Search

Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval (CI), 0.042-0.082]. Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array-CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context.

Ces quinze dernieres annees, l’apport du diagnostic biologique antenatal, correle aux progres de l’echographie, a grandement contribue aux modifications des prises en charge medicale et psychologique des grossesses des petites filles et des femmes pour lesquelles un diagnostic de syndrome de Turner a ete pose.

Summary Biochemical, cytochemical characteristics and electron microscopy subcellular distribution of neutrophil alkaline phosphatase (NAP) were analysed in blood and/or smear samples from 39 trisomy 21 patients (Down's syndrome) aged 11·5-18 years (mean 15·5 years) and 55 normal subjects aged 12-20·5 years (mean 17 years). All patients were karyotyped. NAP cytochemical procedures were carried out on all subjects: biochemical NAP determinations were made in 10 patients and 20 controls: ultrastructural electron microscopy of AP was performed in three patients and four normal subjects. Neutrophil alkaline phosphatase from patients with trisomy 21 displayed the following changes: (1) a significant increase of enzyme activity, (2) a high thermal lability of enzyme. Electron microscope morphology exhibited large deposits of NAP reaction product associated with the plasma membrane and intracellular main organelles, like phosphasomes. The NAP biochemical and cytochemical characteristics suggest that trisomy 21 neutrophils contain a nonspecific AP isoenzyme, closely related to the early placental form.

We report the case of a patient (followed from birth to 15 years) presenting with trisomy 12 mosaicism, and focus on the endocrine phenotype associating a pituitary malformation and ovarian abnormalities. We describe the dysmorphic features and their evolution, the growth retardation and ovarian symptoms. Complete growth hormone deficiency was confirmed on auxological data, stimulation test and was related to pituitary stalk interruption, diagnosed by magnetic resonance imaging. Effect of growth hormone treatment was satisfactory resulting in a normal adult height. She also presented premature thelarche associated with right ovarian hypertrophy (4 to 5 fold the volume of the left ovary) which remained constant until 15 years of age. Diagnosis of trisomy 12 mosaicism was made on skin and ovarian karyotypes. The possible relation between these endocine findings and some genes located on chromosome 12 involved in pituitary and ovarian development is discussed.

Adenylosuccinate lyase deficiency (MIM 103050, ADSL) is a rare autosomal recessive disease causing severe mental retardation and/or autistic features.1,2 Seizures are often observed (80%),3 varying in age of onset (from newborn to late childhood) and nature (tonic-clonic, “suppression burst” pattern, West syndrome, etc), and are very often resistant to all medication. Around 50% of the children show autistic-like behaviour.4 Microcephaly is rare (1/13 of reported cases). Non-specific anomalies of the brain, such as hypoplasia of the vermis, cerebral atrophy,5 lack of myelination,6 white matter anomalies,7 and lissencephaly4 have often been described. ADSL is a homotetramer involved in two distinct steps of purine synthesis, namely (1) the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole carboxamide ribotide (AICAR), and (2) the conversion of adenylosuccinate (S-AMP) into adenosine monophosphate (AMP) in the inosine monophosphate transformation pathway (fig 1). The diagnosis of ADSL deficiency is based on the detection of dephosphorylated SAICAR and S-AMP products, that is, S-Ado (succinyladenosine) and SAICAr (succinylaminoimidazole carboxamide riboside). The modified Bratton-Marshall test is the most …

22q11.2 deletion is a common genetic disorder characterised by a wide spectrum of clinical manifestations. To date no simple genotype-phenotype correlation has been established. Moreover, several reports have mentioned phenotypic discordance between monozygotic twins. No definite mechanism has been demonstrated and mosaicism, a postzygotic second hit, environmental effects and chance events have been proposed. The twinning process itself has been suspected in two cases (11, 23). We report the case of monozygous twins with a 22q11.2 deletion who are discordant for a heart defect. We found no arguments for mosaicism or twin-to-twin transfusion syndrome. The frequent discordance for heart defects in DiGeorge/Velo-cardio-facial syndromes (DGS/VCFS) does not favour the hypothesis of somatic mutations contributing to the phenotypic variation, but rather a complex interaction between genetic and environmental systems.

