X-chromosome monosomy in the myelin-deficient rat mutant

We have identified three examples of female Wistar rats exhibiting the tremor and seizures characteristic of the X-linked myelin deficiency (md) mutation, which is ordinarily seen only in males. Cytogenetic study of two of these animals has shown them to have 41 chromosomes instead of the normal 42. The missing chromosome was identified as an X chromosome by G-banding analysis. These animals thus have an XO genotype comparable to that in Turner's syndrome. Anatomically, one of the animals, which was studied in detail, showed no abnormality of the uterus, and the ovaries, although somewhat smaller than normal, were histologically indistinguishable from those in a normal female rat. No evidence of endocardial fibroelastosis was detected, nor was there any anomaly of the aorta. The myelin deficiency in the central nervous system was comparable to that in hemizygous mutant male rats. XO monosomy in the Wistar rat thus has little effect on phenotype and is more comparable to that in mice than to Turner's syndrome in man. The myelin-deficient rat is useful for studies of X-chromosome monosomy since XO females can readily be identified by the neurological syndrome characteristic of the md mutation.     

Prenatal detection of double aneuploidy trisomy 10/monosomy X in a liveborn twin with exclusively monosomy X in blood

Both double aneuploidy and trisomy 10 are rare chromosome findings. All five published cases of trisomy 10 in liveborns were found to be mosaic with an euploid cell line. In a liveborn female twin, double aneuploidy mosaicism 47,XX, + 10/45,X was detected prenatally by amniocentesis performed because of severe intrauterine growth retardation and malformations. Chromosome analysis from neonatal lymphocyte cultures revealed exclusively the 45,X cell line. Double aneuploidy mosaicism trisomy 10/monosomy X was confirmed from skin fibroblasts. The child died at the age of 7 weeks. This is the first reported case of double aneuploidy involving trisomy 10, and the first case of trisomy 10 without a normal cell line in a liveborn. Prenatal diagnosis of trisomy 10 in a liveborn has not been published so far. The case illustrates that in specific cases amniotic fluid cells may reflect the karyotype of the fetus better than blood.     

Clinical implications of monosomy 7 in acute nonlymphocytic leukemia

A group of 18 patients with acute nonlymphocytic leukemia and the chromosomal aberration monosomy 7 in their bone marrow cells was compared to a group of control patients with the same disease but normal bone marrow chromosomes. The monosomy 7 group of patients had a higher incidence of fever and infections, and a higher white blood cell and granulocyte count compared to the control group at the time of diagnosis. The clinical difference between the groups continued over the first month of hospitalization. Complete remission was obtained in 12% of the monosomy 7 group and in 59% of the control group. Survival was clearly longer in the control group of patients. Monosomy 7 of the bone marrow in acute nonlymphocytic leukemia is therefore to be considered a bad prognostic sign.     

Spurious monosomy 7 in leukemia due to centromeric heteromorphism

We report heteromorphism of the centrometric region of human chromosome 7, which was observed in the cytogenetic assessment of a complete remission of a pre-B acute lymphoblastic leukemia in the bone marrow cells of a 25-year-old woman. Classical cytogenetic study was performed, as well as metaphase and interphase fluorescence in situ hybridization (FISH) carried out with an alphoid DNA probe specific for the chromosome 7 centromere for detection of leukemic clones with monosomy 7 found at the initial diagnosis. We show an important centromeric heteromorphism of this chromosome detected by FISH and clearly visible on all metaphases and nuclei analyzed. This heteromorphism is observable as a fluorescent signal five- or sixfold larger than that on the homologue. To our knowledge, this heteromorphism of chromosome 7 has not been reported in the literature. However, with the use of FISH analysis, it could be easily mistaken for a mosaicism of monosomy 7, which can be misleading in the interpretation of the results.     

A further case of monosomy 10qter

A child with a terminal deletion of chromosome 10 (q26) is described. A comparison of the phenotypic and cytogenetic features is made in the five reported cases of monosomy 10qter. No phenotypic features are found sufficiently characteristic to delineate a syndrome. Enzymatic activities for PGAMA and GOT1 were normal.     

Aplastic anemia and monosomy 7-associated dysmegakaryocytopoiesis

Aplastic anemia (AA) is marrow failure due to an inadequate number of hematopoietic cells in the marrow. Prior reports have described a more aggressive clinical course in aplastic anemia with monosomy 7. We report 3 pediatric cases of AA with normal cytogenetics followed by acquisition of monosomy 7. Bone marrow biopsies were initially diagnostic of AA but later showed monosomy 7 and an increased number of megakaryocytes with small hypolobated nuclei. Immunohistochemical stains for CD61 highlighted the marked dysmegakaryocytopoiesis. The marrow blast percentage was increased in only 1 patient with 4.6% blasts. The 3 patients underwent bone marrow transplantation, and each has remained disease free for 7 to 18 months after transplantation. Pediatric patients with AA and normal cytogenetics may develop monosomy 7 with a myelodysplastic syndrome, unclassified. Patients with AA and monosomy 7 should be evaluated for dysmegakaryocytopoiesis.     

