conventional chromosome analysis were performed on a series of 52 patients with classical Williams-Beuren syndrome (WBS), suspected WBS, or supravalvular aortic stenosis (SVAS). In the classical WBS group, 22/23 (96%) had a submicroscopic deletion of the elastin locus on chromosome 7, but the remaining patient had a unique interstitial deletion of chromosome 11 (del(11)(q13.5q14.2)). In the suspected WBS group 2/22 (9%) patients had elastin deletions but a third patient had a complex karyotype including a ring chromosome 22 with a deletion of the long arm (r(22)(p11-->q13)). In the SVAS group, 1/7 (14%) had an elastin gene deletion, despite having normal development and minimal signs of WBS. Overall, some patients with submicroscopic elastin deletions have fewer features of Williams-Beuren syndrome than those with other cytogenetic abnormalities. These results, therefore, emphasise the importance of a combined conventional and molecular cytogenetic approach to diagnosis and suggest that the degree to which submicroscopic deletions of chromosome 7 extend beyond the elastin locus may explain some of the phenotypic variability found in Williams-Beuren syndrome.     

Chromosome 11 abnormalities in myelodysplastic syndromes.

Cytogenetic studies were performed in 140 patients with myelodysplastic syndrome (MDS) at diagnosis. Chromosome 11 anomalies were found in 7 cases (5%); 2 of these patients had refractory anemia (RA), 2 had refractory anemia with excess of blasts (RAEB), 1 had RAEB in transformation (RAEB-t), and 2 had chronic myelomonocytic leukemia (CMMoL) according to the French-American-British (FAB) Cooperative Group criteria. The chromosome 11 abnormalities comprised trisomy 11 (2 patients), monosomy 11 (1 patient), del(11)(q23) (2 patients), add(11)(p15) (1 patient), and der(11) t(3;11)(p21;q23) (1 patient). Abnormalities involving band q23 of chromosome 11 occurred in 3 cases and were the most common alteration. However, specific chromosomal alterations were not associated with any FAB classification group. These findings and their implications in the biology of MDS are discussed.     

Acute leukemia with abnormal thrombopoiesis and inversions of chromosome 3

Abnormal thrombopoiesis has been described in acute leukemias associated with inv(3) (q21q26.2) or t(3;3)(q21;q26.2). We reviewed 13 patients seen at the Mayo Clinic since 1979 with inversions of chromosome 3 or related abnormalities; 12 acquired and one constitutional. The patient with the constitutional abnormality had an inv(3)(p21q29) and mild leukocytosis and thrombocytosis. Among the 12 patients with acquired abnormalities, five had inv(3) (q21q26.2), three had t(3;3)(q21;q26.2), one had del(3)(q12q21), one had ins(6;3) (p21;q21q26.2), one had inv(3)(p21q12), and one had r(3)(p?21q?21). Each of these patients developed acute leukemia; eight had antecedent myelodysplastic syndrome, eight presented with platelet counts greater than 100 x 10(3)/microliters, and six had atypical megakaryocytic hyperplasia. Five patients had ringed sideroblasts in their marrow, an antecedent refractory anemia with ringed sideroblasts, or erythroleukemia. Seven patients received chemotherapy but showed no response. From the time of chromosome study, the median duration of survival was 4 months. Our results suggest that 1) although abnormal megakaryocytopoiesis is observed in patients with inv(3)(q21q26.2), multiple hematopoietic lineages are also involved in the neoplastic process; 2) an antecedent myelodysplastic syndrome is common in acute leukemia with inv(3) or related abnormalities; 3) affected patients have a poor survival and are resistant to conventional chemotherapy; and 4) abnormal megakaryocytopoiesis in acute leukemia may also be associated with pericentric inversions of chromosome 3.     

Unique karyotypes in two patients with Prader-Willi syndrome.

A physical disruption of the Prader-Willi syndrome (PWS) chromosome region is thought to cause PWS. We describe 2 girls with PWS phenotype, who had unique chromosome 15 abnormalities. The first patient showed mosaicism: 45,XX,t(15;15)(qter----p11.1::q11.200----qter)/46,XX,t(15;15)(qter----p1 1.1::q 11.200----qter), +mar. The band 15q11.2 apparently remained intact in the t(15;15) chromosome, and the mar chromosome was considered as r(15) (p11.1q11.1). The second patient had a karyotype of 47,XX,del(15)(q11.200----q11.207), +idic (15)(pter----q11.1::q11.1----pter). The complex breakage and reunion involving the 15q11.2 regions of the father's homologous chromosomes 15 at meiosis appeared to have resulted in the idic(15) and the del(15) chromosomes. These cytogenetic findings suggest that the PWS chromosome region may be localized on the very proximal portion of band 15q11.2.     

