Cytogenetic findings in a prospective series of patients with DiGeorge anomaly.

High-resolution cytogenetics analysis of peripheral blood lymphocytes was done prospectively on 27 of 28 patients with features of DiGeorge anomaly. Twenty-two patients (81%) had normal chromosome studies with no detectable deletion in chromosome 22. Five patients (18%) had demonstrable chromosome abnormalities. Three patients had monosomy 22q11, one due to a 4q;22q translocation, one due to a 20q;22q translocation, and one due to an interstitial deletion of 22q11. One patient had monosomy 10p13, and one patient had monosomy 18q21.33, although the latter had subsequent resolution of T-cell defects. These findings are consistent with the heterogeneity of DiGeorge anomaly but confirm the association with monosomy 22q11 in some cases. However, monosomy 10p13 may also lead to this phenotype. Because of these associated chromosome findings, cytogenetic analyses should be done on patients with suspected DiGeorge anomaly. This is particularly important since many of the abnormalities involving chromosome 22 are translocations that can be familial with a higher recurrence risk. Since only one subtle, interstitial deletion of chromosome 22 was observed, it is not clear whether high-resolution cytogenetic analysis is cost beneficial for all such patients.     

Digeorge anomaly associated with partial deletion of chromosome 22. Report of a case with X/22 translocation and review of the literature

Partial monosomy of 22q, resulting from a de novo unbalanced translocation t(X;22)(q28;q11) was detected in a newborn female with manifestations of the DiGeorge anomaly including multiple anomalies, type I truncus arteriosus, T-cell abnormalities, thymic aplasia and parathyroid hypoplasia noted on postmortem examination. Although DiGeorge anomaly is causally heterogeneous, our patient, together with 18 previously known cases, confirm that partial monosomy of the proximal long arm of chromosome 22 is the single most common cause of this polytopic developmental field defect.     

Localization of 27 DNA markers to the region of human chromosome 22q11-pter deleted in patients with the DiGeorge syndrome and duplicated in the der22 syndrome

DiGeorge syndrome is a human developmental field defect with the pathological features of an abnormality of embryogenesis at 4 to 6 weeks of gestation. Cytogenetic analyses of patients have revealed a number of instances of monosomy 22q11-pter in this condition. We have analyzed 52 DNA markers that map to 22q11-pter and have found 27 that are deleted in DiGeorge syndrome patients with known monosomy for part of this region and that are duplicated in patients with the der22 syndrome. The set of clones mapping to the DiGeorge region was further assigned to a proximal or a distal location within the deletion.     

Partial monosomy 21 (q11.2→q21.3) combined with 3p25.3→pter monosomy due to an unbalanced translocation in a patient presenting dysmorphic features and developmental delay

We describe a female patient of 1 year and 5 months-old, referred for genetic evaluation due to neuropsychomotor delay, hearing impairment and dysmorphic features. The patient presents a partial chromosome 21 monosomy (q11.2→q21.3) in combination with a chromosome 3p terminal monosomy (p25.3→pter) due to an unbalanced de novo translocation. The translocation was confirmed by fluorescence in situ hybridization (FISH) and the breakpoints were mapped with high resolution array. After the combined analyses with these techniques the final karyotype was defined as 45,XX,der(3)t(3;21)(p25.3;q21.3)dn,-21.ish der(3)t(3;21)(RP11-329A2-,RP11-439F4-,RP11-95E11-,CTB-63H24 +).arr 3p26.3p25.3(35,333-10,888,738)) × 1,21q11.2q21.3(13,354,643-27,357,765) × 1. Analysis of microsatellite DNA markers pointed to a paternal origin for the chromosome rearrangement. This is the first case described with a partial proximal monosomy 21 combined with a 3p terminal monosomy due to a de novo unbalanced translocation.     

11q- syndrome: three cases and a review of the literature.

