Girl with combined cellular immunodeficiency, pancytopenia, malformations, deletion 11q23.3 --> qter, and trisomy 8q24.3 --> qter

We describe here a 3-year-old girl demonstrating combined cellular immunodeficiency of B- and T-cells, pancytopenia, multiple anomalies, and severe mental retardation. Cytogenetic analysis and fluorescent in situ hybridization (FISH) indicated an unbalanced translocation of chromosomes 8q and 11q, resulting in monosomy 11q23.3-qter and trisomy 8q24.3-qter. The association of cellular immunodeficiency and partial deletion 11q and/or partial trisomy 8q has not been described previously; however, the 11q deletion has been reported with humoral immunodeficiency or pancytopenia. Some one-third to one-half of patients with partial monosomy 11q were reported to have pancytopenia, which has been related to the absence of the 11q23-q24 region. Our case narrows down the critical interval for thrombo- or pancytopenia to 11q23.3-q24 and excludes both the ATM (which resides on 11q23.1) and the MLL genes as possible candidate genes. We are proposing that haploinsufficiency of the NFRKB gene on 11q24-q25 and/or the ETS-1 proto-oncogene on 11q24 may have caused or contributed to the immunodeficiency (decreased levels of B- and T-lymphocytes) in our patient.     

Boy with celiac disease, malformations, and ring chromosome 13 with deletion 13q32-->qter

We describe a 2(1/2)-year-old boy with a ring chromosome 13 with distal deletion of 13q32-->qter and celiac disease.     

Inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) with manifestations of partial duplication 4p and Wolf-Hirschhorn syndrome

An 8-year-old girl with a combination of clinical manifestations of partial duplication 4p and the Wolf-Hirschhorn syndrome was studied. Chromosomal G-banding and FISH analyses showed a 33.2-Mb segment of inverted duplication at 4p14-p16.3 and a 2.8-Mb segment of deletion at 4p16.3-pter (including the Wolf-Hirschhorn syndrome critical region). The chromosomes of the parents were normal. Her karyotype was thus 46,XX, inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) de novo. The inverted duplication deletion was assumed to have arisen through chromatid breakage at 4p16.3, U-type reunion at the breakpoints to produce a dicentric intermediate, breakage of the dicentric to result in a monocentric, and telomere capture/healing of the broken end. Olfactory receptor gene clusters at 4p16.3 were ruled out as an intermediary of the duplication deletion process.     

A region on human chromosome 4 (q35.1-->qter) induces senescence in cell hybrids and is involved in cervical carcinogenesis

Human papillomavirus (HPV) types 16 and 18 are known to play a major role in cervical carcinogenesis. Additional genetic alterations are required for the development and progression of cervical cancer. Previously, we showed that the introduction of an entire human chromosome 4 into HPV-immortalized cells by microcell-mediated chromosome transfer (MMCT) can induce senescence in cell hybrids. In the present study, we established eight new murine donor cell lines harboring different fragments of the human chromosome 4. These were tested for their ability to induce senescence by MMCT into HPV16-immortalized keratinocytes (HPK II) and cervical carcinoma cells (HeLa). By exclusion, we could identify a region for a putative senescence gene or genes at 4q35.1-->qter. Further evidence that this locus may be involved in cervical carcinogenesis was obtained by studying sections of high-grade cervical intraepithelial neoplasias (CIN2/3) and cervical cancers from 87 women using a combination of interphase fluorescence in situ hybridization (I-FISH) and microsatellite PCR. I-FISH indicated copy number loss at 4q34-->qter. Microsatellite analysis showed that loss of one or more alleles at chromosome 4 was more frequent in the cervical carcinomas than in the CINs. Loss of heterozygosity (LOH) affected four areas, D4S412 (4p16.3), D4S2394 (4q28.2), D4S3041 (4q32.3), and D4S408 (4q35.1), and was highest at D4S408. LOH at terminal 4q has been reported previously for cervical carcinomas and other human malignancies. This is the first report associating allelic loss at 4q34-->qter with high-grade intraepithelial neoplasia and cervical carcinoma, and the first experimental evidence that this locus or these loci can induce senescence in cervical carcinoma cells and HPV16-immortalized cells.     

