Trisomy 20 mosaicism in two unrelated girls with skin hypopigmentation and normal intellectual development.

The prenatal diagnosis of trisomy 20 mosaicism presents a challenge for practitioners and parents. The diagnosis implies an uncertain risk for an inconsistent set of physical and developmental findings, as well as a substantial chance for a child that is normal physically and developmentally. We report two girls (ages nine years one month and eight years one month) with normal intelligence and hypopigmented skin areas. Both girls were born after a prenatal diagnosis of trisomy 20 mosaicism in amniocytes. Case 1 had 83% and 57% trisomy 20 cells from two separate amniocenteses and Case 2 had 90% trisomy 20 cells from an amniocentesis. Trisomy 20 was confirmed after birth in urinary sediment (25%) and chorionic villus cells (15%) in Case 1, while cord blood lymphocytes (30 cells) and skin fibroblasts (50 cells) had only 46,XX cells. Trisomy 20 was confirmed after birth in urinary sediment (100%), placenta (100%), cord (10%), amniotic membrane (50%), and skin fibroblasts (30%) in Case 2, while cord blood lymphocytes (100 cells) had only 46,XX cells. This is the first report of a hypopigmented pigmentary dysplasia associated with isolated trisomy 20 mosaicism. Our patients are the oldest reported children with trisomy 20 mosaicism confirmed after birth.

Attitudes toward the genetic testing of children among adults in a Utah-based kindred tested for a BRCA1 mutation.

Advances in molecular biology and genetics have led to the identification of the breast/ovarian cancer susceptibility genes BRCA1 and BRCA2, along with tests to detect mutations in these genes. Although the appropriateness of BRCA1/2 genetic testing for children has been debated in the literature, little is known about the attitudes of individuals who have undergone cancer susceptibility testing. The present study focused on attitudes toward BRCA1 testing for children among 218 adults from a Utah-based kindred who had received BRCA1 test results. Results indicated that approximately one-fourth of the participants would permit BRCA1 testing for children under the age of 18. General attitudes about genetic testing were predictive of attitudes toward the testing of children. In addition, men and individuals without a BRCA1 mutation were more likely to agree that minors should be allowed BRCA1 testing. Individuals whose mother had been affected with breast cancer were less likely to permit testing for minors. Among parents of minor children, less than one-fifth indicated that they would want BRCA1 testing for their own children; carrier status was not predictive of attitudes toward testing their own children. As breast/ovarian cancer susceptibility testing continues to be disseminated into clinical settings, there may be an increase in the number of test requests for minors. The findings of the present study represent an important step in exploring attitudes about genetic testing of children among individuals who have received cancer susceptibility test results.

Psychological responses to BRCA1 mutation testing: preliminary findings.

The short-term psychological responses of 60 adult women tested for a BRCA1 gene mutation associated with a high risk of breast and ovarian cancer were investigated. Participants were members of a large kindred enrolled in an ongoing prospective study of the psychosocial impact of genetic testing. Initial results from participants who completed both the pretest baseline and the 1-2 week posttest follow-up interviews are reported. Gene mutation carriers manifested significantly higher levels of test-related psychological distress, as measured by the Impact of Event Scale, when compared with noncarriers. The highest levels of test-related distress were observed among mutation carriers with no history of cancer or cancer-related surgery. Although general distress (state anxiety) declined after testing, carriers were more distressed than noncarriers at follow-up.

BRCA1 Testing: Genetic Counseling Protocol Development and Counseling Issues.

This article discusses the genetic counseling protocols which were developed and counseling issues that have arisen in the first 2 years of evaluating a large kindred with a BRCA1 mutation. The rationale for the development of the genetic counseling protocols and specific genetic counseling visual aids are presented and discussed. The protocols and counseling aids can serve as models for other programs offering cancer susceptibility testing. The observations of study counselors about study subject concerns and responses to genetic testing at the time of the pretest and posttest counseling sessions are presented.

Folic acid and the prevention of neural tube defects: A position paper of the national society of genetic counselors.

Considerable scientific evidence demonstrates the reduction in risk for neural tube defects (NTDs) associated with maternal preconceptional folic acid supplementation. The National Society of Genetic Counselors (NSGC) endorses the U.S. Public Health Service recommendations for folic acid supplementation at the 0.4 mg level for women in the general population and at the 4.0 mg level for women at high or increased risk for NTD pregnancies for at least 4 weeks prior to active pursuit of conception. We encourage targeted educational efforts and surveillance to assess results of this dietary supplementation. The NSGC further urges the Food and Drug Administration to fortify staple foodstuffs with folic acid for a population-based approach to minimize the number of NTD births.

Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk.