Specification of small distal 6q deletions in two patients by gene dosage and in situ hybridization study of plasminogen and alpha-L-fucosidase 2

Gene-dosage and in situ hybridization study of plasminogen (PLG) and alpha-L-fucosidase 2 (FUCA2) was performed on two patients with a small deletion of the distal long arm of chromosome 6, to define the structural abnormality more precisely. The results led to the cytogenetic diagnosis of an interstitial 6q deletion, del(6)(q25.1q25.3), in one patient and of a terminal 6q deletion resulting from a paternal t(1;6)(q44;q2605) translocation in the other patient. The latter patient had congenital noncommunicating hydrocephalus due to obstruction at the level of the foramen of Monro or the third ventricle which has not previously been described in terminal 6q deletions. Review of the literature suggests the emergence of a clinical syndrome associated with terminal 6q deletions.     

Specification of small distal 6q deletions in two patients by gene dosage and in situ hybridization study of plasminogen and α-L-fucosidase 2

Gene-dosage and in situ hybridization study of plasminogen (PLG) and α-L-fucosidase 2 (FUCA2) was performed on two patients with a small deletion of the distal long arm of chromosome 6, to define the structural abnormality more precisely. The results led to the cytogenetic diagnosis of an interstitial 6q deletion, del(6)(q25.1q25.3), in one patient and of a terminal 6q deletion resulting from a paternal t(1;6)(q44;q2605) translocation in the other patient. The latter patient had congenital noncommunicating hydrocephalus due to obstruction at the level of the foramen of Monro or the third ventricle which has not previously been described in terminal 6q deletions. Review of the literature suggests the emergence of a clinical syndrome associated with terminal 6q deletions.     

Unique karyotypes in two patients with Prader-Willi syndrome

A physical disruption of the Prader-Willi syndrome (PWS) chromosome region is thought to cause PWS. We describe 2 girls with PWS phenotype, who had unique chromosome 15 abnormalities. The first patient showed mosaicism: 45,XX,t(15;15)(qter→p11.1::q11.200→ qter)/46,XX,t(15;15)(qter → p11.1::q11.200→ qter), + mar. The band 15q11.2 apparently remained intact in the t(15;15) chromosome, and the mar chromosome was considered as r(15) (p11.1q11.1). The second patient had a karyo-type of 47,XX,del(15)(q11.200→q11.207), + idic (15)(pter → q11.1::q11.1→pter). The complex breakage and reunion involving the 15q11.2 regions of the father's homologous chromosomes 15 at meiosis appeared to have resulted in the idic(15) and the del(15) chromosomes. These cytogenetic findings suggest that the PWS chromosome region may be localized on the very proximal portion of band 15q11.2.     

Frequent deletions in nine newly immortal human cell lines.

Nine newly immortal lines of human fibroblasts transfected with SV40 T antigen were examined for recurrent chromosome losses. In order of decreasing frequency, all nine lines had three or more of the following minimal deletions specifically associated with the immortalization event: del(6)(q21), del(3)(p24), del(1)(p34), del(4)(p25), del(5)(p14), del(11)(p11), del(11)(q14), del(12)(p12), and del(14)(p?). Many other chromosome changes were not clearly associated with immortalization, but were acquired during other stages of this multistep model of neoplastic transformation. We propose that these chromosome loci associated with immortalization are candidates for the location of genes involved in cellular senescence.     

Chromosomal anomaly of 6q in chronic myelogenous leukemia (CML)

Anomalies of chromosome 6q, along with other chromosomal anomalies, are described in the bone marrow cells of two patients with chronic myelogenous leukemia (CML). One patient, a 14-year-old male, developed the karyotype 46,XY,t(1;6)(p36;q15),del(3)(q25),del(17)(p11),? inv(17)(q12q24) during blastic crisis of his disease. The other patient, a 24-year-old male, had the karyotype 46,XY,del(6)(q13),t(9;22)(q34;q11) during the early phase of his disease and evolution of i(17q) in the karyotype late in the disease.     

Chromosome abnormalities in hairy cell leukaemia variant

We describe chromosome abnormalities in 6 patients with hairy cell leukaemia (HCL) variant, a rare B-cell disorder with clinical and laboratory features intermediate between HCL and B-prolymphocytic leukaemia (B-PLL). All but one had marked splenomegaly and a raised white blood cell count (median 40 × 10⁹/l) with over 80% nucleolated hairy cells. These cells had a B-cell immunophenotype distinct from that of typical HCL. All patients but one are alive with stable disease with a median follow-up of 60 months. Numerical chromosome changes included loss of chromosomes 2, 3, 4, 6, 10, 19, 21, and X. Three cases had translocations involving the immunoglobulin gene regions: t(14;17)(q32;q11), t(14;22)(q32;q11), and t(2;8)(p11.12;q24). Immunocytochemistry demonstrated the presence of the MYC protein in cells from the case with t(2;8) but not in two others. Other structural abnormalities included t(3;10)(q27;q22) and t(3;12)(q27;q13) in the same patient, der(17)t(7;10;17) (p11;q27;q22), t(1;3)(q25;p21), t(8;21)(p12;q11), t(17;21)(p11;p11), del(6)(q15), del(7)(q34), and del(14)(q24). Genes Chromosom Cancer 10:197–202 (1994). © 1994 Wiley-Liss, Inc.     

