Cryptic subtelomeric translocations in the 22q13 deletion syndrome

Cryptic subtelomeric rearrangements are suspected to underlie a substantial portion of terminal chromosomal deletions. We have previously described two children, one with an unbalanced subtelomeric rearrangement resulting in deletion of 22q13→qter and duplication of 1qter, and a second with an apparently simple 22q13→qter deletion. We have examined two additional patients with deletions of 22q13→qter. In one of the new patients presented here, clinical findings were suggestive of the 22q13 deletion syndrome and FISH for 22qter was requested. Chromosome studies suggested an abnormality involving the telomere of one 22q (46,XX,?add(22)(q13.3)). FISH using Oncor D22S39 and Vysis ARSA probes confirmed a terminal deletion. A multi-telomere FISH assay showed a signal from 19qter on the deleted chromosome 22. Results were confirmed with 19qtel and 22qtel specific probes. The patient is therefore trisomic for 19qter and monosomic for 22qter. The patient''s mother was found to have a translocation (19;22)(q13.42;q13.31). We also re-examined chromosomes from two patients previously diagnosed with 22q deletions who were not known to have a rearrangement using the multi-telomere assay. One of these patients was found to have a derivative chromosome 22 (der(22)t(6;22)(p25;q13)). No evidence of rearrangement was detected in the other patient. Thus we have found the 22q13 deletion to be associated with a translocation in three of four patients. This report illustrates the usefulness of examining patients with hypotonia, severe language delay, and mild facial dysmorphism for this syndrome and suggests that most of these deletions may be unbalanced subtelomeric rearrangements.     

Identification of an unbalanced cryptic translocation t(9;17)(q34.3;p13.3) in a child with dysmorphic features

We report a case of an unbalanced cryptic telomeric translocation 46,XY,der(17),t(9;17)(q34.3;p13.3) in a boy with dysmorphic features and developmental delay. The proband had intrauterine growth retardation, postnatal short stature, and mild microcephaly. Magnetic resonance imaging showed incomplete myelination, but no evidence of lissencephaly. Cytogenetic analysis of the proband's peripheral blood showed an abnormal 17p. Fluorescence in situ hybridisation (FISH) with a Miller-Dieker cosmid probe did not detect a deletion for that area. Further analysis with a 17p telomere specific probe identified an unbalanced telomeric translocation. The same probe was used to determine the presence of an apparent balanced translocation t(9;17)(q34.3;p13.3) in the mother of the proband. The balanced translocation was confirmed with two cosmids that map distally on 9q34.3. Two phenotypically normal half sibs, a maternal aunt, a maternal uncle, and the maternal grandmother were found to be balanced translocation carriers as well. A subtle translocation carriers as well. A subtle translocation is one mechanism that can produce an abnormal phenotype in a patient who had a normal karyotype at lower band resolution levels.     

Proximal interstitial deletion of 7q: a case report and review of the literature

A male infant with multiple congenital anomalies was found to have a deletion of 7q [46,XY,del(7)(pter----q11.2::q22----qter)]. The father had a balanced rearrangement involving chromosomes 7 and 9, interpreted as 46,XY,dir ins(9;7), (9pter----9p12::7q22----7q11.2::9p12----++ +9qter;7pter---- 7q11.2::7q22----7qter). C-banding showed that the rearrangement occurred as a new event in the paternal grandfather's germ-line. Including the present patient, 16 cases of proximal 7q deletion (q11----q21/q22) have been described to date. This is a sufficient number of cases to permit comparison of manifestations to attempt delineation of karyotype-phenotype relationships in different proximal interstitial deletions of 7q.     

Molecular cytogenetic characterization of a derivative chromosome 8 with an inverted duplication of 8p21.3-->p23.3 and a rearranged duplication of 8q24.13-->qter

A derivative chromosome 8 was observed in a newborn boy who presented with low birth weight, multiple congenital anomalies, and dysmorphic face. The der(8) was further characterized at age 18 months by a high resolution G-banding analysis, spectral karyotyping, and fluorescence in situ hybridization (FISH) with multiple DNA probes. The karyotype was described as 46,XY,der(8)(qter-->q24.13::p21.3-->p23.3::p23.3-->qter), representing an inverted duplication of region 8p21.3-->p23.3 and a duplication of region 8q24.13-->qter, which attaches to the duplicated short arm segment at 8p21.3. Different from previously reported patients with an inverted duplication (8p), no deletion was detected in the distal region of 8p in this case. This young child had manifested a broad nasal bridge, micrognathia, cleft lip, hydrocephalus, partial agenesis of the corpus callosum, Dandy-Walker malformation, congenital heart defects, dysplastic kidneys, hydronephrosis, marked hypotonia, and significant psychomotor retardation. These features are compared with those commonly seen in cases with an inverted duplication of 8p and cases with a partial trisomy of 8q.     

