Langer-Giedion syndrome with and without del 8q. Assignment of critical segment to 8q23

Summary Two patients with typical Langer-Giedion or trichorhino-phalangeal type II syndrome are reported. One had an apparently normal karyotype. The second had an intercalary del 8q23. Attention is drawn to the severe bone defects seen in the latter and observations from the literature are discussed. The critical segment is assigned to band 8q23. The syndrome may result in a number of cases from a visible deletion, and in other instances from a more conventional gene mutation, although the molecular mechanism is uncertain.     

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD?=?4.51, α?=?0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD?=?3.60, α?=?0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD?=?3.07, α?=?0.29; dominant HLOD?=?3.03, α?=?0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD?=?3.02, α?=?0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.     

Familial Klippel-Feil syndrome and paracentric inversion inv(8)(q22.2q23.3).

Klippel-Feil Syndrome (KFS) is characterized by congenital vertebral fusion believed to result from faulty segmentation along the embryo's developing axis. KFS appears to be a heterogeneous disease often associated with craniofacial malformation. Here we provide the first evidence of a familial KFS gene locus on 8q, where an inv(8)(q22.2q23.3) has been found segregating with congenital vertebral fusion. The four-generation KF2-01 family present with dominant form of the KFS where the sequence of vertebral fusion was confined to the cervical spine (always including the C2-3 fusion and reduced expression of the C4-5 and C6-7 fusions) in association with malformation of laryngeal cartilages and mild-to-severe vocal impairment.     

Localization of human c-mos to chromosome band 8q11 in leukemic cells with the t(8;21) (q22;q22)

Summary Chromosome in situ hybridization studies locate c-mos to chromosome band 8q11 in leukemic cells carrying the t(8;21) (q22;q22). This amends the previous assignment of c-mos to chromosome band 8q22 and conforms with its recent assignment to 8q11 in normal cells and in a cell line with a structurally abnormal chromosome 8. C-mos lies proximally to, and distant from, the breakpoint at 8q22 in the t(8;21) and is unlikely to have a role in the onset of acute myeloid leukemia characterized by this translocation.     

A jumping translocation (5p;15q), (8q;15q), and (12q;15q) (author's transl)]

Three balanced karyotypes (5p;15q), (8q;15q), and (12q;15q) were found simultaneously in a child with the Willi-Prader syndrome. The hypothesis is presented of a "jumping# translocation by affinity of telomeric and interstitial palindromes. The relationship between the Willi-Prader syndrome and a juxtacentric anomaly of the long arm of chromosome 15 is discussed.     

Human proto-oncogene c-mos maps to 8q11.

The c-mos proto-oncogene is the cellular counterpart of the viral oncogene v-mos isolated from Moloney murine sarcoma virus. The c-mos gene locus has previously been assigned to human chromosome 8. By both in situ hybridization and molecular hydridization to sorted chromosome DNA (using a c-mos probe) we have localized the c-mos gene to band 8q11. This regional localization is at variance with the one previously reported at 8q22 and may explain why no rearrangement of c-mos has been found in acute leukaemia with the chromosomal translocation t(8;21)(q22;q22).     

Familial paracentric inversions inv(2)(q31q35) and inv(8)(q22.3q24.13) ascertained through reproductive abnormalities

Summary Two cases of familial paracentric inversion, one in the long arm of chromosome 2 and the other in the long arm of chromosome 8, are described. The first was ascertained in a woman who was studied because of recurrent abortions. The second was ascertained in the father of a girl with the trichorhinophalangeal syndrome and an interstitial deletion in 8q. The latter is the first case in which unequal crossing over in an inversion loop can be inferred in a male carrier of a paracentric inversion. The reasons for the relatively low frequency of paracentric inversions observed and factors which affect the pregnancy outcome are discussed.     

Frequent gains on chromosome arms 1q and/or 8q in human endometrial cancer

Comparative genomic hybridization (CGH) was employed to survey genomic regions with increased and decreased copy number of the DNA sequence in 15 endometrial cancers [10 cases with microsatellite instability positive (MI+) and 5 cases with MI–]. Twelve of these 15 tumors (80%) showed abnormalities in copy number at one or more of the chromosomal regions. There were no regions with frequent chromosomal losses. Conversely, 11 of 15 cases (73%) showed gains on chromosome arms 1q (8/15; 53%) and/or 8q (6/15; 40%). Concordant gains of both chromosome arms 1q and 8q were observed in all three endometrial cancers of histological grade 3. These results suggest that these two chromosomal regions may contain genes whose increased expression contributes to development and/or progression of endometrial carcinogenesis. Two cases were further analyzed by fluorescence in situ hybridization (FISH) using three probes on chromosome 1 and two probes on chromosome 8 to more accurately determine increases in copy number. We found gains of chromosome 1q to 2.9–3.6 copies per cell and on 8q to 4.4 copies per cell. Received: 9 March 1997 / Accepted: 2 June 1997     

8q24.12 Interstitial deletion in trichorhinophalangeal syndrome type I

Summary In the present report we present the first example of a small interstitial 8q24.12 deletion in a patient with trichorhinophalangeal syndrome type I.     