Immunoreactivity, cytochemical, immunocytochemical characteristics and subcellular distribution of neutrophil alkaline phosphatase (NAP) were investigated in blood and/or smear samples from 18 women aged 23-46 years (mean 32.5 years) with trisomy 21 fetuses (17-21 weeks) and 28 women aged 20-42 years (mean 31 years) with normal fetuses (17-22 weeks). Immunochemical NAP investigations were carried out in 8 pathological and 8 normal pregnancies; cytochemical and immunocytochemical procedures were carried out in 18 pregnant women with trisomy 21 fetuses and 28 controls. NAP from women with trisomy 21 fetuses is characterized by: (1) a significant decrease in reactivity with anti-liver-type alkaline phosphatase (AP) and anti-NAP antisera; (2) low or very slight reactivity with antiplacental or anti-intestinal antibodies; (3) marked dispersion of NAP lead citrate reaction products or anti-NAP antibody colloidal gold-labelling in neutrophil cytoplasms, as detected by electron microscopy. This subcellular AP distribution (extramembranous) is different from that of normal NAP sites associated with plasma membrane, nuclear membrane and secretory vesicles. The NAP immunochemical and cytochemical characteristics suggest that neutrophils of a woman with a trisomy 21 fetus contain two AP isoenzymes: the liver/bone type and an atypical AP.

A 26-year-old woman presented widespread angiokeratomas predominantly in a swimsuit distribution pattern associated with acroparesthesia in all four limbs. The tentative diagnosis of Fabry’s disease (FD) was confirmed by optical and electron-microscopic findings and by appropriate biochemical testing. The work-up showed ocular and renal manifestations of the disease. The monozygous twin sister of the patient was asymptomatic although she was shown to be heterozygous for the enzymatic defect. These 2 cases illustrate the concept of extreme lyonization which can explain observed phenotypic differences in heterozygous females with X-linked hereditary diseases. The father and mother of the patient were shown to be noncarriers of the trait, suggesting de novo mutation in the twin pregnancy. However, biochemical testing for the detection of FD heterozygous females cannot rule out the possibility of the mother being heterozygous with normal enzyme activity.

In the context of the aetiological investigation of male infertility, the authors stress the place and the contribution of blood karyotype testing in the light of their personal experience based on 1,612 subjects. This examination has an important place, as about 15% of azoospermic subjects and 6 to 7% of subjects with oligospermia less than 10 million spermatozoa per ml, either alone or in combination with other abnormalities of the semen examination, present a congenital chromosomal abnormality. A remarkable constancy of the results was observed according to identical recruitment criteria. The contribution of this examination is also important: the medical and psychological value of detecting the cause of azoospermia, genetic counselling and antenatal chromosomal diagnosis for non-azoospermic subjects with an equilibrated structural abnormality, in whom treatment allows a chance of procreation, genetic counselling for the family of these subjects in order to prevent the appearance of a chromosomally abnormal infant. In conclusion, the authors argue in favour of the routine use of this test in all infertile subjects with at least isolated oligospermia less than 10 million spermatozoa per ml.

A comparative study of karyotypes, hematological variables and neutrophil alkaline phosphatase (NAP) was performed in 106 parents (53 couples) of children with free, homogeneous trisomy 21 and of 220

Neutrophil alkaline phosphatase (NAP) was analysed in 25 pregnant women with trisomy 21 foetuses whose chromosomal aberration was recognized by cytogenetic study after amniocentesis. Enzyme investigation was performed at 20-22 weeks of gestation using cytochemical and biochemical techniques. Twenty-nine women at the same stage of normal pregnancies were selected as controls. In parallel, each mother was karyotyped. Ten subjects from each series underwent biochemical and immunological investigation: measurement of enzyme levels, thermostability study and immunological tests with alkaline phosphatase isoenzyme antibodies. NAP from pregnant women with trisomy 21 foetuses was characterized by: (1) a lower rate of enzyme activity, (2) a large amount of heat-stable enzyme (T = 56 degrees C for biochemical assays, T = 85 degrees C for cytochemical tests), and (3) a marked loss of liver antigenicity. These findings suggest the presence in trisomy 21 pregnancies of a non-specific alkaline phosphatase isoenzyme which appears as an "enzyme marker" in maternal circulating neutrophils.