Parallel karyotypic evolution and tumor progression in uterine leiomyoma

Cytogenetic evidence of clonal evolution was detected in five uterine leiomyomas. In two tumors, two clones were found, the third tumor had four, the fourth had nine, and the fifth had 12 clones. The first tumor had trisomy 12 as the primary anomaly and a sideline that also contained a del(7)(q21q31). Both clones of the second tumor had three structural changes in common but differed by the presence in the more advanced clone of an inv(7)(q31q34). Two cytogenetically unrelated pairs of clones were seen in the third tumor. One clone had a stemline of 46 and an r(1); a sideline had developed through duplication of this clone. The other pair had a del(7)(q21q31) in common. The last two tumors both had t(12;14)(q14-15;q23-24) as the primary abnormality. They also had a high frequency of telomeric associations that involved certain chromosome arms only. One of the secondary changes in the fourth tumor was a del(7)(q21q31); the principal secondary change in the fifth case was a ring chromosome 1 of variable size in the different clones. The analysis of these five uterine leiomyomas and the collation of the results with previously obtained data lead us to conclude that del(7)(q21q31) is secondary to t(12;14) and + 12 in this tumor type, and that ring formation involving chromosome 1 material, often with duplication of segments, is a common phenomenon during clonal evolution. The fact that the tumors were classified as cellular and had an increased mitotic rate indicates a parallel development between histologically detectable tumor progression and cytogenetically recognizable clonal evolution in uterine leiomyomas.     

"Masked" Ph1 chromosome in a complex three-way translocation

A patient with myelofibrosis was found to have a 46,XX,del(1)(q24),del(11)(p11),-22,+mar karyotype in unstimulated peripheral blood (PB) and spleen cells. On detailed cytogenetic examination it was determined that this patient had an apparently "masked" Ph1 chromosome contained in a complex three-way translocation. Since phytohemagglutinin (PHA)-stimulated PB and spleen cells were essentially normal, the masked Ph1 chromosome was assumed to be an acquired cytogenetic abnormality. The portion missing from the masked Ph1 chromosome was apparently translocated onto del(1). Thus, the detailed karyotype was 46,XX,t(1;11;22)(q24;p11;q11 or q12),t(1;22)(q24;q11 or q12). This complex rearrangement was present primarily in cells belonging to the granulocyte-macrophage cell lineage, whereas E-rosetting cells, and presumably T lymphocytes, had normal karyotypes.     

A myelodysplastic syndrome with marrow eosinophilia terminating in acute nonlymphocytic leukemia, associated with an abnormal chromosome 16

A patient presented with a myelodysplastic syndrome and bone marrow eosinophilia that evolved six months later into an acute nonlymphocytic leukemia (ANLL). Cytogenetic analyses of the bone marrow revealed 86% of the metaphases with 45,X-Y,inv(16)(p13;q22),t(11;17) (q11;q25),del(21)(q13) and 14% of the metaphases with the same abnormalities but with a Y chromosome. The association of ANLL, bone marrow eosinophilia, and abnormal chromosome 16 has previously been reported and has been suggested to have a favorable prognosis. Our patient is unique in that ANLL was preceded by a preleukemic phase associated with bone marrow eosinophilia. When complete remission was achieved, the bone marrow cytogenetics returned to normal, and the eosinophilia disappeared.     

Three rearrangements of chromosome 5 in a patient with myelodysplastic syndrome: an atypical deletion 5q, a complex intrachromosomal rearrangement of chromosome 5, and a paracentric inversion of chromosome 5

We report the case of a 74-year-old man who sought care for de novo myelodysplastic syndrome (RAEB-1). Conventional cytogenetic techniques showed a karyotype with two different deletions of the long arm of chromosome 5 distributed in three clones: 46,XY,del(1)(p34),del(5)(q14q23)[2]/46,XY,del(1)(p34),del(5)(q14q34)[10]/46,idem,inv(5)(q?11q?34)[7]. Precise characterization of the breakpoints, delineation of the deleted regions, identification of the complex intrachromosomal rearrangement of chromosome 5, and sequential accumulation of chromosomal abnormalities were elucidated by several fluorescence in situ hybridization analyses. We also assessed the clinical, biological, and cytogenetic evolution under lenalidomide treatment and after its interruption.     

