Iosif W. Lurie

Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell Syndrome (SRS): Results from a large cohort of patients with SRS and SRS-like phenotypes.

Background: Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous condition characterised by severe intrauterine and postnatal growth retardation. Loss of DNA methylation at the telomeric imprinting control region 1 (ICR1) on 11p15 is an important cause of SRS. Methods: We studied the methylation pattern at the H19-IGF2 locus in 201 patients with suspected SRS. In an attempt to categorise the patients into different subgroups, we developed a simple clinical scoring system with respect to readily and unambiguously assessable clinical features. In a second step, the relationship between clinical score and epigenetic status was analysed. Results and conclusions: The scoring system emerged as a powerful tool for identifying those patients with both a definite SRS phenotype and carrying an epimutation at 11p15. 53% of the 201 patients initially enrolled fulfilled the criteria for SRS and about 40% of them exhibited an epimutation at the H19-IGF2 locus. Methylation defects were restricted to patients who fulfilled the diagnostic criteria for SRS. Patients carrying epimutations had a more severe phenotype than either the SRS patients with mUPD7 or the idiopathic SRS patients. The majority of patients with methylation abnormalities showed hypomethylation at both the H19 and IGF2 genes. However, we also identified SRS patients where hypomethylation was restricted to either the H19 or the IGF2 gene. Interestingly, we detected epimutations in siblings of normal parents, most likely reflecting germ cell mosaicism in the fathers. In one family, we identified an epimutation in an affected father and his likewise affected daughter.

The Wolf-Hirschhorn syndrome. I. Genetics.

Four new cases of the Wolf‐Hirschhorn syndrome are presented, two of which were due to t(4;22)mat. Review of the literature (more than 100 cases of the Wolf‐Hirschhorn syndrome) showed that 13 % of all the reported cases were not mutations but segregations of parental chromosomal aberrations, primarily translocations. Similar data were obtained previously for other deletions (5p‐, 18p‐, 18q ‐). Analysis of data on some “new” deletion syndromes (4q ‐, 8p‐, 9p‐, 10p‐, 11p ‐, 11q ‐) revealed that 14.5% were inherited cases. Thus, all human autosomal deletions have virtually the same genetic pattern.

The Wolf-Hirschhorn syndrome: II. Pathologic anatomy

Most cases of Wolf‐Hirschhorn syndrome occurring among children who die during the perinatal period are not diagnosed by morphologists. However, analysis of the morphological data on the Wolf‐Hirschhorn syndrome reveals that association of typical external features and abnormalities of the brain (shortening of the H2 area of Ammons horn, dystopic dysplastic gyrae in the cerebellum), eyes (colobomata, microphthalmos, retinal dysplasia) and kidneys (bilateral or unilateral agenesis, cystic dysplasia or polycystosis) with diaphragmatic hernia allows the establishment of a diagnosis of the syndrome without cytogenetic investigation.

Atrioventricular septal defects: Possible etiologic differences between complete and partial defects

BACKGROUND Recent advances in clinical, pathological, and genetic aspects of atrioventricular septal defects (AVSD) have set the stage for epidemiologic investigations into possible risk factors. Previous analyses of the total case group of AVSD included complete and partial subtypes without analysis of the subsets. METHODS To address the question of possible morphogenetic heterogeneity of AVSD, the Baltimore-Washington Infant Study data on live-born cases and controls (1981-1989) was reanalyzed for potential environmental and genetic risk-factor associations in complete AVSD (n = 213), with separate comparisons to the atrial (n = 75) and the ventricular (n = 32) forms of partial AVSD. RESULTS Complete and ventricular forms of AVSD had a similar proportion of isolated cases (12.2% and 15.6%, respectively, without associated extracardiac anomalies) and high rates of Down syndrome, whereas the atrial form of partial AVSD included 55% isolated cases. Trisomy 18 occurred in 22% of infants with the ventricular form, compared with <2% in the other AVSD groups. Analysis of potential risk factors revealed further distinctions. Complete AVSD as an isolated cardiac defect was strongly associated with maternal diabetes (odds ratio [OR] = 20.6; 95% confidence interval [CI] =5.6-76.4) and also with antitussive use (OR = 8.8; CI = 1.2-48.2); there were no strong associations other than maternal age among Down syndrome infants with this type of heart defect. Isolated cases with the atrial type of partial AVSD were associated with a family history of heart defects (OR = 6.2; CI = 1.4-24.4) and with paternal occupational exposures to ionizing radiation (OR = 5.1; CI = 1.4-27.4), but no risk factors were associated with Down syndrome. There were no significant associations of any risk factors in the numerically small subsets of isolated and Down syndrome cases with the ventricular form of partial AVSD. CONCLUSIONS These results indicate a similar risk profile of complete AVSD and the ventricular type of partial AVSD, with a possible subset of the latter due to trisomy 18. Maternal diabetes constituted a potentially preventable risk factor for the most severe, complete form of AVSD.

Isochromosome 18p results from maternal meiosis II nondisjunction.

