Biomedical subjects
Publications and source records attributed to E Sujansky.
We report a kindred manifesting clinical features and muscle biopsy findings of inclusion body myositis (IBM). In this family, multiple members were affected in two generations with direct male-to-male and female-to-male transmission. This is the first reported instance of autosomal dominant inheritance in IBM, which usually occurs sporadically or, rarely, may be transmitted as an autosomal recessive disorder.
Tetralogy of Fallot, the most common cyanotic heart defect, has not been closely associated with a specific chromosome defect. The San Luis Valley Recombinant Chromosome 8 [SLV Rec(8)] syndrome is strongly associated with congenital heart disease, particularly tetralogy of Fallot. This article reviews SLV Rec(8) syndrome and other chromosome 8 aberrations to suggest locations for cardiogenic genes. SLV Rec(8) [rec(8),dup q,inv(8)(p23q22)] syndrome has been found in Hispanic families in the southwestern United States. Congenital heart disease is found in 93.3% of SLV Rec(8) individuals (n = 45), with tetralogy of Fallot constituting 40.5% of all lesions and conotruncal defects, 55.6%. These frequencies exceed the incidence of tetralogy of Fallot (10%) and conotruncal defects (20%) among all children with heart defects (P less than 0.003 for both). Review of patients with deletion 8p (n = 13) showed heart defects in 84.6% with 27.3% being conotruncal defects. Among duplication 8q patients (n = 20), 45% had heart defects with conotruncal defects constituting 44%. Neither group differed significantly from expected in its incidence of conotruncal defects. Among patients with mosaic trisomy 8 (n = 47), 12 had heart abnormalities including one conotruncal defect. Among 3 patients with other rec(8) chromosomes, one had a ventricular septal defect. The cause of heart defects in SLV Rec(8) cannot be assigned to either the deletion of 8p or the duplication of 8q. The lack of an association between other chromosome 8 abnormalities and tetralogy of Fallot suggests that genes at the SLV Rec(8) breakpoints or an interaction between genes on both arms of chromosome 8 are important.
One hundred forty-one individuals with autosomal dominant polycystic kidney disease (ADPKD) and 137 at-risk individuals from 107 kindreds answered a questionnaire to determine knowledge and attitudes about ADPKD and the use of gene linkage analysis for prenatal and postnatal presymptomatic diagnosis. Both groups of individuals displayed a high level of knowledge about the disease. Although 87% of affected individuals considered the recurrence risk of ADPKD high, only 11% of ADPKD did not have children for this reason after diagnosis. Ninety-seven percent of at-risk individuals would utilize gene testing for themselves. Eight-eight percent of ADPKD and 89% of at-risk individuals would test offspring (not significant, NS) and 65% of ADPKD and 50% of at-risk individuals between the ages of 18 and 40 would use prenatal testing (NS). Only 4% of ADPKD and 8% of at-risk individuals between the ages of 18 and 40 would terminate a pregnancy for ADPKD. A greater percentage would terminate a pregnancy for a serious medical problem. The factors influencing presymptomatic testing were analyzed. The data suggest that presymptomatic testing will not substantially modify incidence of ADPKD since it may only occasionally alter reproductive plans.
Autosomal dominant polycystic kidney disease has been shown to be closely linked to the alpha-hemoglobin complex on the short arm of chromosome 16. We describe a five-generation kindred, descendants of Sicilian immigrants, in which the disease occurs but without linkage to the alpha-hemoglobin complex. DNA probes were used in genetic-linkage studies on blood samples from 163 family members, of whom 71 were affected by or at risk for autosomal dominant polycystic kidney disease. Diagnoses were confirmed by ultrasound examination. In this family the frequency of recombination between the alpha-hemoglobin complex and the region previously shown to contain the mutation causing polycystic kidney disease exceeded 24 percent, indicating a mutation at a different locus. The clinical findings in this family were indistinguishable from those in other families with polycystic kidney disease. We conclude that there is a second gene for autosomal dominant polycystic kidney disease. This apparent heterogeneity means that prenatal and presymptomatic diagnosis must be approached with caution until a method is found to distinguish between the two forms of the disease.