We report on three children with de novo terminal deletions of the long arm of chromosome 11 (11q-) and breakpoints in 11q23-q24. Eighty-nine other patients with partial monosomy 11q have been reported and were reviewed by us. Salient features of 11q- syndrome are psychomotor retardation, trigonocephaly, telecanthus/hypertelorism, broad depressed nasal bridge, micrognathia, low set abnormal ears, cardiac anomalies and hand/foot anomalies. Renal agenesis and anal atresia are reported first here. Supratentorial white matter abnormality on CT and MRI present in our second patient was reported in three patients. Increased mortality is caused by cardiac anomalies. A third of all patients with partial monosomy 11q had thrombocytopenia or pancytopenia and this seems to be related to the absence of band 11q23-q24. Seventy-six percent of patients have de novo deletions with breakpoints in 11q21-q25. There is no obvious correlation between the length of the deleted segment and the severity of the symptoms. In unbalanced chromosomal patterns with deletions of 11q involving bands 11q23-q24 the typical phenotype of 11q- syndrome remains recognizable. Deletions distal to 11q24.1 do not produce the typical 11q- syndrome.     

Partial trisomy and monosomy 21 in an infant with an unusual de novo 21/21 translocation

A 3-month-old boy with a 46,XY,--21,+t(21;21)(pter leads to q22.3::q22.3 leads to q11::p11 leads to pter) karyotype, implicating trisomy for the 21q11 leads to 21q22.2 segment and monosomy for the 21q22.3 sub-band, is described. Most of the clinical features corresponded to Down syndrome ; other signs such as large ears, prominent nasal bridge and retromicrognathia were interpreted as the expression of 21q22.3 monosomy. The abnormal monocentric chromosome had satellites and stalks on both ends as a result of a 21q;21q translocation followed by deletion of one centromere region. Despite similar stalk size and NOR-Ag positiveness a significantly higher association frequency of the centrometric end as compared to the acentric end was found. This observation suggests that the satellite association phenomenon is not exclusively NOR-dependent, but that the centromeric and/or p11 regions of acrocentrics also play an important role.     

Partial monosomy due to long-arm deletion of chromosome 11 : del (11) (q23) (author's transl)]

A girl, who died at 25 days of age, was found to have a partial monosomy due to a 11q23 leads to 11qter deletion. The main clinical findings were trigonocephay, facial dysmorphia, and congenital heart disease. A review of developmental and dysmorphic features of the seventeen recognized cases is presented.     

Assignment of human porphobilinogen deaminase to 11q24.1----q24.2 by in situ hybridization and gene dosage studies

In situ hybridization and gene dosage-effect studies were conducted to determine the detailed chromosomal location of the gene encoding human porphobilinogen deaminase (PBGD). Red cell PBGD activity was normal in one patient with monosomy for 11q24.2----qter but was increased 1.5 times in another patient with trisomy for 11q22.2----qter. The cDNA probe for PBGD was found to be specifically hybridized to band 11q24. These results suggest that the gene for PBGD is localized within the region 11q24.1----q24.2.     

11q Aneuploidy: Partial monosomy and trisomy in the children of a mother with a t(3;11)(p27;q23) translocation

Summary A woman with a balanced translocation t(3;11)(p27;q23) has had three abnormal children. The first child died in infancy, and of the two survivors who show segregation of the derivative maternal translocated chromosomes, one exhibits partial trisomy 11q and the other partial monosomy 11q. The two cases are compared with each other and with reported examples. Moreover, 11q break points are discussed.     

De novo unbalanced t(11q;21q) leading to a partial monosomy 21pter-q22.2 and 11q24-qter in a patient initially diagnosed as monosomy 21

We describe a patient in whom full monosomy 21 was initially assumed from routine GTG banded karyotyping. Re-examination with chromosome painting demonstrated an unbalanced translocation between the long arms of chromosomes 11 and 21. Fluorescence in situ hybridization (FISH) and microsatellite marker analysis revealed partial monosomy of chromosome 21 (pter-q22.2) and 11 (q24-qter). The patient was prematurely born in the 31st week of gestation and expired 3 days after delivery. She showed multiple minor anomalies, a complex cardio-vascular malformation, intestinal malrotation and cerebellar hypoplasia.     

