De novo trisomy 4pter→q21

Summary Clinical and cytogenetic findings in an infant girl with multiple congenital anomalies, principally anophthalmia, are presented. The patient's karyotype was 47,XX, +del(4)(pterq21), the largest partial trisomy of chromosome 4 reported. The possible mechanism of the origin of this abnormality is discussed.To whom offprint requests should be sent     

A case of trisomy 3q21→qter syndrome

Summary An infant with karyotype 46,XY,der(8),t(3;8)(q21;p23) is presented. The presence of trisomy 3q21qter syndrome is suspected on the basis of comparison of the clinical and laboratory findings of this patient with those of cases that have been reported as partial 3q trisomy. The common phenotypic features of this syndrome include growth failure and mental or developmental retardation, hypotonia, persistent lanugo, distorted head, congenital glaucoma, short and upturned nose, prominent maxilla, micrognathia, short, webbed neck, short limbs, retroflexed third and fourth toes, cutaneous syndactyly of the second, third and fourth toes, and elevated galactose-1-phosphate uridyl transferase activity in the red blood cells.     

Maternal age and trisomy – a unifying mechanism of formation

The mechanism of trisomy formation and its relationship to increased maternal age is not understood. Molecular analysis of the pattern of inheritance of DNA markers in trisomy families shows trisomies can be grouped according to whether the affected chromosomes inherited from their mothers are heterozygous or homozygous with respect to the centromeres. Furthermore, molecular analysis reveals that those that are heterozygous have fewer chiasmata, which are located more distally, while those that are homozygous have more chiasmata proximally located. Cytogenetic analysis of human oocytes shows that the kind of imbalance predicted by the classic hypothesis of nondisjunction, i.e. extra whole chromosomes at the second metaphase, is rarely found, whereas the common expression of imbalance is seen as single chromatids. We hypothesise that one mechanism links these data: the mechanism depends on the prediction from the cytogenetic data that cohesion within the bivalent complex is severely weakened during the extended dictyate stage in older women. Consequently, when meiosis resumes, at the time of ovulation, the bivalent emerges as four chromatids held together only by its chiasmata. In accordance with the rules of orientation on the spindle, the final balanced shape of the configuration achieved at metaphase I, in this case determined by the position of the chiasmata, will dictate whether the subsequent segregation of the chromatids will result in their heterozygosity or homozygosity. It follows that the concept of "first division" and "second division" errors, i.e. of nondisjunction originating at first or second meiotic division as defined by centromeric hetero- or homozygosity, may be erroneous.     

Are cells with trisomy 10 always malignant in hematopoietic disorders?

Two patients with acute myeloid leukemia (AML-M7 and AML-M4) and trisomy 10 as the sole chromosome abnormality are reported. In the first patient, all karyotypes were abnormal. A karyotypically normal cell population was present in the second patient and the trisomic cells were less numerous than the normal ones at diagnosis. A review of the literature shows the rarity of isolated trisomy 10 in hematopoietic disorders and the diversity of the involved diseases. Moreover, in some patients, the trisomic cell population was less numerous than the normal one. These data are discussed in relation with the hypothesis that cells with trisomy 10 can belong to nonmalignant clones, at least in some cases, as previously shown for trisomy 7 in other conditions.     

Atypical presentation of the Prader-Willi syndrome. Mosaic trisomy 15?

We report a female with Prader-Willi syndrome and hemihypertrophy. We discuss the possibility of an undetected mosaicism for trisomy 15 explaining this unusual feature.     

Variation in alphoid DNA size and trisomy 21: a possible cause of nondisjunction

The cause of nondisjunction of chromosome 21 remains largely unknown. In the present report, we investigate the hypothesis that variation in alphoid DNA size has a role in trisomy formation. Pulsed-field gel electrophoresis was used to examine the chromosome 21 alphoid DNA array lengths in 23 families (all of Northern European ancestry) with an affected child with trisomy 21 in whom the parental and meiotic origin of nondisjunction had been determined as maternal meiosis I, and in 38 controls. Initially, the combined alphoid size of both chromosome 21 homologues was assessed. This indicated an association between small combined alphoid size and maternal meiosis I nondisjunction. Moreover, in a subset of the families under study (n=12), it was possible to study the alpha21-I size of individual chromosome 21 homologues (simple alphoid size); this provided further evidence that the risk for nondisjunction is related to the size of the alphoid array of one of the two chromosome 21 homologues being small.     