Tetrasomy 15q25-->qter: cytogenetic and molecular characterization of an analphoid supernumerary marker chromosome

Tetrasomy for the distal long arm of chromosome 15 is a rare finding. It has been previously described in seven patients, all of whom had a supernumerary marker chromosome (SMC) derived from distal 15q. These SMC contained no apparent centromeres (C-band/alpha-satellite negative), and belong to a novel class of SMC with neocentromeres. We present the oldest surviving patient with tetrasomy for distal 15q. The proposita was a 10-year-old girl with moderate to severe mental retardation, absent speech, hypotonia, minor facial anomalies, unusual digits, and pigmentation anomalies. Mosaicism for a symmetrical SMC was identified in metaphases from lymphocytes and fibroblasts. Parental karyotypes were normal, indicating a de novo origin for the SMC. FISH with a whole chromosome paint for chromosome 15 showed that the SMC was derived entirely from chromosome 15. However, C-banding and FISH with chromosome 15 probes D15Z1, D15S11, SNRPN, and PML were all negative. FISH with the FES probe at 15q26 showed hybridization to both ends of the SMC. The marker was interpreted as an analphoid inverted duplication of 15q25-->qter containing a presumed neocentromere. Previous molecular studies suggested either a mitotic or paternal meiotic origin for these distal 15q SMC. However, molecular analysis with chromosome 15 polymorphic markers showed that the analphoid SMC(15) in the proposita originated from a maternal meiotic error. The origins and mechanisms involved in formation of these distal 15q SMC appear to be more diverse than for the proximal pseudodicentic SMC(15).     

Whole-arm t (X;17) (Xp17q;Xq17p) and gonadal dysgenesis

A 19-year-old female patient with gonadal dysgenesis and a de novo t(X;17) (Xp17q;Xq17p) is described. Since the critical segment Xq13----q26 was intact, this case is a further exception to the critical region hypothesis.     

Partial trisomy for the distal long arm of chromosome 5 (region q34→qter). A new clinically recognizable syndrome

This report describes a family in which eight individuals in three generations had mental retardation in association with a characteristic pattern of clinical problems and physical abnormalities including short stature, eczema, hernias, delayed puberty, dysmorphic facies and digital anomalies. The family history was consistent with a chromosomal rearrangement with transmission through balanced carriers. Routine ASG banding studies showed extra chromosomal material on a chromosome 16 but failed to demonstrate any differences between the affected individuals and the presumed carriers. However, subsequent studies utilizing trypsin banding and microspectrophotometry of individual chromosomes demonstrated that the affected individuals were partially trisomic for the distal band of the long arm of chromosome 5 and that 0.273 units of a chromosome 5 were translocated to chromosome 16. This definitive cytogenetic diagnosis permitted accurate prenatal diagnosis to be carried out on the fetus of a balanced carrier female. The application of these techniques to previously obscure familial dysmorphic syndromes is recommended.     

Drayer's syndrome of mental retardation, microcephaly, short stature and absent phalanges is caused by a recurrent deletion of chromosome 15(q26.2-->qter)

We reevaluated a unique family with two sibs who had a presumed autosomal recessively inherited syndrome characterized by mental retardation, microcephaly, short stature and absent phalanges. This family was originally described by Drayer et al. in 1977. Using modern molecular techniques, we demonstrated that the syndrome is caused by the recurrence of an apparently de novo 15qter deletion of 5.8 Mb. Analysis of polymorphic markers revealed that the deletion was of maternal origin in both cases, indicating germline mosaicism in the clinically unaffected mother. This study demonstrates the possibility of parental mosaicism and the risk of recurrence in sibs for terminal subtelomeric deletions.     

