Helga Rehder

Down's syndrome in the male. Reproductive pathology and meiotic studies.

SummaryStudies on testicular histology and meiosis were carried out by the use of light and electron microscopy in an 18-year-old Downs syndrome male in an attempt to follow the fate of the extra chromosome 21 and to evaluate the effects of this condition on spermatogenesis and the reproductive functions. The histological changes in the testes corresponded to spermatogenic arrest. Electron microscopic whole-mount spreadings of meiotic cells in the pachytene stage showed that in most nuclei an extra chromosome 21 was not detectable. Only in a small number of nuclei, univalents or trivalents with segmental pairing structures of an extra chromosome could be discovered. In contrast, the great majority of (C-banded) diakinesis figures showed the presence of a supernumerary G (no. 21) chromosome. The absence of a traceable extra chromosome 21 in most pachytene cells is explained by the assumption that it is intimately connected with and hidden in the sex vesicle, whose complex structure does not allow the identification of single elements. Strong support for this assumption is seen (a) in the general tendency of narrow spatial association of unpaired segments with the XY complex and (b) in close structural similarities occurring between univalents or nonsynapsed segments of trivalents and the nonpaired segments of the sex chromosomes. It is suggested that the association or connection of an extra chromosome with the XY complex during pachytene interferes with the phenomenon of X inactivation. In animal systems such abnormal interference is related with spermatogenic breakdown and, in a general way, with male hybrid type sterility. So far, the range of sterility vs. fertility in cases of male Downs syndrome is not yet fully clear, but it appears that impairment of fertility, and sterility are most frequent. If so, it is proposed that the effect of the trisomy 21 condition on spermatogenesis (and fertility) is a consequence of the behavior of the extra chromosome in the meiotic prophase.

Microdeletion 22q11 in complex cardiovascular malformations

Abstract Besides DiGeorge, velocardiofacial and conotruncal anomaly face syndromes, some of the isolated congenital heart diseases have also been associated with a chromosomal deletion in 22q11. These disease entities, which had originally been considered to have a different genetic background, are now included in the CATCH-22 microdeletion complex. CATCH 22 is an acronym for cardiac defect, abnormal facies, thymic hypoplasia or aplasia and T-cell deficiency, cleft palate, hypoparathyroidism, and hypocalcemia. In the present study, we focused on the complex cardiovascular defects (CCVD) and screened 40 patients for a microdeletion of 22q11 by fluorescence in situ hybridization using the D22S75 DNA probe and for associated CATCH features. The patients were from genetic counseling (n = 15) or fetopathology (n = 3) of the Clinical Genetics Department in Marburg and from the Pediatric Cardiology Department (n = 22) in Mainz. Monosomy 22q11 was detected in 9 cases (= 22.5%). Familial transmission with one mildly affected parent and one affected sib each was proven in two cases. The CCVDs comprised complex conotruncal defects such as tetralogy of Fallot, double outlet right ventricle, transposition of great arteries and truncus arteriosus communis, or anomalies of the derivatives of the branchial arch arteries in association with a ventricular septal defect, including one case of atresia of the ductus arteriosus with pulmonary artery aneurysm and resulting in fetal hydrops. All 13 patients with a deletion of 22q11 showed at least one additional CATCH symptom. Most consistently, facial dysmorphy was apparent (92%), while hypocalcemia, mostly at threshold values, was present in 62% and thymic hypoplasia including borderline low T-lymphocyte numbers was observed in 41%. None of the patients presented with a cleft palate. A high intrafamilial variability in expression was also evident with respect to the CCVD. Our findings indicate that seemingly isolated complex cardiovascular defects associated with a 22q11 microdeletion most probably do not represent a distinct subgroup within the CATCH-22 complex but are syndromal in nature with extracardiac features that are often overlooked.

