A gene for hypospadias in a child with presumed tetrasomy 18p.

The proband and his elder brother had intrauterine growth retardation, hypospadias, cryptorchism, a high palate, distally placed axial triradii, and a functional and maturational CNS defect that improved with age and included the inability to suck, severe swallowing difficulties, and frequent vomiting. Their hypospadias is due to an autosomal dominant gene. The proband also had a small extra metacentric chromosome presumed to be an isochromosome 18p.

Direct duplication of 8p21.3-->p23.1: a cytogenetic anomaly associated with developmental delay without consistent clinical features.

We report six cases in two families and a sporadic case with a direct duplication of region 8p21.3-->23.1. In one family, the duplication started in the mother and was transmitted to one son and one daughter. In the second family, the father was mosaic for the anomaly that was transmitted to his two daughters. The cytogenetic anomaly was initially described as an 8p+ with banding analysis and then delineated with fluorescence in situ hybridization (FISH) using whole-chromosome 8 painting, 8p specific painting, and 8p or 8p/8q subtelomeric probes. Deletion was not detected in the subtelomeric region of the abnormal chromosome 8 examined in one family and in the sporadic case. The phenotypic picture varies from normal to moderate mental retardation in the affected individuals. No consistent minor anomalies or congenital defects were observed among these cases. After comparing the chromosome region involved in our cases with those in others having direct or inverted duplications of 8p, it is thought that the segment 8p21.1-->21.3 might be the critical region for an 8p duplication syndrome. The parental origin of the duplication does not seem to impact its clinical significance.

Sister-chromatid exchange in highly purified human CD4+ and CD8+ lymphocytes.

Sister-chromatid exchange (SCE) frequencies were determined in human peripheral blood CD4+ and CD8+ T lymphocyte subpopulations which were rapidly and highly purified from pooled T lymphocytes by immunological methods. The purified lymphocytes were stimulated with phytohemagglutinin (PHA) for 4 days. CD4+ lymphocytes showed significantly higher SCE frequencies than autologous CD8+ lymphocytes when measured simultaneously after identical bromodeoxyuridine (BrdU) incubation times. Differences in SCE frequencies between CD4+ and CD8+ lymphocytes were also detected when mitomycin C (MMC) was added to the cultures. Higher SCE frequencies in CD4+ lymphocytes were associated with lower proliferating rate indices (PRI) as compared to autologous CD8+ lymphocytes. Abnormalities in CD4+ T lymphocyte function and number in peripheral blood have been observed in several diseases characterized by immunological disorders. Thus, our data may suggest a link between some immunological disturbances and abnormal SCE frequencies in T lymphocyte subsets.

[Hereditary juvenile dystrophy of the macula in a large family from Epirus]. / Dystrophie héréditaire juvénile de la macula chez une famille nombreuse d'Epire.

The authors present a clinical, epidemiologic and genetic study of juvenile macular dystrophy (Stargardt's disease) in a large kindred from Epirus in Greece. The family tree consists of 372 individuals spanning six generations over more than a century. 257 are direct descendants of the founding couple. Nineteen individuals were found to suffer from Stargardt's disease, thirteen of whom are still alive today. Segregation analysis of the data showed that in this pedigree, the disease is transmitted with the autosomal dominant mode of inheritance.

The cis-trans effects of crossing-over on the penetrance and expressivity of dominantly inherited disorders.

A surprisingly simple model based on the cis-trans effects of meiotic and mitotic crossing-over is proposed to explain apparent non-penetrance and reduced expressivity in dominantly inherited disorders. Sex differences, discordant monozygotic twins, multifactorial inheritance and allelism are also discussed.

The cis-configuration effects of rare chromosomal fragile sites.

Rare chromosomal fragile sites may adversely affect specific alleles of closely linked genes when in cis-configuration. This is illustrated by data published in Sutherland & Hecht (1985) on chromosome 16 at band q22.1.

Wilms' tumour and related syndromes. A unifying theory.

The major role of somatic crossing-over in the aetiology of Wilms' tumour and other forms of cancer is emphasized. A model is proposed to show that tumour development is due to a cis-trans disruptive effect of somatic crossing-over on the maintenance of differential parental imprinting.

Centrometric linkage in autosomal trisomies.

A detailed description of the cytological mechanisms leading to autosomal trisomy shows that the proportion of trisomics carrying three alleles from three of their grandparents is bound to be greater than zero for any locus anywhere on a trisomic chromosome. The likelihood method used to estimate this proportion in pedigree data can be applied to the detection of linkage, or to investigations on the origin of trisomy when linkage is known.

Genetic markers in trisomies 13 and 18.