Partial trisomy of the short arm of chromosome 3 (3p25→3pter)

Summary Two profoundly mentally mentally retarded brothers with partial trisomy for the distal part of the short arm of chromosome 3 (3p253pter) are described. Their anomaly arose as a segregation product of a balanced t(3p-;18q+) translocation in the mother. Compared with the other cases of partial 3p trisomy reported up to now, the present patients display a similar craniofacial dysmorphism with hypertelorism, broad nasal tip, short upper lip with prominent philtrum, and a large mouth with down-turned corners. Other stigmata, such as a prominent, high forehead with frontal bossing and full cheeks, were present during childhood but progressively disappeared.     

DSCR1 (ADAPT78) lethality: evidence for a protective effect of trisomy 21 genes?

Over the last several years, suggestive evidence has accrued supporting a possible involvement for DSCR1 (ADAPT78) in Down syndrome. Toward testing this, we attempted to generate DSCR1 transgenic mice. Surprisingly, in almost every case, embryonic lethality was observed. In C57Bl/6 mice, DSCR1 human transgene was identified in developing embryos prior to lethality and up to day 9.5. Its mRNA expression was also observed and varied relative to control. In rare instances (twice) where transgenics survived to term, no mRNA expression was observed, suggesting that expression is required for lethality. This lethal phenotype contrasted with, and was surprising in light of, mouse models of Down syndrome where multiple chromosome 21 genes including Dscr1 are overexpressed and survive to term. To explain the seemingly contradictory lethal effect of DSCR1 by itself but not in combination with other trisomy genes, we propose that some trisomy genes (including DSCR1) confer lethality, but others suppress it.     

Smith‐Lemli‐Opitz syndrome in trisomy 13: How does the mix work?

BACKGROUND: Trisomy 13 and Smith-Lemli-Opitz syndrome (SLOS) are both well-recognized multiple congenital anomaly/mental retardation syndromes. CASE: In this report we describe a male newborn with trisomy 13 who also has features of SLOS, such as 2/3 toe syndactyly and a shawl-like scrotum. Biochemical analysis was consistent with SLOS, and limited molecular analysis revealed 1 mutation in the DHCR7 gene. CONCLUSIONS: The challenges in establishing the diagnosis of SLOS in this patient are presented and the unique coexistence of the 2 major malformation syndromes is discussed. Given the overlapping phenotype of the 2 syndromes, our report should encourage further research on cholesterol biosynthesis in patients with trisomy 13.     

Moderate Down's syndrome in three siblings having partial trisomy 21q22.2→qter and therefore no SOD-1 excess

Summary Three mentally retarded siblings with moderate stigmata of Down's syndrome were found to have a partial trisomy 21q22.2qter resulting from a maternal translocation t(4q+;21q-). By the exclusion of any excess of SOD-1 in them, we can confirm the nonessentiality of the sub-band 21q22.1 and of the SOD-1 excess for most of the Down's syndrome stigmata including the mental retardation. However, the sub-band 21q22.1 in triplicate might be required for the completion of the full syndrome, as for example is shown by the incomplete dermatoglyphic pattern on the palms in the patients.     

“de novo” trisomy 1q32→1qter and monosomy 3p25→3pter

Summary The syndrome of familial lymphedema (type Meige) with distichiasis was observed in father and son. The association with uvula bifida and submucous cleft of the palate is described for the first time.     

Partial trisomy 13q21→qter de novo due to a recombinant chromosome rec(13)dup q

Summary A female is described who has a karyotype with an additional distal half of 13q in a recombinant rec(13)dup q chromosome. Since her parents have normal karyotypes, the origin of her karyotype is assumed to be a premeiotic pericentric inversion de novo with crossing-over within the inversion loop at meiosis. By means of various banding techniques, the breaks preceding the rearrangement could be located exactly. The joint between the duplicated segment and the satellites of the receptor chromosome is of special note. The phenotype of the patient stated at the age of 9 months and at the age of 71/2 years was found to be related to the segments involved in the partial trisomy. The clinical features were largely in accordance with previous case reports having an identical extent of the triplicated 13q segment.     