Maternal translocation (9;18) with two abnormal offspring each with different chromosome derivatives.

We report a phenotypically normal woman with an apparently balanced reciprocal translocation between chromosomes 9 and 18 [46,XX,t(9;18)(p22;p11.2)], giving rise to unbalanced chromosome complements in two of her children, each of whom received a different derivative chromosome. The proband's karyotype is 46,XY,-18,+der(18), t(9;18)(p22;p11.2)mat, which results in a duplication of the distal portion of the short arm of chromosome 9 with a concomitant deletion of much of the short arm of chromosome 18. The karyotype of the proband's brother is 46, XY,-9,+der(9),t(9;18)(p22;p11.2)mat, which results in a deletion of the distal short arm of chromosome 9 and a duplication of most of the short arm of chromosome 18. The phenotype of each child is significantly different from that of his sib and is not consistent with any previously reported chromosome abnormality.     

Maternal balanced translocation leading to partial duplication of 4q and partial deletion of 1p in a son: Cytogenetic and FISH studies using band-specific painting probes generated by chromosome microdissection

A 9-month-old boy with pre- and post-natal growth retardation, microcephaly, plagiocephaly, and several minor anomalies had the initial karyotype: 46,XY,der(1)t(1;?)(p36.1;?). Further analysis showed that the der(1) was derived from an unfavorable segregation of a maternal complex chromosome rearrangement, i.e., 46,XX,der(1)t(1;?)(p36.1;?), der(4)t(4;?)(q?;?). Whole chromosome fluorescence in situ hybridization (FISH) and chromosome microdissection were used to clarify the maternal karyotype as: 46,XX,der(1)t(1;4)(4qter→4q33::1p36.13→1qter),der(4)t(1;4)inv(4)(4pter→ 4q31.3::1p36.33→1p36.13::4q33→4q31.3::1p36.33→1pter). Therefore, the karyotype of the boy actually was 46,XY,der(1)t(1;4)(p36.13;q33). Clinical comparison of the patient's clinical findings showed similarities to individuals with partial del(1p) and dup(4q). To our knowledge the above cytogenetic abnormalities have not been described previously. This case further demonstrates the advantages of chromosome microdissection and FISH in the identification of anomalous chromosome regions and breakpoints. Am. J. Med. Genet. 71:160–166, 1997. © 1997 Wiley-Liss, Inc.     

Ebstein anomaly associated with rearrangements of chromosomal region 11q

Ebstein anomaly (EA) is a relatively uncommon congenital heart defect and it is very rarely associated with a chromosomal anomaly. We report two distinct rearrangements of the chromosomal region 11q arm in two unrelated patients with Ebstein anomaly, renal malformation, minor anomalies, and the Pierre Robin sequence. The first patient had an interstitial deletion of chromosome 11 [46,XY,del(11)(11q21q23), and the other had a tertiary trisomy of chromosome 11qter (47,XX,+der(22)t(11;22)(q23; q11.2) Its association with either a chromosome 11q deletion or a duplication in some individuals suggests that a rearrangement of the 11q region is likely to cause a shift of the individuals' underlying liability to develop EA above a certain threshold. Am. J. Med. Gen. 80:157–159, 1998. © 1998 Wiley-Liss, Inc.     

Constitutional t(5;7)(q11;p15) rearranged to acquire monosomy 7q and trisomy 1q in a patient with myelodysplastic syndrome transforming to acute myelocytic leukemia

We report the case of a 61-year-old woman who presented with a myelodysplastic syndrome (MDS) and a t(5;7)(q11.2;p15) in her bone marrow cells. Subsequent analysis of phytohemagglutinin-stimulated peripheral blood lymphocytes and cultured skin fibroblasts showed that the translocation was constitutional. Disruption of chromosome bands 5q11.2 and 7p15 has been described recurrently in MDS and acute myelocytic leukemia (AML) and, although the age of onset was not earlier than usual, it is nonetheless possible that genes interrupted by this translocation may been a predisposing factor for her condition. With progression to AML, a further rearrangement of the constitutional der(7)t(5;7) occurred, involving chromosome arm 1q. Fluorescence in situ hybridization (FISH) with whole-chromosome paints showed that the result of the second rearrangement, a t(1;7)(q32.1;q32), was observed, leading to trisomy of the segment 1q32.1 approximately qter and monosomy of the segment 7q32.1 approximately qter. The acquired imbalances, particularly loss of 7q, are commonly associated with MDS/AML and a poor prognosis; however, this patient remained in remission after treatment for more than two years before AML relapse, perhaps because the affected regions fall outside of the critical regions of imbalance.     

