Partial trisomy 21 (21q21 - 21q22.2)]

An abnormal chromosome 21 is reported in a child with a phenotype strongly reminiscent of trisomy 21 syndrome. It is shown to result from duplication of the segment 21q21 leads to 21q22.2. Comparison of the phenotype with that of other partial and total trisomics shows that the characteristic features of the trisomy 21 syndrome (mongolism), the mental retardation in particular - is due to trisomy 21q22.2 and perhaps 21q22.2.     

Isochromosome not translocation in trisomy 21q21q

Summary After primary trisomy, de novo 21q21q trisomy is the most frequent chromosomal aberration responsible for Down syndrome. This rearrangement is more commonly referred to as a Robertsonian translocation or centric fusion product than as an isochromosome, e.g., t(21q;21q) instead of i(21q); however, in practice, it has not so far proved possible to distinguish between these alternatives. The aim of this work was to establish which of the two alternatives is acceptable.     

Ring chromosome 21 in the mother and 21/21 translocation in the fetus: karyotype: 45,XX,-21,-21,+t(21;21)(p11;q11)

In 1984 we reported a ring chromosome 21 in a normal woman with recurrent fetal wastage (Kleczkowska and Fryns, 1984). A 46,XY normal fetal karyotype was found after prenatal diagnosis at 14 1/2 weeks in a third pregnancy of this woman. In the present paper we report the prenatal diagnosis of a 21/21 translocation in a female fetus from her fourth pregnancy.     

CYP21 mutations in Brazilian patients with 21-hydroxylase deficiency

Congenital adrenal hyperplasia caused by 21-hydroxylase deficiency is a common autosomal recessive disorder resulting from mutations in the 21-hydroxylase (CYP21) gene. To develop a strategy to screen for the most commonly occurring CYP21 mutations in Brazil, we performed molecular genotype analysis on 73 children with CAH representing 71 unrelated families. The techniques used for CYP21 molecular genotype analysis were: restriction fragment length polymorphism, single-strand conformational polymorphism, allele-specific oligonucleotide hybridization, allele-specific polymerase chain reaction amplification, and heteroduplex analyses. Mutations were identified on all but eight affected alleles. The intron 2 splicing mutation was the most frequently identified mutation. Screening for the most common mutations detected at least one mutation on 132/142 (93%) alleles. Multiple CYP21 mutations were detected on 16.2% of alleles. The high frequency of multiple mutations on a single allele emphasizes the importance of thorough and accurate molecular genotype analysis of the complex CYP21 locus.     

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.     

Diversity of the CYP21P-like gene in CYP21 deficiency

More than 90% of cases of congenital adrenal hyperplasia (CAH) are caused by mutations of the CYP21 gene. The occurrence of defective CYP21 genes, including 15 mutations, has been attributed to intergenic recombination of DNA sequences from CYP21P, and shows no influence on the RP1-C4A-CYP21P-XA-RP2-C4BCYP21- TNXB gene locus on chromosome 6p21.3. However, multiple gene deletions in this region produce at least three categories of gene arrangements: (a) C4A-CYP21P/CYP21-TNXB, in which there is a CYP21P/CYP21 fusion gene; (b) C4A-XCYP21-TNXB, where XCYP21 indicates that the CYP21 gene contains mutations of IVS2 (-12A/C>G and 707-714delGAGACTAC); and (c) C4A-CYP21P-TNXA/TNXB, in which the TNX A and B genes are fused. Among them, seven different structures of the CYP21 haplotype were found at these three loci. Formation of the C4A-CYP21P/CYP21-TNXB locus produced four distinct CYP21P/CYP21 chimeras. The C4A-XCYP21-TNXB locus contained the IVS2 mutation -12A/C>G and 707-714delGAGACTAC from the XCYP21 gene; and two kinds of TNXA/TNXB hybrids were found in the C4A-CYP21P-TNXA/TNXB locus. The seven different CYP21 alleles produced 3.2 kb Taq I fragments caused by deletion of the RP2-XA-C4B locus. Therefore, production of a 3.2-kb CYP21 allele shows diversity, but is not a unique feature of the CYP21P gene. Most of these gene arrangements probably exist in the C4A-XCYP21-TNXB and C4A-CYP21P/CYP21-TNXB gene loci. The existence of the C4A-CYP21P-TNXA/TNXB locus might not be common in CAH patients with 21-hydroxylase deficiency.     