Possible trisomy 1q25→1q32 in a malformed girl with a de novo insertion in 1q

Summary A newborn female is described who exhibited a characteristic facial dysmorphology including deep-set eyes, broad nasal bridge, small mouth, higharched and narrow palate, severely receding mandible and misshapen ears; constant flexion of the proximal interphalangeal joints, and short distal phalanges and nails of fingers; a congenital heart defect; marked muscular hypotonia, motor and growth retardation. She died at 4 months of age. Her karyotype revealed an additional band in 1q. Banding patterns and clinical picture suggest duplication of the segment 1q251q32.     

Significant increase in trisomy 21 in Berlin nine months after the Chernobyl reactor accident: temporal correlation or causal relation?

OBJECTIVE--To assess whether the increased prevalence of trisomy 21 in West Berlin in January 1987 might have been causally related to exposure to ionising radiation as a result of the Chernobyl reactor accident or was merely a chance event. DESIGN--Analysis of monthly prevalence of trisomy 21 in West Berlin from January 1980 to December 1989. SETTING--Confines of West Berlin. RESULTS--Owing to the former "island" situation of West Berlin and its well organised health services, ascertainment of trisomy 21 was thought to be almost complete. A cluster of 12 cases occurred in January 1987 as compared with two or three expected. After exclusion of factors that might have explained the increase, including maternal age distribution, only exposure to radiation as a result of the Chernobyl reactor accident remained. In six of seven cases that could be studied cytogenetically the extra chromosome was of maternal origin, confirming that nondisjunction had occurred at about the time of conception. CONCLUSION--On the basis of two assumptions--(a) that maternal meiosis is an error prone process susceptible to exogenous factors at the time of conception; (b) that owing to the high prevalence of iodine deficiency in Berlin a large amount of iodine-131 would have been accumulated over a short period--it is concluded that the increased prevalence of trisomy 21 in West Berlin in January 1987 was causally related to a short period of exposure to ionising radiation as a result of the Chernobyl reactor accident.     

Numerical chromosome abnormalities in the spermatozoa of the fathers of children with trisomy 21 of paternal origin: generalised tendency to meiotic non-disjunction

The purpose of this study was the evaluation of aneuploidy frequencies in the spermatozoa of two fathers (DP-4 and DP-5) who had children with Down syndrome (DS) of paternal origin and in whom a previous sperm analysis by fluoresence in situ hybridisation (FISH) had suggested a generalised tendency to meiotic non-disjunction. Sperm samples were simultaneously hybridised with FISH probes for chromosomes 4, 13 and 22. Disomy frequencies for each of the chromosomes and diploidy frequencies were compared with data obtained from nine control donors. Both DS fathers had a statistically significant increase in the frequency of disomy for chromosomes 13 and 22. DP-5 also had an increased frequency of diploid spermatozoa. Our data suggest that the two DS fathers have a generalised susceptibility to meiotic non-disjunction and that acrocentric chromosomes seem to be more sensitive to such disturbance in the meiotic process.     

Trisomy: Chromosome competition or maternal strategy?: Increase of trisomy incidence with increasing maternal age does not result from competition between chromosomes

Axelrod and Hamilton (Science 211:1390, 1981) suggested that trisomies may result from an end-game strategy between chromosomes competing to get on the gamete as the mother approaches menopause. We tested this hypothesis by reviewing studies of the parental origin of the extra chromosome in trisomy 21 births. These data show that there is no significant rise in trisomy 21 conceptions as the mother ages. The increase in trisomies with maternal age results not from an increase in nondisjunctions, but from a decrease in rejection of trisomy zygotes, which may be adaptive for the mother towards the end of her reproductive life. This decreasing rate of rejection may result from the changing inclusive benefits of two maternal strategies as menopause approaches.