Quantitative Histology of Human Fetal Testes in Chromosomal Disease

Morphometric studies on male gonads were performed in 35 midterm fetuses aborted after prenatal diagnosis of a chromosome anomaly and in 11 chromosomally normal controls. A significant reduction of the number and volume percentage of premeiotic germ cells was observed in the chromosomally abnormal cases. Germ cell depletion was correlated with the severity of the chromosomal disease. It was least expressed in the XYY condition. In trisomy 13 and 18, depletion lead to values of less than a half or even a fourth the values of controls. Complex anomalies with XXY or XYY in addition to an autosomal disorder showed a moderate effect on germ cell reduction. No morphological differences were observed in germ cells or in Sertoli cells in a comparative electron microscopic study. Paucity of fetal germ cells can result from impaired colonization of the gonadal ridge, from low mitotic activity, or from increased premeiotic cell loss. All three factors seem to contribute to the above findings.

Molecular cytogenetic studies in three patients with partial trisomy 2p, including CGH from paraffin-embedded tissue.

We report on three cases of partial trisomy 2p in which the identification and exact localization of the duplicated chromosome segment was possible only by application of molecular cytogenetic techniques. These included fluorescence in situ hybridization by use of wcp2, N-myc, and subtelomeric 2p probes and comparative genomic hybridization with DNA isolated from blood samples, frozen fetal tendon, and formalin fixed, paraffin-embedded fetal lung tissue. Two of the cases concerned fetuses of gestational week 20 and 24 with duplication of nonoverlapping terminal (2pter-->p24) and more proximal (2p25-->p23) segments and with distinctly different phenotypes. The third case was due to a de novo inverted duplication of 2p25-->p23, with loss of the subtelomeric region of 2p. This 53-month-old girl was a Bloom syndrome carrier. The patient had prenatal growth failure, borderline microcephaly, dilated lateral horns of the cerebral ventricles, transient cortical blindness, myopia, muscle hypotonia, and dilatation of the left renal collecting system. Dermal cysts were found on the glabella, the soles of both feet, and the vocal cord, causing respiratory embarrassment. Previously reported cases of pure trisomy 2p are reviewed, in an attempt to correlate clinical findings to overlapping regions in 2p. These cases illustrate the effectiveness of molecular cytogenetic methods in resolving subtle chromosomal aberrations in order to coordinate more accurately a chromosome regionspecific phenotype.

Perinatal Deaths in a Family with Autosomal Dominant Polycystic Kidney Disease and a PKD2 Mutation

The authors report on a four-generation family carrying a mutation in the gene for ADPKD2 (PKD2) with previously undetected polycystic kidney disease. In the present generation, however, perinatal ...

Duplication Dup(1)(q32q44) Detected by Comparative Genomic Hybridization (CGH): Further Delineation of Trisomies 1q

Partial trisomy 1q is rare and mostly the result of an abnormal segregation of parental translocation chromosomes and their homologues. Only 31 cases have been described with pure partial trisomy 1q. In the fetus presented, chromosome analysis after amniocentesis had shown an unbalanced male karyotype with an aberrant chromosome 1. A de novo terminal duplication of the long arm was suspected but could not be verified by FISH in 1994. Five years after fetal death, retrospective identification of the additional material in 1q could finally be achieved by comparative genomic hybridization (CGH) using DNA extracted from formalin-fixed and paraffin-embedded fetal tissues. A direct duplication dir dup (1)(pter→q44::q32.1→qter) was found. Only 6 other individuals with duplication of this segment have been described so far. Comparative delineation of a dup1q phenotype with regard to size and origin of the dup (1q) segment evidenced that large duplications as well as proximal and interstitial duplications coincide with more severe visceral malformations, severe mental retar- dation and a short life span. Terminal duplications (1q32→qter) concur with less severe malformations and longer periods of survival, but marked mental retardation. With small terminal duplications (1q42→qter) dysmorphisms are usually mild and intellectual performance is mostly in the normal range.

Pigmentary mosaicism in hypomelanosis of Ito. Further evidence for functional disomy of Xp.

We report on a female with mental and motor retardation, facial dysmorphism, abnormal pigmentation reminiscent to hypomelanosis of Ito (HI), and karyotypic mosaicism involving a small supernumerary marker chromosome. The marker chromosome was defined by fluorescence in situ hybridisation (FISH) as a ring X chromosome with breakpoints in the juxtacentromeric region. FISH analysis showed that the ring does not include the XIST locus at the X-inactivation centre and, therefore, may not be subject to X inactivation. X-inactivation studies with the HUMARA (human androgen receptor) and FMR1 assay showed a skewed X-inactivation pattern (85:15) with preferential inactivation of the paternal X chromosome. These results are discussed with respect to the role of functional disomy of Xp in the pathogenesis of HI.