Proximal trisomy 13q and distal monosomy 8p in a dysmorphic and mentally retarded patient with an isodicentric chromosome 13q and a 13q/8p translocation chromosome

A 40 year-old dysmorphic and mentally retarded female is reported with a de novo unbalanced chromosomal rearrangement (karyotype: 46,XX,der(8)t(8;13)(p23;q123),idic(13)(pter-->q123: q123-->pter) resulting in an isodicentric chromosome 13 and a double aneusomy including partial trisomy 13 (13pter-q123) and distal monosomy 8p (8pter-p23). The main clinical findings consist of developmental/mental retardation, behavioural disturbances and minor congenital defects, not consistent with the clinical pattern of either of the two aneusomies. A mechanism for the chromosome rearrangement is proposed and the absence of specific physical findings in the present patient is discussed in the light of the available literature data.     

Microduplications in 22q11.2 and 8q22.1 associated with mild mental retardation and generalized overgrowth

The 22q11.2 microduplication is a genomic disorder, characterized from a variable phenotype ranging from different defects to normality. The most common microduplication of 22q11.2 is 3 Mb in size, but there are also cases reported with atypical duplications between 0.8 Mb and 6 Mb.     

De novo deletion 7q36 resulting from a distal 7q/8q translocation: phenotypic expression and comparison to the literature

We report on a 6-year-old male patient with de novo 7q36 deletion and 8q24.3 duplication diagnosed by combining traditional G-banding and FISH studies. His clinical history was remarkable for pre- and postnatal growth retardation, neonatal feeding problems and developmental/mental retardation with non-verbal communication. He presented microcephaly, large ears, narrow palpebral fissures with blepharoptosis, epicanthic folds, large depressed nasal bridge, bulbous nasal tip, right cryptorchidism and delayed bone age on X-rays. There was no evidence of holoprosencephaly (HPE) or sacral agenesis sequence. By using in FISH analysis a series of YACs linearly ordered along the 7q36 region, the precise breakpoint on 7q36 was found to be within the target region of the YAC 742G8, a YAC that appeared to be only partially deleted. Clinical and chromosomal findings in this patient are compared to those previously recorded in similarly investigated patients from the literature with terminal 7q deletion.     

PLAG1 activation in lipoblastoma coinciding with low-level amplification of a derivative chromosome 8 with a deletion del(8)(q13q21.2)

Lipoblastoma is a benign uncommon soft-tissue-tumor resembling fetal adipose tissue affecting mainly children under three years of age. In lipoblastoma, the typical cytogenetic changes are clonal rearrangements involving chromosomal region 8q11-->q13. The oncogene PLAG1 (pleomorphic adenoma gene 1) is located within this chromosomal region on band 8q12. Recent reports have demonstrated that in lipoblastoma, the PLAG1 gene is activated by 'promoter-swapping'. Herein, we demonstrate that in lipoblastoma, the PLAG1 gene may also be activated by low-level amplification. We report on a lipoblastoma with the karyotype 48 approximately 50,XX,del(8)(q13q21.2),+del(8)(q13q21.2)x4[cp12]. Subsequent FISH analysis on uncultured tumor cells confirmed this result and demonstrated a low-level amplification of the chromosomal region 8pter-->8q13 and 8q21.2-->8qter. A partial monosomy was seen for the chromosomal region 8q13-->8q21.2. No other gains or losses were observed by CGH analysis. RT-PCR analysis showed that the PLAG1 gene is activated in the tumor sample of the lipoblastoma analyzed, in contrast to normal fatty tissue without PLAG1 expression. In conclusion, our results demonstrate that low-level amplification is a further mechanism of PLAG1 activation in lipoblastomas.     

Mapping of the MYC gene to band 8q24.12----q24.13 by R-banding and distal to fra(8)(q24.11), FRA8E, by fluorescence in situ hybridization

The MYC gene was mapped to R-banded human prometaphase chromosomes and to chromosomes expressing fra(8)(q24.11) by fluorescence in situ hybridization. By high-resolution banding analysis, the fluorescent signals were localized to R-positive band q24.12----q24.13 of the long arm of chromosome 8. Furthermore, the signals were localized near the middle part, q24.12----q24.13, of the distal portion of fra(8)(q24.11) expression. Thus, the precise localization of MYC was to the subband 8q24.12----q24.13.     

Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia

Although KIT mutations are present in 20–25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.     

Deletion of the long arm of chromosome 8 resulting from a de novo translocation t(4;8) (q13;q213)

Summary Report is given of a mentally retarded and dysmorphic patient with a partial monosomy 8q, resulting from a de novo translocation t(4;8)(q13; q213).Determination of erythrocyte gluthathione reductase (E-GSR) activity in the proposita shows activity in the normal range. Previous evidence for of the assignment of E-GSR locus to the short arm of chromosome 8 is confirmed.