Incidence of numerical chromosome aberrations in meningioma tumors as revealed by fluorescence in situ hybridization using 10 chromosome-specific probes

OBJECTIVE: Although information on the cytogenetic characteristics of meningioma tumors has accumulated progressively over the past few decades, information on the genetic heterogeneity of meningiomas is still scanty. The aim of the present study was to analyze by interphase fluorescence in situ hybridization (FISH) the incidence of numerical abnormalities for chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y in a group of 70 consecutive meningioma tumors. Another goal was to establish the potential associations among the altered chromosomes, as a way to assess both intertumoral and intratumoral heterogeneity. METHODS: For the purpose of the study, 70 patients diagnosed with meningioma were analyzed. Interphase FISH for the detection of numerical abnormalities for chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y was applied to fresh tumor samples from each of the patients studied. RESULTS: The overall incidence of numerical abnormalities was 76%. Chromosome Y in males and chromosome 22 in the whole series were the most common abnormalities (46% and 61%, respectively). Despite the finding that monosomy of chromosome 22/22q(-) deletions are the most frequent individual abnormality (53%), we have observed that chromosome gains are significantly more common than chromosome losses (60% versus 40%). Chromosome gains corresponded to abnormalities of chromosomes 1 (27%), 9 (25%), 10 (23%), 11 (22%), 14 (33%), 15 (22%), 17 (23%), and X in females (35%) and males (23%) whereas chromosome losses apart from chromosome 22 frequently involved chromosomes 14 (19%), X in males (23%), and Y in males (32%). Although an association was found among most gained chromosomes on one side and chromosome losses on the other side, different association patterns were observed. Furthermore, in the latter group, monosomy 22/22q(-) was associated with monosomy X in females and monosomy 14/14q(-) was associated with nulisomy Y in males. In addition, chromosome losses usually involved a large proportion of the tumor cells whereas chromosome gains were restricted to small tumor cell clones, including tetraploid cells. CONCLUSIONS: Our results show that meningiomas are genetically heterogeneous tumors that display different patterns of numerical chromosome changes, as assessed by interphase FISH.     

Precocious puberty associated with partial trisomy 18q and monosomy 11q

We report a 10-years-old female patient with a partial trisomy 18q and monosomy 11q due to a maternal translocation. The phenotype of our proband is partially common with Jacobsen syndrome and duplication 18q but she has also some atypical anomalies such as precocious puberty, a retinal albinism and hypermetropia. Based on cytogenetics and FISH analysis, the karyotype of the proband was 46,XX,der(11)t(11;18)(q24;q13). To the best of our knowledge, this is the first report of precocious puberty associated with either dup(18q) or del(11q) syndromes.     

Novel translocation t(3;11)(p21;q24) in multiple myeloma characterised by FISH

We present a 72 year old man with multiple myeloma (MM). Cytogenetic and FISH analysis of bone marrow aspirate showed a novel translocation -der(11)t(3;11)(p21;q24). The unbalanced karyotype led to substantial partial trisomy for chromosome 3p and small partial monosomy 11q. Structural rearrangements of chromosome 3 are uncommon in MM and these are reviewed. The patient died 2 years after the diagnosis of MM was made.     

Correlations between cytogenetics and morphology in myelodysplastic syndromes

In order to detect possible relationships between cytogenetic abnormalities and morphologic features in myelodysplastic syndromes (MDS), 48 patients with MDS were investigated. Clonal cytogenetic abnormalities were present in bone marrow cells from 27 patients (56%). The most frequent single anomaly was del (5 q) (10 cases), followed by monosomy 7 (3 cases), trisomy 8 (3 cases) and del (20 q) (2 cases). Complex anomalies were present in 6 patients. Morphologically, according to the French-American-British (FAB) classification: 17 cases were considered as refractory anemia (RA), 17 as RA with excess of blasts (RAEB), 2 as RAEB in transformation, 2 as acquired idiopathic sideroblastic anemia and 10 as chronic myelomonocytic leukemia. With regard to the FAB classification, del (5 q) was often associated with RA and complex cytogenetic anomalies with RAEB. When myelodysplasia was studied in individual myeloid lineages, del (5 q) was associated with hypolobulated megakaryocytes, monosomy 7 with micromegakaryocytes and complex chromosomal anomalies with the association of two or more features of dysmegakaryocytopoiesis. Del (11 q) was associated with increased iron storage and del (20 q) with marked dyserythropoiesis. No correlation was observed between cytogenetic anomalies and features of dysgranulocytopoiesis.     