A rec(8) dup(q) syndrome, secondary to a pericentric inversion--inv(8)(p23q22)--has been identified in 26 probands from Hispanic kindreds in the southwestern United States. The clinical phenotype of the Hispanic rec(8) syndrome includes a dysmorphic facies, cardiovascular and urinary-tract malformations, and mental retardation. Segregation analysis utilizing pedigree and cytogenetic data from 31 kindreds including five additional kindreds from additional sources has provided computation of genetic risks for counseling. An inv(8) carrier parent has a 6.2% risk of having a rec(8) child. The transmission rate of the inv(8) was significantly higher for inv(8) carrier mothers (59%) than for carrier fathers (42%). The combined transmission rate for both sexes was 53%. Risk for spontaneous abortion or stillbirth (11.3%) was not higher than the general population frequency of 13%-15%. It is significant that all kindreds identified to date are of Hispanic background with ancestors traced to the southern Colorado/northern New Mexico region. By means of extended pedigree information, three independently ascertained kindreds have been linked through common ancestry 4 generations in ascendance. The Hispanic background, geographic localization, and common ancestry in three kindreds suggest a single founder of the Hispanic inv(8) in the Southwest.
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Clinical records, autopsy reports, and microscopic slides from 11 infants with the recombinant 8 syndrome, an inherited abnormality of chromosome 8 affecting Hispanics from New Mexico and Colorado, were evaluated. A prevalence of cardiac and genitourinary anomalies was found, while few central nervous system abnormalities were observed. Dysmorphic features associated with recombinant 8 syndrome are presented, with descriptions of the inheritance pattern and recurrence risk. Because recombinant 8 syndrome is a chromosomal disorder that will appear more and more frequently as kindreds enlarge, pathologists must be alert to its diagnostic characteristics and genetic implications.
Amniotic bands can cause a wide variety of deformities and mutilations. They are generally considered sporadic. Two families are presented with apparent familial amniotic band anomalies. Additional cases in the literature are reviewed. These aggregations may be coincidental, and recurrence risk is apparently low. However, amniotic band malformations may be an indication for caution in the use of amniocentesis in future pregnancies.
Previous studies indicate that parents who have had one child with trisomy 21 have an increased risk of having another affected child. To establish whether sibs, aunts, uncles, and cousins of an index case with trisomy 21 are also at increased risk for having an affected child, 219 kindreds of trisomy 21 probands were surveyed and compared with a control group of 247 kindreds. Control kindreds were ascertained through a child with a nonchromosomal disorder. Empiric risks were obtained and a risk interval calculated for each type of relationship. The results of this study suggest that for most families who have had a child with trisomy 21, the risk to second- and third-degree relatives is increased somewhat but still low (less than 1%). Analysis of those rare families who present with one or more affected second- or third-degree relative with trisomy 21 in addition to the proband suggests that they represent a small subpopulation with a markedly increased risk. Sibs and second-degree relatives in such families should be offered the option of amniocentesis, regardless of maternal age.
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Eight children from seven presumably unrelated families were identified independently as having an unbalanced recombinant chromosome resulting in the presence of extra material on the short arm of a chromosome 8. Parental chromosomes were analyzed, and one member of each couple (four fathers and three mothers) was found to carry a pericentric inversion of a chromosome 8 [inv(8)(p23q22)]. The propositi had an unbalanced recombinant chromosome [rec(8),dup q,inv(8)(p23q22)]. The affected infants all had developmental delay, congenital heart disease, and unusual appearance. A common origin of the pericentric inversion was suggested because of geographic location and Mexican--American ancestry of the seven families.
Thirty reports of partial 4p trisomy have been published. The manifestations and cytogenetic findings in four additional cases from two families are described in the present paper. Segregation analysis has been performed on the 21 families reported to date. The risk of having unbalanced offspring was the same in carrier mothers and carrier fathers. The risk of trisomic offspring was 14%. Among phenotypically normal progeny, normal karyotypes and balanced translocation states occurred with about equal frequency.
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The triad of aniridia, ambiguous genitalia, and mental retardation (AGR triad) is the characteristic clinical feature of three unrelated patients with previously unreported chromosome 11 short arm interstitial deletions. A Wilms' tumor in one patient establishes one cause for the aniridia-Wilms' tumor association. The genetic heterogeneity of aniridia, the AGR triad, and Wilms' tumor are demonstrated, and Wilms' tumor is indicated to be a neoplastic birth defect which can result from a variety of embryologic insults, some of which may be chromosomal or heritable.
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