A study of karyotypes and neutrophil alkaline phosphatase (NAP) was carried out for 66 parents (33 couples) of trisomy 21 children and for 60 control parents (30 couples). Enzyme activity was determined simultaneously by biochemical and cytochemical techniques. In the mothers of trisomy 21 children we found: (a) by biochemical techniques, a significant increase of NAP activity in polymorphonuclear leukocyte (PMN) homogenates (P less than 0.01) and a lower supernatant/pellet ratio (P less than 0.01); (b) by cytochemical techniques (with or without thermal and urea treatments) NAP activity was significantly higher (P less than 0.001) than in control mothers; in the fathers, the two techniques gave normal NAP activity results.

En France, dans le cadre de l’assistance medicale a la procreation (AMP) avec tiers donneur, il est propose de lever l’anonymat de la personne qui a donne ses gametes, afin de pouvoir avoir acces a ses «origines genetiques»: tel est un des leitmotivs maintes fois proclame «haut et fort», tant le nombre d’enfants en recherche de leur «geniteur» est grandement minoritaire (de l’ordre de 25 sur 50 000 enfants nes par insemination avec donneur [IAD]). Leur porte-parole, A. Kermalvezen, n’a-t-il, d’ailleurs, pas ecrit, alors que tout le monde s’accorde a dire qu’il s’agit davantage d’une recherche du donneur en tant que personne: «Mon histoire est pour ainsi dire sans debut puisque je n’ai pas acces a mes origines genetiques» [1].

Two thousand one hundred and thirty six couples with one or more spontaneous abortions (SAB) before 13 weeks of gestation and with or without one normal liveborn child (NLC) were karyotyped. In 4.31% of the couples one partner was a carrier of a major chromosomal abnormality. Couples with SAB only have 2-fold more chromosomal aberrations than couples with SAB and NLC. A correlation between the frequency of chromosomal abnormalities and the number of SAB was observed. Finally, the various types of chromosome aberrations were analysed.

The authors relate the association XX male and syndrome of Pierre Robin in a child whose father presents a reciprocal equilibrated translocation 46,XY t (16;17) (p13;q21). They discuss the possible relation between these different anomalies and notably the possibility of a genic effect.

Chromosomal anomaly was detected in 7.6% of a cytogenetic survey of 1,444 infertile male azoospermia or oligozoospermia with a sperm count below 20 million/ml. Anomalies are especially of the sex-chromosome and of autosomal robertsonian translocation type. Distribution of these subjects on account of the sperm count has pointed out an increase of chromosomal anomalies in inverse ratio to the sperm count.

A cytogenetic analysis of more than 7000 subjects has been performed in the aetiological screening of infertile couples. This study revealed that infertile couples can be divided into three groups: those with one or more spontaneous abortions before 13 weeks of gestations, those with primary sterility (no gestation for at least 24 months) or those with secondary sterility (after one or more children, no further gestation for at least 24 months). The frequency of chromosomal abnormalities observed in this population is 2,9%, i.e. 1/17 couple. The results, according to sex of subjects bearing the chromosomal abnormality, were then analysed in each of the three groups. From this study, the authors insist on the advantage of systematically performing a chromosome analysis in the case of infertile couples for two main reasons: frequency of chromosomal abnormalities is relatively high in this population, detection of such abnormalities enables some couple to be rapidly directed to other solutions (Artificial Insemination), and others, due to prenatal chromosomal diagnosis, to have offspring in safety.

The authors report an observation of a child with both trisomy 12(pter----q12) and monosomy 21(pter----q21). It is thus possible to detect the clinical signs which can be attributed to trisomy 12p and to monosomy 21ql respectively. The authors point out the originality of the maternal translocation which differs from the translocations affecting these two chromosomes previously described in the literature. Finally, the rarity of the type of adjacent-2 segregation is shown, and discussed according to the literature already published.

Two unrelated patients with partial trisomy 10p due to a paternal balanced translocation are reported. Though the sizes of the trisomic segment are not identical, both patients show: severe growth retardation, important psychomotor retardation and a dysmorphic mouth recalling a "tortois mouth". These observations are compared to twelve others from the literature.

A comparative study of karyotypes and neutrophil alkaline phosphatase (NAP) was carried out for 70 parents (35 couples) of trisomy 21 children and their 35 trisomy 21 children and for 110 control parents (55 couples) and their normal children. In the trisomy 21 families we found a significant increase in NAP: mother P less than 10-4; father P less than 10-4; children P less than 10-9; the NAP level in affected child is approximately equal to the sum of the NAP levels of the two parents (P = 0.80; sigma2 = 5%). In one parent of a trisomy 21 child, a karyotype anomaly was present.