Microsatellite analysis with 13 microsatellites spread over 18p was performed to determine the origin of the marker chromosome in 9 patients with additional metacentric marker chromosomes. Phenotypes and banding patterns suggested that the markers were isochromosomes 18p. Maternal origin was determined in all 8 cases where both parents were available for study. Six cases showed 3 alleles (one paternal, one maternal each in single and double dose) of informative markers located close to the telomere while markers close to the centromere on 18p were reduced to homozygosity (one paternal allele in single dosage and one maternal allele presumably in triple dosage). A similar result was obtained in the patient with no parents available for examination. The other 2 patients were uninformative for maternal hetero- versus homozygosity, but at some loci the maternal band was clearly stronger than the paternal one whereas the opposite was never observed. Trisomy 18 differs from trisomy 21, XXX and XXY of maternal origin through a preponderance of meiosis II versus meiosis I nondisjunction. Thus, the results of our study and the advanced mean maternal age at delivery of patients with additional i(18p) indicate that in most if not all cases the marker chromosome originates from maternal meiosis II nondisjunction immediately followed by isochromosome formation in one of the 2 maternal chromosomes 18. Possible explanations of these results include a maternally imprinted gene on 18q with a lethal effect if the paternal homologue is lost and a mechanism through which nondisjunction in some cases could be connected with isochromosome formation.

Interrupted aortic arch: an epidemiologic study.

BACKGROUND Interruption of the aortic arch (IAA) is a rare but severe anomaly associated with major intracardiac defects and with multisystem noncardiac malformations, recently linked to chromosome deletion of 22q11.2. METHODS The Baltimore-Washington Infant Study (1981-1989), a population-based epidemiologic study of cardiovascular malformations, evaluated 53 infants with IAA in comparison with 3,572 controls. Risk factors for the anatomic subtypes were evaluated in 14 cases of IAA type A and 32 cases of IAA type B, but no molecular genetic tests were available. The distribution of associated cardiac defects was similar for both types. RESULTS DiGeorge syndrome (DGS) occurred more frequently in IAA type B. Case-control comparisons demonstrated that infants in both groups were growth retarded at birth. A family history of noncardiac defects occurred only in IAA type B cases and included relatives with cleft lip and/or cleft palate. Candidate risk factors were associated only in type B cases and differed for those with (n = 10) and for those without (n = 19) DGS: a family history of noncardiac defects (odds ratio [OR] = 7.2, 95% confidence interval [CI] = 1.5-39.2) and maternal use of aspirin during the critical period (OR = 4.8, 95% CI = 1.3-25.4) occurred with DGS, while previous stillbirth (OR = 9.4, 95% CI = 1.3-53.1), bleeding during pregnancy (OR = 3.7, 95% CI = 1.4-11.4), and maternal exposure to arts/crafts paints (OR = 4.8, 95% CI = 1.3-17.4) were associated in those without DGS. CONCLUSIONS These findings confirm the heterogeneity of IAA and of the type B subtype. Risk factors specific for cases with DGS may open a window to further investigations of the etiology of IAA and of the associated molecular genetic abnormalities.

Genetics of the +p9 syndrome.

SummaryAn analysis of data about the+p9 syndrome revealed that this clinical entity may occur in some different genetic forms. The recurrence risk in cases with familial translocations is due to the type of meiotic segregation, 2:2 or 3:1. It was shown a nonrandomness of involvement of chromosomes 15 and 22 in translocations with chromosome number 9.

The pathological anatomy of the Smith-Lemli-Opitz syndrome

Two cases of the Smith‐Lemli‐Opitz syndrome are described, together with the autopsy findings. In both cases, the typical appearance and visceral malformations were present. Hypoplasia of the frontal lobes and corpus callosum, and aplasia of the splenium constitute abnormalities of the brain which may be useful in the diagnosis of this disorder at autopsy. The autosomal recessive mode of inheritance of this syndrome was confirmed.

Further evidence for the autosomal-recessive inheritance of the COFS syndrome.

Recently, Pena & Shokeir (1974) and Preus & Fraser (1974) described a new syndrome of multiple congenital malformations, including abnormalities of the brain, eyes, face and skeleton. The abbreviation ‘COFS’ (Cerebro Oculo Facio Skeletal) has been suggested. Parental consanguinity was established in two out of four known families: in the family of Preus & Fraser the parents were first-cousins; and in Family 1 of Pena & Shokeir, a multiple consanguineous mating was established. These observations support the view that the COFS syndrome is a disorder with an autosomalrecessive type of inheritance. We have recently observed a child with the COFS syndrome. This girl was also born in a family where there was parental consanguinity. The purpose of this article is to present our case of the COFS syndrome and to describe the internal malformations of the proposita and the pedigree of the family.

Complex chromosomal rearrangements: some breakpoints may have cellular adaptive significance

Cytogenetic study of a 3‐year‐old girl with developmental delay and some minor abnormalities revealed a complex chromosome rearrangement (CCR) involving seven chromosomes with eight breakpoints, leading to monosomy of segment 5q15‐q22. According to breakpoint distribution, CCRs may be classified as those with primary intrachromosomal abnormalities (including inversions, insertions, duplications, etc.) and those without them. Only the latter group of CCRs was used in this analysis. Comparison of theoretical and observed breakpoint distributions in 33 cases demonstrated that recurrent involvement of some chromosome(s) (“re‐entry”) occurs more frequently than expected. One possible explanation for this observation suggests that the initial event leads to an unstable provisional rearrangement, and subsequent breaks are necessary to stabilize the karyotype.