Complex chromosomal rearrangement involving chromosomes 11, 13, 14 and 18 resulting in monosomy for 13q32----qter

A five-year-old boy with speech delay, minor facial abnormalities and borderline psychomotor retardation was found to have a complex de novo double translocation involving four chromosomes resulting in monosomy for the segment 13q32----qter. Chromosomes involved were 11, 13, 14, and 18. The translocation between chromosome 11 and 13 was unbalanced with the loss of the segment 13q32----qter. The second translocation between 14 and 18 was apparently balanced.     

The deletions of 22q11--the Portuguese experience

The patients with a chromosome 22q11 deletion have a variable phenotype which includes DiGeorge (DG) and Velocardiofacial (VCF) syndromes. The aim of the present study is to characterize the phenotype of DG and VCF using facial biometry in 12 portuguese patients. We found 4/12 patients with the DG phenotype: 3/4 had telecanthus, small mouth and retrognathia; 1/4 had telecanthus, short nose with bulbous tip and a normal mouth. These patients had major cardiac defects associated with hypoplastic or absent thymus and monosomy 22q11. We did not find velopharyngeal insufficiency in patients with the so called DG phenotype 8/12 patients had the VCF phenotype: typical facies with variable features. Four of these had velopharyngeal insufficiency and learning disabilities. Four patients had cardiac defects and 5/8 had monosomy 22q11. Probably this clinical variability is due to mutations in critical genes involved in embryonic development.     

Molecular studies of segmental aneusomy: FISHing for the atypical cry in del(5)(p15.3)

We report a newborn male with multiple congenital anomalies including growth retardation, hypotonia, dysmorphic facies, widely-spaced nipples, micropenis, cryptorchidism, optic nerve hypoplasia, heart disease, and a striking, high-pitched cry. Chromosome analysis revealed de novo partial trisomy 11q due to a der(5)t(5;11)(p15.3;q22). Fluorescence in situ hybridization (FISH) showed loss of the 5p telomere signal on the der(5) chromosome, indicating the infant has partial monosomy 5p in addition to partial trisomy 11q. Among cases involving trisomy 11q, an unusual cry has only been documented in the presence of a der(5)t(5p;11q). This apparent dependence of the abnormal cry on monosomy 5p suggested the same genetic mechanism that occurs in Cri du chat syndrome (CDCS) may be responsible for the atypical cry in der(5)t(5p;11q) individuals. Neither a commercial CDCS probe (LSI D5S23, D5S721) nor a series of BAC clones encompassing distal regions implicated in the CDCS-associated cat-cry were deleted in our patient. These results suggest a second cry-modifying locus maps telomeric to BAC RP11-94J21 in band 5p15.33. This locus may not only cause the abnormal cry in individuals with a der(5)t(5p;11q) but could also contribute to the phenotypic variability and discordant mapping studies observed for CDCS.     

Monosomy 10q26-qter and trisomy 11q13-qter as a result ofde novo unbalanced translocation

A male infant with partial monosomy 10 q and partial trisomy 11q as a result ofde novo unbalanced translocation between the long arms of chromosomes 10 and 11: der(10)t(10;11)(q26;q13) is described. He had craniofacial dysmorphy, congenital heart defects, urogenital and cerebral anomalies, and severe developmental delay. To the best of our knowledge, this is the first report of this combination of chromosomal abnormalities.     

Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome

It is well established that DiGeorge syndrome (DGS) may be associated with monosomy of 22q11-pter. More recently, DNA probes have been used to detect hemizygosity for this region in patients with no visible karyotypic abnormality. However, DGS has also been described in cases where the cytogenetic abnormality does not involve 22q11; for instance, four cases of 10p- have been reported. In this study we have prospectively analyzed patients, by using DNA markers from 22q11, to assess the frequency of 22q11 rearrangements in DGS. Twenty-one of 22 cases had demonstrable hemizygosity for 22q11. Cytogenetic analysis had identified interstitial deletion in 6 of 16 cases tested; in 6 other cases no karyotype was available. When these results are combined with those from our previous studies, 33 of 35 DGS patients had chromosome 22q11 deletions detectable by DNA probes.