Drad21, a Drosophila rad21 homologue expressed in S-phase cells

Cohesin is an evolutionarily conserved multiprotein complex required to establish and maintain sister chromatid cohesion. Here, we report the cloning and initial characterization of the Drosophila homologue of the fission yeast rad21 cohesin subunit, called Drad21. The Drad21 coding region was localized to centromeric heterochromatin and encodes a 715 amino acid (aa) protein with 42% aa identity to vertebrate Rad21p-homologues, 25% with Scc1p/Mcd1p (S. cerevisiae) and 28% with Rad21p (S. pombe). Sequences with similarity to the sites of proteolytic cleavage identified in Scc1p/Mcd1p are not evident in DRAD21. Northern blot and mRNA in-situ studies show that Drad21 is developmentally regulated, with high levels of expression in early embryogenesis, in S-phase cells of proliferating imaginal tissues, and in the early endocycling cells of the embryonic gut.     

Radioimmunoassay of urinary 21-deoxytetrahydroaldosterone in primary aldosteronism and 21-hydroxylase deficiency

A radioimmunoassay of 21-deoxytetrahydroaldosterone was developed. Normal daily excretion of the unconjugated metabolite was 1.2 +/- 1.3 micrograms and of the glucuronized metabolite, 11.9 +/- 7 micrograms. The tetrahydroaldosterone/21-deoxytetrahydroaldosterone ratio varied more in patients with primary aldosteronism than in control subjects. Thus, measurements of the urinary excretion of the tetrahydroaldosterone or 21-deoxytetrahydroaldosterone alone did not provide an accurate expression for aldosterone production. Their sum correlated well with the clinical condition, i.e. clear-cut elevation in patients with primary aldosteronism. The diminished tetrahydroaldosterone/21-deoxytetrahydroaldosterone ratio found in patients with 21-hydroxylase deficiency may be attributed to increased bacterial conversion of tetrahydroaldosterone to 21-deoxytetrahydroaldosterone but could also stem from a deficiency implicating zona glomerulosa (aldosterone biosynthesis) regardless of the stage and clinical presentation of the disease.     

Interleukin-21 (IL-21)-mediated pathways in T cell-mediated disease

Interleukin-21 (IL-21) is produced mostly by activated CD4+ T cells and controls the differentiation and functional activity of effector T helper cells, counteracts the suppressive effects of regulatory T cells, and stimulates non-immune cells to make inflammatory mediators. IL-21-driven tissue damage has been demonstrated in a number of organs, such as the gut, pancreas, and brain. Therefore new treatment modalities to neutralise IL-21 in vivo would be a valuable addition to the therapeutic armamentarium to combat immune-mediated inflammation. Here we describe the emerging role of IL-21 in the initiation and progress of the tissue-damaging inflammatory response in immune-mediated pathologies.     

Gonadal function in trisomy 21

Endocrinologic evaluation of 39 patients with trisomy 2 and associated hypogonadism demonstrated elevations of follicle-stimulating hormone and luteinizing hormone; consequently, it can be concluded that both germinal and Leydig cell function are affected. A negative correlation between testicular size and plasma follicle-stimulating hormone was documented. Plasma testosterone levels were found to be normal in male patients as were estradiol levels in female patients with trisomy 21. On the basis of these findings, the simplest and most practical diagnostic approach to evaluate germinal cell function appears to be a single plasma follicle-stimulating hormone determination supplemented by an accurate measurement of testicular volume in males.     

Monosomy 21 in spontaneous abortus

Summary Chromosome analysis of the amnion from a missed abortus revealed a 45,XX,G-karyotype. Giemsa banding pattern technique identified the chromosome involved in monosomy as No. 21.

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Zusammenfassung Die Chromosomenanalyse des Amnions eines verhaltenen Abortus ergab einen 45,XX,G-Karyotyp. Dank der Anwendung der Giemsa banding pattern-Technik konnte festgestellt werden, daß die Monosomie das Chromosom Nr. 21 betrifft.

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This study was supported by the Ford Foundation Population Program, Grant No. 640-0411 B, and by the World Health Organisation.     