Unbalanced translocation 9;16 in two children with dysmorphic features, and severe developmental delay: Evidence of cross-over within derivative chromosome 9 in patient #1

We describe 2 children with dysmorphic features, and severe developmental delay presenting with overlapping unbalanced translocations of 9q34.3 and 16p13. Patient #1: A 4 year old African-American female with normal karyotype with a pericentric inversion on one chromosome 9 known to be a benign variant. Low resolution array CGH revealed a single BAC clone loss at 9q34.3 and a single BAC clone gain at 16p13.3, confirmed by FISH. Whole genome SNP array analysis refined these findings, identifying a terminal 1.28 Mb deletion (138,879,862-140,164,310) of 9q34.3 and a terminal 1.62 Mb duplication (45,320-1,621,753) of 16p13.3. Sub-telomeric FISH showed an unbalanced cryptic translocation involving the inverted chromosome 9 and chromosome 16. FISH of the father showed a balanced t(9;16)(q34.3;p13.3) involving the non-inverted chromosome 9, and a pericentric inversion on the normal 9 homologous chromosome. The presence of two rearrangements on chromosome 9, both an unbalanced translocation and a pericentric inversion, indicates recombination between the inverted and derivative 9 homologues from her father. Patient #2: A 1 year old Iraqi-Moroccan female with normal karyotype. Array-CGH identified a 0.56 Mb deletion of 9q34.3 (139,586,637-140,147,760) and an 11.31 Mb duplication of 16p13.3p13.13 (31,010-11,313,519). Maternal FISH showed a balanced t(9;16)(q34.3;p13.13). Both patients present with similar clinical phenotype.     

Adjacent-2 disjunction of a maternal t(9;22) leading to duplication 9pter→q22 and deficiency of 22pter→q11.2

The proposita presented at birth with multiple congenital anomalies including craniofacial anomalies, bilateral cleft lip and palate, abnormalities of the urogenital system, talipes equinovarus, and the DiGeorge sequence. Cytogenetic investigation showed a 46,XX,- 22,+der(9)t(9;22)(q22;q11.2) karyotype. The mother, maternal uncle, and maternal grandmother of the infant are carriers of a reciprocal balanced translocation involving chromosomes 9 and 22 at regions q22 and q11.2, respectively. The unbalanced karyotype seen in the proposita arose due to an adjacent-2 disjunction of the quadrivalent in the mother. Prenatal diagnosis of the second pregnancy of this woman showed a similar karyotype. Review of the literature shows that adjacent-2 disjunction may occur preferentially when certain chromosomes are involved in translocations.     

A de novo complex karyotype with two independent balanced translocations and a double inversion of chromosome 6 presenting with multiple congenital anomalies

We report a 4-year-old female with a de novo complex karyotype with multiple chromosomal rearrangements and a distinctive phenotype. Her medical history is significant for having been a twin born at 35 weeks gestation, breech presentation, with feeding problems and poor growth as an infant, gastroesophageal reflux disease, peripheral pulmonic stenosis, omphalocele, high myopia, and severe mental retardation. She is small for her age with microcephaly, posteriorly sloping forehead, shallow orbits, long palpebral fissures, prominent nose, wide mouth, absent uvula, kyphosis, brachydactyly, bridged palmar crease, and hypertonia. Peripheral blood lymphocytes revealed a karyotype of 46,XX,t(1;12)(p22.3;q21.3),inv(6)(p24q23),t(7;18)(q11.2;q21.2) in all cells. Parental karyotypes and that of her twin were normal. Spectral Karyotyping (SKY) and fluorescence in situ hybridization (FISH) with whole chromosome paints for chromosomes 1, 6, 7, 12, and 18 did not reveal additional rearrangements. Prometaphase G-banding analysis suggested that the "inverted" chromosome 6 might contain a cryptic rearrangement. Although no deletion nor duplication was detected using metaphase comparative genomic hybridization (CGH), multicolor high resolution banding (mBAND) demonstrated a double inversion of chromosome 6, resulting in a final karyotype as above but including der(6)(pter --> p23::q21 --> q22.3::q21 --> p23::q22.3 --> qter).     

Therapy-related acute leukemia with mixed phenotype and t(9;22)(q32;q11.2): a case report and review of the literature

Therapy-related acute leukemia showing mixed phenotype is extremely rare. We report a 49-year-old woman who presented with palpable masses in her neck and back. She had received systemic chemotherapy (adriamycin and cisplatin) and radiotherapy for endometrial adenocarcinoma 7 years before. Her peripheral blood and bone marrow showed increased blasts, which coexpressed myeloid (CD13, CD33, and myeloperoxidase) and B-lymphoid antigens (CD19 and CD79a). Cytogenetic analysis showed a karyotype of 46,XX,dup(1)(q21q32),add(5)(q33),t(9;22)(q34;q11.2)[12]/47,idem,+der(22)t(9;22)[8], and BCR/ABL1 rearrangement was detected. Leukemic infiltration was also confirmed in her back mass. After induction chemotherapy with idarubicin, cytarabine, and imatinib, she achieved complete remission. Only 2 cases of therapy-related acute leukemia with mixed phenotype have been reported so far: one with hyperploidy and the other with t(1;21)(p36;q22). To the best of our knowledge, this is the first case of therapy-related acute leukemia with mixed phenotype and t(9;22) as well as extramedullary leukemic infiltrations.     