A new case of partial trisomy 13 through unbalanced de novo translocation t(X;13) is reported. In situ hybridization has been used to specify breakage points on the X chromosome. This case is cytogenetically comparable with another reported case; the phenotypical aspect of these two patients is however different. This discrepancy is discussed.

Neutrophil alkaline phosphatase (NAP) from 12 mothers of normal children was investigated and the results compared to those of 7 mothers with trisomy 21 offsprings, in an attempt to determine a parental molecular change in this chromosomal abnormality. The biochemical properties of the enzyme were analyzed by the procedures of isoenzyme characterization, i.e. enzyme assays, thermostability, inhibition patterns and slab gel electrophoresis. Immunological properties were determined on 5 samples from normal mothers and on the same sample number of mothers with affected children. In these latter NAP showed characteristics that were to some extent different from the ones of normal controls. The following changes were observed: highly significant loading of membrane and nucleus pellets in NAP activity, poor effect of inhibitors on thermostable component and immunodepletion measured by a significant decrease of the normal affinity for antiliver and antiplacental alkaline phosphatase antisera. These findings are discussed in the light of our knowledge of alkaline phosphatase isoenzymes.

A major chromosomal abnormality was observed in 10.3% of subfertile men in this study. This result is similar to a previous survey using the same criteria for selection of probands. The high frequency of chromosomal abnormalities emphasizes the importance of cytogenetic examination in subfertile men. The detection of such an abnormality should be followed by chromosome analysis in the patient's family. Prenatal diagnosis is indicated if a subfertile man with an abnormal karyotype fathers a child.

The authors studied the karyotype in blood and marrow of 34 patients with Paget's disease and compared the results with those of a control group of the same age. Structural abnormalities are more frequent in the blood than in the marrow, but there is no significant difference in comparison with the abnormalities in the control group. Ionizing radiations and drugs do not seem to be responsible for the abnormalities encountered. The numerical abnormalities are characterized by an increase in the number of hypodiploidies, particularly involving the chromosome groups A, B and D, whereas chromosomal damage affecting the C and G groups is less than normal. These abnormalities were encountered in a limited number of patients. The authors discuss the significance of these chromosomal abnormalities in the more general context of the genetics of Paget's disease.

Two cases of retinoblastoma in two children showing a chromosomal rearrangement in the karyotype were reported. In the first case, a pericentric inversion of chromosome 9 was observed both in the child and his father. In the second case, a reciprocal translocation t (3;12)(q29;q15) present also in the paternal karyotype was identified. A strict connection cannot be established between the tumour itself and the family chromosomal aberrations, but these observations raise the problem of a possible "interchromosomal effect".

In order to give a genetic counsel to the mother and the two twin-sisters of an Hemophilia A boy, a familial investigation has been carried out. The study with the restriction fragment length polymorphism probes together with the hemostasis screening enabled to specify the status of each member of the family with respect to hemophilia A gene. This investigation evidenced the presence of two maternal alleles and one paternal allele in one of the twin-sisters. This led us to assume that she had a chromosomal abnormality in spite of her normal phenotype. The 47, XX, +(X) result of her karyotype confirmed this assumption. Therefore an accurate genetic counsel was provided to the members of this family and more particularly to the triple X subject.

A comparative study of karyotypes, hematological variables and neutrophil alkaline phosphatase (NAP) was performed in 106 parents (53 couples) of children with free, homogeneous trisomy 21 and of 220 parents (110 couples) of normal children. In the parents of trisomy 21 children we found a significant increase of the NAP (p0.05) and a nonsignificant difference in the number of white blood cells. In 4 cases, we also found an anomaly in the karyotype. A modification of the metabolism of the neutrophils seems possible.

A new case of monosomy 10p without associated chromosomal abnormality is reported. This observation, compared with three others from the literature, shows the following common symptoms: microcephaly, antimongoloid slant of the palpebral fissures, low-set ears, prominent anthelix, congenital heart disease, abnormalities of the limbs. Cranial tomography demonstrates a midline developmental anomaly of the brain (cavum vergae associated with cavum septi pellucidi).