Data on centromeric linkage for trisomies 13 and 18 are presented. There is no substantial evidence that any of these loci studied are on either chromosome. There is weak evidence relating the locus defining the Kidd groups to chromosome 18.

Beta-thalassaemia: increased chromosomal anomalies in lymphocyte cultures.

Lymphocyte cultures from homozygotes for the beta-thalassaemia gene were found to contain chromosomal gaps, breaks, and rearrangements more often than those from controls. Culture time seemed to have a determinant effect on the results. The possible influence of folic acid deficiency is discussed.

Twinning and mitotic crossing-over: some possibilities and their implications.

Mitotic crossing-over does occur in man and is much more frequent and important than generally assumed. Its postzygotic occurrence before an embryo differentiates into MZ twins is theoretically predicted to have disrupting effects on genomic imprinting and cis-acting sequences, with consequences ranging from early lethality to MZ twin discordance. Some predictions are at odds with classical views on twinning and include a high discordance rate of MZ twins for some genetic diseases. A review of MZ twin discordance and an attempt at explaining some of the data lead one to hypothesize both the existence of a sex differences in the rate of mitotic crossing-over and the impossibility for crossed X chromosomes to undergo inactivation. The close interrelationship of twinning and midline malformations further suggests a major role of mitotic crossing-over in the induction of the twinning process itself. The model can be tested with molecular methods and provides a new approach for the gene mapping of so-called multifactorial diseases and of rarer disorders with apparently irregular inheritance.

The fragile site on the long arm of chromosome 16.

A boy and his father were found to have very small testes and a fragile site on the long arm of chromosome 16. This fragility would not have been detected in culture medium 199.

The cytogenetic and clinical implications of a ring chromosome 2.

Ring chromosome formation can occur without deletion, through the abnormal pairing of the palindromic DNA base sequences thought to make up the telomeres. The normal occurrence of sister chromatid exchanges within a ring constantly produces further chromosomal anomalies that are less likely to survive when the chromosome involved is large and/or its aneuploidy incompatible with life. These abnormal products (abbreviated pro) were only found in the present case after two or more cell cycles in lymphocyte cultures. Their elimination in vivo implies a very high cellular death rate and an enormous waste of metabolism that should have the same phenotypic effects no matter what chromosome is involved. These phenotypic anomalies form a ring syndrome that can be clinically recognized and consists of severe growth failure, mental retardation and a pleasant personality. The syndrome is usually masked by the more severe abnormalities produced by the deletions present in most cases of ring chromosomes.

Fryns syndrome without deletion 16q.

Fryns and his colleagues described two children with a remarkably similar phenotype, and suggested their condition was due to a partial or total deletion of the long arm of chromosome 16 distal to band q21. We report the same phenotype in a boy whose blood karyotype was normal.

Partial trisomy 6p with karyotype 46,XY,der(22), t(6;22)(p22;q13)mat.

A case of partial trisomy 6p is reported with a review of the various characteristics of this syndrome.

A cascade of chromosomal aberrations in three generations: a fragile 16q, an extra fragment and a rearranged 20.

The propositus' grandmother has a fragile 16q and belongs to a large family where several abortions and congenital anomalies were recorded. The portion distal to the fragile site was inherited as an extra fragment by the proposius' father who has it in 11% of his lymphocyte metaphases. This phenotypically harmless fragment has a high affinity for satellited chromosomes and was probably a main factor in the causation of the rearrangement that produced the partial trisomy 20p found in the propositus.

Hypothyroidism and sex chromosomes.

The observation of Campbell and Price in 1979 that their Unit had diagnosed four subjects with both Klinefelter's syndrome and congenital hypothyroidism raised the suspicion of an association between the two conditions. This, and the published reports of an XX male, five XXY males, and one mosaic XY/XXY with congenital or acquired forms of hypothyroidism, together with the higher incidence in women and the absence of sex difference among inherited congenital cases, suggested a possible sex chromosome effect in the aetiology of sporadic hypothyroidism. Various hypotheses can be tested either by examining the frequency of hypothyroidism in sex chromatin positive males or by establishing a higher frequency of sex chromatin positive males among hypothyroid cases than in normal males. We examined 57 boys with hypothyroidism for the presence of sex chromatin and found all to be negative. From this relatively small sample we can only exclude the possibility of a very large (100 fold) difference in frequency between the two populations and therefore more data are needed.

Oligohydramnios syndrome and XYY karyotype.

A case of oligohydramnios syndrome was found to have an XYY karyotype and an inherited 9qh inversion. It is suggested that normal and extra Y chromosomes are a predisposing factor in the aetiology of severe congenital renal anomalies.