A cryptic unbalanced translocation t(2;9)(p25.2;q34.3) causes the phenotype of 9q subtelomeric deletion syndrome and additional exophthalmos and joint contractures

We report on a 26-year-old woman with microcephaly, typical facial features of 9q subtelomeric deletion syndrome, exophthalmos, contractures of elbow and knee joints, severe muscular hypotonia, no ability to walk, and no speech development.Array CGH revealed a cryptic 9q34.3 deletion and 2p25.2-p25.3 duplication transmitted by her mother, who was carrying a balanced translocation of chromosomes 2p and 9q. There are about 50 reported cases of deletions of the subtelomeric part of chromosome 9q, however, duplications of only the terminal part of chromosome 2p are rare. Neuroblastoma, diaphragmatic hernia, neural tube defects, broncho-pulmonary abnormalities, and congenital heart defects are conditions associated with partial trisomy of larger fragments of 2p. To our knowledge there is only one case described with an isolated duplication as distal as in the patient reported here. Joint contractures and exophthalmos observed in this patient are also seen in our patient. These features are not allegeable by the deletion 9q34.3 identified in the patient reported here and may be a hint that terminal duplication of 2p could be associated with exophthalmos and contractures.     

Breakpoint mapping in a case of mosaicism with partial monosomy 9p23 --> pter and partial trisomy 1q41 --> qter suggests neo-telomere formation in stabilizing the deleted chromosome

We report on a clinical and molecular cytogenetic study of a patient who presents a complex chromosomal rearrangement with two different cell lines. Using high-resolution GTG banding and fluorescence in situ hybridization (FISH) with several probes, including bacterial artificial chromosomes (BACs), the karyotype was defined as 46,XX,del(9)(p23)[54]/46,XX,der(9)t(1;9)(q41;p23)[46], indicating the presence of monosomy 9p23 in all cells and trisomy 1q41 in approximately 50% of the cells. The patient studied presents most of the manifestations of the 9p deletion and 1q duplication syndromes. The breakpoint was mapped at 9p23 with a loss of approximately 13.9-Mb of DNA. The duplicated segment consists of approximately 35 Mb from 1q41-qter region. We also suggest that a mechanism for telomere capture and interstitial telomeric sequences (ITs) is involved in a neo-telomere formation in one of the cell lines. This study highlights the importance of combining high-resolution chromosome and FISH with BACs in order to make genotype-phenotype correlations and to understand the mechanisms involved chromosomal aberrations.     

9p deletion and distal 9q duplication due to a paternal pericentric inversion 9(p22q32)

A female infant with 46,XX,rec(9), dup q,inv(9)(p22q32)pat is presented. She had a duplication from 9q32 to qter and a deletion from 9p22 to 9pter. Phenotypical abnormalities observed corresponded with features noted in cases with distal dup (9q), while pathognomonic features of del(9p) syndrome were not observed.     

9p Deletion and distal 9q duplication due to a paternal pericentric inversion 9(p22q32)

A female infant with 46,XX,rec(9), dup q,inv(9)(p22q32)pat is presented. She had a duplication from 9q32 to qter and a deletion from 9q22 to 9pter. Phenotypical abnormalities observed corresponded with features noted in cases with distal dup (9q), while pathognomonic features of del(9p) syndrome were not observed.     

A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome

Patients with 9q34.3 terminal deletion usually show a clinically recognizable phenotype characterized by specific facial features (microcephaly, flat face, arched eyebrows, hypertelorism, short nose, anteverted nostrils, carp mouth and protruding tongue) in combination with severe mental retardation, hypotonia, and other anomalies. We analyzed six unrelated patients with a various 9q34.3 terminal deletion. While having different-sized 9q34.3 deletions, all of these patients shared several distinctive anomalies. These anomalies are likely to arise from a commonly deleted region at distal 9q34.3. Fluorescence in situ hybridization (FISH) analysis using a dozen BAC clones mapped at the 9q34.13-q34.3 region defined the shortest region of deletion overlap (SRO) as a 1-Mb segment proximal to 9qter containing eight known genes. Possible candidate genes delineating specific phenotypes of the 9q34.3 terminal deletion syndrome are discussed.