Del(X) (q26) in a phenotypically normal woman and her daughter who also has trisomy 21

We present a phenotypically normal woman with del(X)(q26) with no evidence of mosaicism, who had two pregnancies resulting in two live-born infants. Her first child had trisomy 21 Down syndrome and the del(X)(q26). To our knowledge, this woman is the first known case of presumably nonmosaic del(Xq) producing live-born infants. This finding can be explained on the basis of persistence into adulthood of germ cells in ovaries of the rare del(Xq) individuals. The normal phenotype in this woman supports the hypothesis that the absence of genes of middle Xq segment.(q13 → q26) is responsible for the somatic manifestations of the Ullrich-Turner syndrome. Our finding suggests that prenatal diagnosis should be offered not only to pregnant women with numerical X chromosome abnormalities, as suggested previously, but also to those with structural X chromosome abnormalities, because of the possibility of chromosome aberrations in the offspring of such women.     

Another case of interstitial del(12) involving the proposed cardio-facio-cutaneous candidate region

Recent reports of patients with interstitial deletions involving the long arm of chromosome 12 have led to the proposal of a candidate region for the cardio-facio-cutaneous syndrome (CFCS) at (12)(q21.2q22). We now report a patient with an interstitial deletion, del(12)(q21.1q21.3) that overlaps the proposed critical region. The patient is an 11-year-old female with developmental delay. Her growth was normal but she is microcephalic with low set ears. In common with other patients with deletions in this region, she had fine, sparse head and eyebrow hair and a hyperkeratotic follicular rash, which involved her face and limbs. She does not have the diagnostic features of the CFC syndrome.     

Partial monosomy of distal 10q: three new cases and a review.

We report on 3 patients with partial deletions of the long arm of chromosome 10-46,XY,del (10)(q26.2), 46,XX,del(10) (q25.3q26.3) or 46,XX,del(10)(q26.1), and 46,XX,del (10)(q26.1). They are compared with other known cases with interstitial or terminal deletions involving chromosome bands 10q25 or q26. Unique manifestations are identified, including scoliosis and a severe behavior disorder with attention deficit and hyperactivity in a 12-year-old boy as well as patchy alopecia in a 6-year-old patient.     

New somatic cell hybrids for physical mapping in distal Xq and the fragile X region

Somatic cell hybrids were constructed from 3 patients carrying X chromosome abnormalities with breakpoints in distal Xq: 1) 94-3, from a patient with 46,XX,t(X;15)(q25 or q26;q25), 2) 8121-A1, from a patient with 46,X,del(X)(q26), and 3) 2384-A2, from a patient with 46,X,del(X)(q27). The breakpoint of patient 94 is proximal to HPRT in q26, a significant distance from the fragile X locus. The breakpoint of patient 8121 is distal to F9, but proximal to DXS98, and is thus proximal to the fragile site region. The breakpoint of 2384 is distal to DXS98 but proximal to DXS52, placing it within the region of the fragile site. Use of these physical mapping reference points will aid in the rapid localization of new DNA markers to distal Xq and the fragile X region.     

Interstitial del(20)(q11.2q12) - clinical and molecular cytogenetic characterization

A 2-year-old male patient with dysmorphic facial features and multiple congenital anomalies suggestive of a chromosome syndrome is presented. The facial features consisted of a large and high forehead, mild metopic ridging, a small triangular face, depressed nasal bridge, microphthalmia (right more than the left), protruding ears, and mildly prominent anteverted nose with long and smooth philtrum. Cytogenetic analysis showed 46,XY,del(20)(q11.2q12). Parental karyotypes were normal. Molecular characterization of del(20)(q11.2q12) by high-resolution microarray comparative genomic hybridization (arrayCGH) showed an approximately 6.8 Mb deletion. To our knowledge this is the first report of a de novo interstitial del(20)(q11.2q12) characterized by arrayCGH.     

Two cases of acute myeloblastic leukemia (M2 type) with karyotypes 45X,-X,t(6;8)(q27;q22),inv(9) and 46,XY,t(8;21)(q22;q22),del(9)(q22)

Two patients with acute myelogenous leukemia (AML) are described. The first case is that of a patient with AML who had a low leukocyte alkaline phosphatase level associated with a variant (6;8)(q27;q22) translocation, coupled with loss of an X chromosome in bone marrow and unstimulated blood cells. The second case is that of an AML patient in whom the karyotype of the leukemic cells at the time of diagnosis was 46,XY,t(8;21)(q22;q22),del(9)(q22); at relapse, the patient acquired an additional chromosome #19. The lack of involvement of chromosome #21 in the first case, as well as the occurrence of an abnormality of chromosome #9, in addition to the t(8q-;21q+) in the second case are discussed with reference to the character of the possible specific chromosomal events in patients with type M2 AML.