Molecular characterization of cytogenetic alterations associated with the Beckwith-Wiedemann syndrome (BWS) phenotype refines the localization and suggests the gene for BWS is imprinted.

To define the region of 11p15 involved in Beckwith-Wiedemann syndrome (BWS), we have carried out a molecular genetic analysis of six patients with features of BWS and constitutional cytogenetic abnormalities involving chromosome band 11p15. Molecular analysis confirmed the 11p origin of the duplicated material and defined the smallest region of overlap for such duplications, within which a gene involved in BWS must be located. This region encompasses the beta-globin gene complex (HBB) to 11pter. In both of our informative cases, the 11p duplication was found to be of paternal origin. Two BWS associated balanced translocations of 11p15 were studied to localize the breakpoints on 11p15. Somatic cell hybrids, Southern blotting and fluorescent in situ hybridization (FISH) showed that both breakpoints were between D11S12 and the insulin-like growth factor 2 (IGF2) gene. A non-BWS translocation breakpoint was more proximal, between HBB and calcitonin-A (CALCA). Pedigree analysis showed that both BWS associated 11p15 translocations were transmitted by phenotypically normal mothers. The data are compatible with the hypothesis that the BWS gene is imprinted and that the maternally inherited BWS gene is normally suppressed whereas the paternally inherited allele is active. Thus, duplications of paternal origin would lead to increased dosage of the BWS gene. Similarly increased dosage of the BWS gene could account for the findings in maternally inherited 11p15 translocations by altering normal imprinting, so that the translocated maternal allele remains active. This study defines one or more gene loci for BWS on 11p15.5 in the genomic region from D11S12 to IGF2.

Cri du chat syndrome due to meiotic recombination in a pericentric inversion 5 carrier.

A female infant presented at birth with hypotonia, growth retardation, distinctive facies, multiple congenital anomalies, and a high-pitched mewing cry characteristic of cri du chat syndrome. Chromosome studies from both peripheral blood and fibroblasts showed a 46,XX,5p- karyotype. Parental chromosome studies revealed that the mother carried an apparently balanced pericentric inversion of one chromosome no. 5, 46,XX,inv(5)(p14q35). Meiotic crossing-over in the mother within the inverted segment of chromosome 5 gave rise to the unbalanced karyotype, 46,XX,rec(5)dup q, inv(5)(p14q35)mat in the infant. A small terminal segment of the long arm of chromosome 5 (q35-pter) is duplicated with a deletion of the short arm of chromosome 5 (p14-pter), accounting for the features of cri du chat syndrome. Fewer than 1 in 200 of cri du chat syndrome cases are due to recombination aneusomy arising from a parental inversion of chromosome 5. Some of these cases, however, do not have typical cri du chat syndrome, reflecting significant duplication of 5q material. These cases are reviewed with the present case, and recombination behaviour leading to chromosome imbalance is discussed.

Cytogenetic analysis of 400 sperm from three translocation heterozygotes.

Sperm chromosome complements were studied in three men who carried reciprocal translocations. A total of 400 sperm were karyotyped after in vitro penetration of hamster eggs: 217 sperm from t(2;9) (q21;p22), 164 from t(4;6)(q28;p23) and 19 from t(7;14) (q21;q13). All possible 2:2 and 3:1 meiotic segregations were observed for t(2;9) and t(4;6); for t(7;14) only 2:2 segregations were observed. For alternate segregations, the number of normal sperm was not significantly different from the number of sperm carrying a balanced form of the translocation in any of the translocations, as theoretically expected. The percentage of sperm with an unbalanced form of the translocation was 57% for t(2;9), 54% for t(4;6) and 47% for t(7;14). There was no evidence for an interchromosomal effect in any of the translocations since the frequencies of numerical abnormalities (unrelated to the translocation) were within the normal range of control donors. The frequencies of X- and Y-bearing sperm did not differ significantly from 50%. Results from a total of 17 reciprocal translocations studied by sperm chromosomal analysis were reviewed.

A familial interstitial deletion of the long arm of chromosome 21.

A mother and daughter with an interstitial deletion of the chromosome segment 21q11 to 21q21.3 have similar minor dysmorphism and mild mental retardation. These two patients are compared to others in the literature with deletion of the same region of chromosome 21. Molecular analysis of DNA from our patients localizes the DNA segments D21S1, D21S11, D21S8, and D21S22 within the deleted region.

Chromosome 6q deletions: a report of two additional cases and a review of the literature.

Here we report on two additional cases of distal 6q deletions with one case showing a terminal deletion of chromosome 6 (46,XY, del(6)(pter----q26:)) and one case showing an interstitial deletion of chromosome 6 (46,XY, del(6)(pter----q23::q25----qter)). The association of retinal abnormalities in 6q deletions is supported, and the additional manifestations of skin hyperextensibility, sacral abnormality, and imperforate anus are described.

Multiple malformations and exposure to therapeutic ultrasound during organogenesis.

We present a case of sacral agenesis, microcephaly, and developmental delay. The pregnancy with this child was complicated by left psoas bursitis that was treated by 18 applications of ultrasound between days 6 and 29 of gestation.

Autosomal recessive juvenile cataract in Hutterites.

Autosomal recessive inheritance of juvenile cataract is described amongst several related sibships of Lehrerleut Hutterites. The main features of the cataract include onset between three and seven years of age; rapid progression to maturity within one to three months; normal intelligence; no systemic associations, and no urinary reducing substances and normal erythrocyte galactokinase activity. Genetic analysis demonstrates the close relationship between parents of affected sibships with a coefficient of inbreeding of affected sibships of 0.0512. Estimates of heterozygote frequency within Lehrerleut Hutterites at 0.128 indicate that if current inbreeding practice continues additional cases can be expected.

Screening for methylmalonic aciduria in Alberta: a voluntary program with particular significance for the Hutterite Brethren.

A selective, voluntary urine screening program has been established to facilitate detection and early treatment of infants with methylmalonic acidurias (MMA), a group of rare, potentially lethal, autosomal recessive disorders of organic acid metabolism. The laboratory methods have been modified for newborn infants so that urine specimens can be collected on filter paper in the diaper and tested by the thin-layer chromatography method. One Hutterite child was previously known to have methylmalonyl-coenzyme A (MMCoA) mutase deficiency (mut0) which is unresponsive to vitamin B12 but is responsive to diet and other therapeutic measures. No undiagnosed existing cases of MMA were identified by the voluntary screening program among 1,165 Hutterite infants and preschool children.

The Bowen-Conradi syndrome -- a highly lethal autosomal recessive syndrome of microcephaly, micrognathia, low birth weight, and joint deformities.

This paper describes six Hutterite children from five families who appear to have been affected by the same syndrome that was described in two brothers by Bowen and Conradi [1]. Our additional cases confirm that the major features of the syndrome include porportionate intrauterine growth retardation, microcephaly, micrognathia, a prominent nose, rocker-bottom feet, joint limitation, and failure to thrive, with death within the first year of life. Bowen-Conradi syndrome is an autosomal recessive trait and pedigree records show that all six families now known are related to each other through two couples born in the late 1700s but that there are additional earlier possible sources of the responsible gene. The differential diagnosis of this syndrome is discussed.