Variability in the phenotypic expression of Fryns syndrome: A report of two sibships

We report on two sibships with four fetuses of 12, 15, 17, and 20 weeks of gestation, respectively, and 1 preterm baby of 31 weeks of gestation affected by a multiple congenital disorder with manifestation suggestive of Fryns syndrome. In addition to the characteristic malformation pattern in Fryns syndrome, they presented with fetal hydrops, cystic hygroma, and multiple pterygias, allowing prenatal ultrasound diagnosis as early as in the 11th week of gestation. The two affected fetuses of family 1 showed severe craniofacial anomalies with bilateral cleft lip and palate, acral hypoplasia, postaxial oligodactyly, persistent truncus arteriosus, and interrupted aortic arch, asplenia sequence, and complex central nervous system midline malformations. In family 2 with three affected sibs, ear anomalies with atresia of the auditory canals, postaxial hexadactyly, intestinal atresias, callosal defects, and eye colobomas were the most outstanding features. On the basis of the present findings and former reports, the inter- and intrafamiliar phenotypic variability in Fryns syndrome, possible pathogenetic mechanisms, and the value of prenatal diagnosis are discussed. In the pathogenetic discussion, a special emphasis is put on the neural crest cell developmental field.

Neuropathology of Raine syndrome

Abstract. We present three cases of Raine syndrome occurring in siblings of consanguineous parents. Raine syndrome is characterised by generalised osteosclerosis with craniofacial anomalies and intracranial calcifications. So far, only nine cases have been reported, and no evaluation of the distribution and extent of the cerebral mineralisations, as well as their impact on the surrounding tissue, has been undertaken yet. In our cases, calcifications were unevenly distributed throughout the central nervous system, not associated with neuronal loss or dystrophic events and appeared mostly as single calcospherites within the neuropil with occasional confluent deposits at advanced gestational age. There was intense perifocal microgliosis around single immature calcospherites, as well as mild astrogliosis around and within the confluent lesions, in which occasional macrophages could be found. Rarely, mineralisations occurred in blood-vessel walls, mainly affecting basal ganglia. Preferential sites of calcification were parietal and occipital periventricular white matter and corpus callosum, while frontal lobes were mildly affected. The cortex, temporal lobes as well as internal capsule, brain stem, cerebellum, leptomeninges, pituitary gland and choroid plexus were devoid of mineralisations. The subcortical grey matter was moderately involved in the putamen and pallidum, mildly in the caudate nucleus and subependymal germ cell matrix and not at all in the thalamus, Ammons horn, amygdala and substantia nigra. The distribution of mineral deposits was thus inversely correlated to regional blood circulation and capillary density, with calcifications being concentrated in more sparsely perfused areas but lacking in highly vascularised tissue. This inverse relationship between mineralisation and regional blood flow was reflected in the varying distribution of calcospherites in grey and white matter as well as in the white matter of different lobes.

Polyploidies in abortion material decrease with maternal age.

Among 639 spontaneous abortions between the 8th and 14th week of gestation 342 (53.5%) revealed an abnormal karyotype. While the rate of trisomies distinctly increased with advancing maternal age, a decrease in the rate of 45,X conceptuses and polyploidies was observed among abortions from older women. The overall relation of XXXX∶XXYY among the tetraploidies was 14∶11 and that of XXX∶XXY∶XYY among the triploidies was 26∶ 36∶1. However, when the latter was related to maternal age, a reversal of the XXX∶XXY ratio of 1∶2 in the younger to 2∶1 in the older age groups became evident. Furthermore a decrease in the rate of “paternally” derived partial hydatidiform moles was found among the triploid abortion specimens from older women. From these observations we conclude that digyny plays a major role in the origin of triploidy in the increased maternal age groups, while diandry related to immaturity of oocytes and impairment of oocyte cortical function is more frequent in triploid abortions from younger women.