A new case of dup(3q) syndrome due to a pure duplication of 3qter

The characteristic clinical features of the dup(3q) syndrome include typical facial features, mental and growth retardation, and (often) congenital heart anomalies. However, pure duplication of 3qter is rare because most of the reported cases are patients who carry an unbalanced translocation and, in addition to the duplication for 3qter, have a deletion for another chromosomal segment. A new case with a pure duplication of 3q detected in a 2-month-old boy is presented here. Extensive cytogenetic analysis revealed an inverted duplication of the distal part of 3q (chromosomal band 3q26.3 up to the telomere), with no (detectable) loss of the original telomeric sequences. Clinical evaluation revealed several phenotypic hallmarks characteristic for the dup(3q) syndrome. By comparing the duplicated region of this patient with the duplicated regions of the other patients with a pure duplication of 3q, we were able to localize the critical region for the dup(3q) phenotype to band 3q26.3. Alongside this new case with a pure duplication of 3q, an overview of six previous cases is given.     

At least nine cases of trisomy 11q23-->qter in one generation as a result of familial t(11;13) translocation.

Carriers of balanced reciprocal translocations may have a (high) risk for producing liveborn children with an unbalanced karyotype. We report a large family in which a translocation between the long arm of chromosome 11 and the short arm of chromosome 13 is segregating in at least five generations. During the course of our study 15 carriers of the balanced translocation were identified and nine cases of partial trisomy of the long arm of chromosome 11 were detected during pre- and postnatal studies. Several of the patients were thoroughly clinically examined and compared with similar published cases.     

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.     

Characterization of an analphoid supernumerary marker chromosome derived from 15q25-->qter using high-resolution CGH and multiplex FISH analyses

Supernumerary marker chromosomes (SMCs) without detectable alphoid DNA are predicted to have a neocentromere and have been referred to as mitotically stable neocentromere marker chromosomes (NMCs). We report the molecular cytogenetic characterization of a new case with analphoid NMC derived from 15q25-->qter using high-resolution comparative genomic hybridization (HR-CGH) and multiplex fluorescence in situ hybridization analyses with various alpha-satellite DNA probes, all-human-centromere probe (AHC), whole chromosome painting probes, and a subtelomere probe. The propositus is a dysmorphic infant who, at age 3 months, showed accelerated growth, partial deafness, and a phenotype similar to that of the eight previously reported cases of distal 15q tetrasomy. Chromosome studies showed that he had a de novo extra SMC in 80% of cells examined. HR-CGH revealed rev ish enh(15)(q25qter). Molecular cytogenetic analysis and molecular DNA polymorphism study demonstrated that this extra SMC is an NMC containing an inverted duplication of the distal long arm of chromosome 15 (tetrasomy 15q25-->qter) which originated paternally, i.e. ish der(15)(qte-->q25::q25[neocen]-->qter)(AHC-, CEP15-, WCP15+, PCP15q++). This case further elucidates the phenotype related to tetrasomy of this specific chromosome segment and represents a new report of a neocentromere on distal chromosome 15q suggesting that this region appears to be susceptible to the formation of neocentromeres.     

Ullrich-turner syndrome (45,X/46,X,i[Xq]) in a child with a familial inversion of chromosome 3

We report a girl with shortness of stature and minor anomalies representing a mild form of the Ullrich-Turner syndrome. Cytogenetic studies showed 3 distinct anomalies: (1) a familial pericentric inversion, inv(3) (p25q21)pat, in all cells examined; (2) monosomy X (45,X) in 70% of cells; (3) isochromosome X (46,X,i(Xq)) in 30% of cells. The karyotype designation is: 45,X,inv(3) (p25q21)pat/46,X,i(Xq), inv(3) (p25q21)pat. The pedigree, which was originally interpreted as representing the segregation of a 2;3 translocation, is corrected and updated. Reproductive risks in families with pericentric inversions are discussed.