Genitourinary phenotype in XX patients with distal 9p monosomy

Although testicular development has been shown to be variably impaired in XY patients with distal 9p monosomy, ovarian and other genitourinary phenotype has poorly been studied in XX patients monosomic for the distal 9p region. Thus, we studied a 13-month-old infant with 46,XX,der(9)t(9;10)(p23;p13) (case 1) and an 11-year-old girl with 46,XX,der(9)t(9;16)(p23;q22) (case 2). Case 1 had primary hypogonadism (basal serum follicle stimulating hormone [FSH], 40.0 mIU/mL; leteinizing hormone [LH], 1.2 mIU/mL; estradiol [E2], <10 pg/mL), whereas case 2 had age-appropriate pubertal development (breast, Tanner stage 4; pubic hair, Tanner stage 3; menarche 11.7 years of age) and hormone values (FSH, 7.3 mIU/mL; LH, 6.7 mIU/mL; E2, 47 pg/mL). In addition, case 1 had hypoplastic labia majora, short distance between the vaginal orifice and the anus, and five renal cysts, and case 2 had anal atresia, short distance between the vaginal orifice and the anus, bilateral hydronephrosis of grade 3 with probable ureteropelvic junction stenosis, and renal dysfunction (serum creatinine, 1.52 mg/dL; urea nitrogen, 34.5mg/dL). Fluorescence in situ hybridization analysis for five regions and microsatellite analysis for 10 loci on 9p confirmed hemizygosity for the distal 9p region with the breakpoints between IFNA and D9S285 in case 1 and between D9S168 and D9S286 in case 2. The results, in conjunction with the previous data in XX patients with molecularly defined distal 9p monosomy, are consistent with the presence of a gene(s) involved in the development of indifferent gonad or subsequent ovarian differentiation in a approximately 11 Mb region distal to D9S168. In addition, it is possible that a gene(s) for anoperineal and renal development also maps distal to D9S168 and that for external genital development maps distal to D9S285 at the position approximately 16 Mb from the 9p telomere.     

Cryptic mosaicism for monosomy 20 identified in renal tract cells

We report a post-natal case of mosaic aneuploidy for chromosome 20 in a 4 months old male baby with an abnormal phenotype including dysmorphic features (asymmetric facial growth), ventricular septal defect, hypotonia and bilateral vesicoureteric reflux. Conventional cytogenetics on peripheral blood showed 1 cell of 200 with 47,XY,+20. Further investigations using fluorescent in situ hybridization (FISH) on a urine sample, with a centromere probe for chromosome 20, revealed 39 of 50 cells giving one signal indicative of monosomy 20. FISH analysis of a buccal smear was consistent with disomy 20 as was conventional cytogenetics on skin fibroblasts. This is the fourth reported case of mosaic monosomy 20, the second case where monosomy 20 is present with a trisomy 20 cell and the first case with each aneuploidy found in two separate tissues. The identification of mosaicism is a difficult task since the abnormal cells can be present only in certain tissues and may disappear with selection as the fetus develops, thus leading to single-cell abnormalities that may get dismissed (pseudomosaicism). The use of FISH in this case was crucial in identifying the cryptic mosaic monosomy 20 cell line. The likely mechanism of origin is post-zygotic nondisjunction giving rise to monosomy, disomy and trisomy cell(s) in the same or different tissues. Although no other trisomy 20 cells were found, the abnormal phenotype plus the finding of a monosomy 20 cell line make this mechanism the most plausible explanation. Had we dismissed the single-cell abnormality, the cryptic mosaicism of monosomy 20 would not have been identified. A detailed analysis of all tissues accessible in conjunction with careful consideration of all clinical information available is the best course of action in suspected mosaicism.     

Left-ventricular non-compaction in a patient with monosomy 1p36

We report on a new-born girl with left ventricular non-compaction (LVNC), dysmorphism and epilepsy. Array-CGH at 1 Mb resolution revealed a deletion of the terminal 4.6 to 5.9 Mb of the short arm of chromosome 1. Cardiac abnormalities such as dilated cardiomyopathy and structural cardiac defects are common findings in patients with monosomy 1p36. This is however the first report describing LVNC in association with the 1p36 deletion syndrome, broadening the spectrum of cardiac anomalies found in association with this syndrome.     

Familial partial monosomy 7 and myelodysplasia: different parental origin of the monosomy 7 suggests action of a mutator gene

Two sisters are reported, both with a myelodysplastic syndrome (MDS) associated with partial monosomy 7. A trisomy 8 was also present in one of them, who later developed an acute myeloid leukemia (AML) of the M0 FAB-type and died, whereas the other died with no evolution into AML. Besides FISH studies, microsatellite analysis was performed on both sisters to gather information on the parental origin of the chromosome 7 involved in partial monosomy and of the extra chromosome 8. The chromosomes 7 involved were of different parental origin in the two sisters, thus confirming that familial monosomy 7 is not explained by a germ-line mutation of a putative tumor-suppressor gene. Similar results were obtained in two other families out of the 12 reported in the literature. Noteworthy is the association with a mendelian disease in 3 out of 12 monosomy 7 families, which suggest that a mutator gene, capable of inducing both karyotype instability and a mendelian disorder, might act to induce chromosome 7 anomalies in the marrow. We postulate that, in fact, an inherited mutation in any of a group of mutator genes causes familial monosomy 7 also in the absence of a recognized mendelian disease, and that marrow chromosome 7 anomalies, in turn, lead to MDS/AML.     

Distal 11q monosomy. The typical 11q monosomy syndrome is due to deletion of subband 11q24.1

In this paper we describe two new patients with distal 11q monosomy and precisely localize breakpoints using high resolution banding techniques. The findings in these two patients further contribute to the precise localization of the crucial band for 11q monosomy syndrome as being at 11q24.1. A very distal 11q24.2 deletion in the second patient resulted in a completely different phenotype.     

Partial monosomy 12p13.1----13.3.

We describe a 27 month old female child with partial monosomy for the short arm of chromosome 12: 46,XX,del(12)(p13.1----p13.3). She differs from the eight cases described by others, in that she is less severely affected. Her main clinical features are developmental delay, protruding tongue, strabismus, slightly unusual facies, slight micrognathia, and speech delay.