Telomeres in trisomy 21 amniocytes

Individuals with trisomy 21 have an increased risk of developing leukemia and premature dementia. They also have a higher rate of telomere loss. The aim of the study was to compare telomere length and the hTERC gene copy number, which encodes the telomerase RNA subunit, in amniocytes of trisomy 21 conceptions and normal pregnancies. A quantitative fluorescence-in-situ protocol (Q-FISH) was used to compare telomere length in amniocytes cultured from 11 trisomy 21 conceptions and from 14 normal pregnancies. Quantification was conducted using novel computer software. Fluorescence in situ hybridization (FISH) was used to assess the percentage of cells with additional copies of hTERC. We found that the immunofluorescence intensity, which represents telomere length, was significantly lower in amniocytes from trisomy 21 conceptions compared to the control group. The trisomy 21 group had a higher number of cells with additional copies of hTERC. This observation could be one of the cytogenetic parameters that represent a state of genetic instability and might play a role in the pathomechanism of typical features of Down syndrome, such as dementia and malignancy.     

"本刊编委展望21世纪生命科学座谈会"的部分发言

21世纪的生命科学:活力论的复兴?吴家睿(中国科学院上海生物化学研究所):　　从古至今,在对生命现象的研究中一直存在着两种对立的观点。一种是“活力论”,认为生命世界不同于非生命的无机世界,有其特有的性质,难以甚至不能从一般的物理和化学角度进行认识和解释。另一种是“还原论”,认为生命现象虽然很复杂,但同样遵循着基本的物理、化学规律,可以通过对构成生命的物质基础的研究来揭示生命的活动规律。(1)20世纪的“还原论”:分子生物学在20世纪的生命科学研究中,还原论占据着主导地位。生命有两个主要的特征,新陈代谢和自我繁殖。科学家…     

De novo 21/21 translocation Down syndrome

Summary Among ten families with de novo 21/21 translocation Down syndrome (tDS), four were informative, according to the studies of structural variants of chromosome 21, about the origin of the aberrant chromosome. In three of these, the translocation originated in the paternal and in one in the maternal gametogenesis. The parents with meiotic failure were compared with 20 control individuals (10 males and 10 females). There were no significant differences between them in the association coefficient of chromosome 21 and in the frequency of 21–21 associations. Similar results were obtained previously with the entire sample of tDS parents. The results obtained, unless they reflect too small a sample, suggest that the origin of the aberrant chromosome is not related to an increased chromosome 21 association tendency. It could be supposed that in the case of an apparent 21/21 translocation, the 21q isochromosome, morphologically indistinguishable from the Robertsonian translocation, is in question. The Ag-NoR negative acrocentrics in the tDS parents reappeared in the probands confirming the heritability of that nucleolus organizer regions (NOR) trait.     

t(21q21q)/r[t(21q21q)] mosaic in two unrelated patients with mild stigmata of Down's syndrome

Two cases of t(21q21q)/r[t(21q21q)] mosaic in unrelated infants, 17 and 14 months old respectively are reported. The proportion of cells with the ring chromosome was 45% in the former, 80% in the latter. Both cases had mild manifestations of the Down's syndrome. The origin of this unusual mosaicism as well as the significance of the difference in the proportions of the ring chromosome in the two have been discussed.     

A paradox: elevated 21-hydroxypregnenolone production in newborns with 21-hydroxylase deficiency

21-Hydroxypregnenolone and its metabolite 5-pregnene-3 beta, 20 alpha 21-triol have been measured in the sulfate fraction of neonatal urine. These two steroids are the major two 21-hydroxylated 5-pregnenes produced by neonates and are almost exclusively excreted as disulfates. The excretions of these steroids by normal infants and infants with 21-hydroxylase deficiency were compared. In addition to measurement of the absolute excretion, the excretion relative to the total 3 beta-hydroxy-5-ene output was also determined. The results show that 21-hydroxypregnenolone excretion is highly elevated in 21-hydroxylase deficiency (affected, mean 887 micrograms/24 h, range 453-1431 micrograms/24 h; normal, mean 117 micrograms/24 h, range 17-263 micrograms/24 h), but when compared to excretion of other delta 5 steroids the excretion is slightly low [(21-hydroxypregnenolone + 5-pregnene-3 beta, 20 alpha, 21-triol)/total 3-beta-hydroxy-5-ene steroids, 2.9% affected; 3.6% normal]. This difference was not statistically significant. There is thus no evidence that the 21-hydroxylase acting on pregnenolone is deficient in congenital adrenal hyperplasia. The explanation of the normal activity of "pregnenolone 21-hydroxylase," although not clearly defined, is probably associated with two recent findings by other workers: (a) that the human fetus has an active 21-hydroxylase distinct from the adrenal enzyme and (b) that a 21-hydroxylase structurally very different from the adrenal enzyme, with high activity towards pregnenolone (but no activity towards 17-hydroxyprogesterone), has been isolated from rabbit hepatic microsomes.