The natural history of trisomy 18 and trisomy 13 was investigated using data derived from parent questionnaires and medical records from 98 families with an index case of trisomy 18 and 32 families with an index case of trisomy 13. Data are presented on pregnancy, delivery, survival, medical complications, immunizations, growth, cause of death, cytogenetics, and recurrence risk. Half of the trisomy 18 babies were delivered by C-section. Fetal distress was a factor in half, and the only reason in a third of C-section deliveries. One minute Apgar scores were significantly lower in C-section and breech deliveries. There were more small for gestational age babies than in the general population, but most of the low birth weight newborns were small for gestational age, unlike the general population. Survival in this group of children was better than in other studies due to ascertainment bias. There were more girls than boys at all ages for both conditions, and the sex ratio decreased with time. Growth curves for length, weight, head circumference, and weight vs height are provided. Long-term survival did not appear to be due to mosaicism. We found no adverse reactions attributable to immunizations. At age 1 year there was an average of approximately 2 operations per living child. We report the second case of successful major cardiac surgery in a trisomy 18 child. Almost 70% of deaths were attributed to cardiopulmonary arrest. The sibling recurrence risk for trisomy 18 or trisomy 13 was 0.55%.

Natural history of trisomy 18 and trisomy 13: II. Psychomotor development.

Developmental data were abstracted from medical records on 50 trisomy 18 individuals ranging in age from 1 to 232 months and 12 trisomy 13 individuals ranging in age from 1 to 130 months. Data on the age when trisomy 18 and trisomy 13 children achieved developmental skills were collected from a larger group of 62 trisomy 18 individuals and 14 trisomy 13 individuals whose families filled out parent questionnaires. Developmental quotient (DQ), defined as developmental age divided by chronological age, averaged 0.18 for trisomy 18 and 0.25 for trisomy 13. There was a dramatic drop in DQ from infancy to later childhood. The highest DQs and the greatest variation in DQs were in the first 2-3 years of life. Developmental ages in 7 skill areas were significantly different, with daily living and receptive language having the highest values and motor and communication skills having the lowest. When chronological age was taken into account, there was no significant difference in DQs in the same 7 skill areas, although there was a trend that was similar to the pattern of differences with developmental age. Older children could use a walker, understand words and phrases, use a few words and/or signs, crawl, follow simple commands, recognize and interact with others, and play independently. Walking and some toileting skills were also reported for trisomy 13. Although individuals with trisomy 18 and trisomy 13 were clearly functioning in the severe to profound developmentally handicapped range, they did achieve some psychomotor maturation and always continued to learn.

Prenatal diagnosis of distal arthrogryposis.

We report the prenatal diagnosis of distal arthrogryposis type I by ultrasound at 18 wk gestation in a family with two other affected members (mother and sister of the fetus). The pregnancy was followed with serial ultrasounds, and the diagnosis was confirmed after birth. The clinical findings in all affected family members are described. A literature survey of prenatally diagnosed cases of multiple joint contractures is presented. These include cases with many different diagnoses. This is the first report of the prenatal diagnosis of distal arthrogryposis type I. It helps to illustrate the variability and prenatal natural history of the condition and the subtlety of the prenatal ultrasound findings.

Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17.

Linkage analysis of 15 Utah kindreds demonstrated that a gene responsible for von Recklinghausen neurofibromatosis (NF) is located near the centromere on chromosome 17. The families also gave no evidence for heterogeneity, indicating that a significant proportion of NF cases are due to mutations at a single locus. Further genetic analysis can now refine this localization and may lead to the eventual identification and cloning of the defective gene responsible for this disorder.

The genetic aspects of neurofibromatosis.

Although the genetic pattern in NF has been definitely established as autosomal dominant, more precise data regarding penetrance, natural history, prevalence, and heterogeneity are needed for the counseling of families. NF is the prototypic disorder for the study of the biologic mechanisms of variable expressivity. The widely cited prevalence figure of Crowe is probably too high; thus the mutation ratio estimation in NF is among the highest in man but close to other common Mendelian disorders. With the existing data on frequency of Lisch nodules and with future prospective date on café-au-lait spot development, an age-of-onset penetrance curve for NF could be constructed for genetic counseling purposes. The segmental form of NF is of interest as cases of this presentation may be helpful in studying the hypothesis of human somatic mutation when DNA analysis is available. Guidelines for routine evaluation and ongoing health supervision of individuals with neurofibromatosis need to be developed; multidisciplinary NF clinics and collaborative study groups are appropriate settings for this undertaking. Neurofibromatosis is an important disorder for the study of the psychodynamic processes that families experience in dealing with uncertainty.

Clinical studies of a large family with Wilson's disease.

We have identified 11 individuals with Wilson's disease, members of five sibships within a larger family which was traced through seven generations. Of 206 other family members evaluated for Wilson's disease, none had abnormally low serum ceruloplasmin or copper levels and none had Wilson's disease. There were two documented instances of consanguinity, associated with two of the five affected sibships and four of the 11 affected individuals. The patterns of occurrence of Wilson's disease within the family is consistent with the hypothesis that the disorder is transmitted as an autosomal recessive characteristic. It is likely that the apparently high frequency of disease within the family can be explained solely by the founder effect.

Analysis of a large pedigree with elliptocytosis, multiple lipomatosis, and biological false-positive serological test for syphilis.

Elliptocytosis, multiple lipomatosis, and biological false-postive serological test for syphilis (BFPSTS) were found in a single individual. One hundred eighty relatives were tested for the three diseases: 74 were typed for seven blood group antigens, and 58 were typed for four electrophoretic enzyme markers. Likelihood analysis of the pedigree data confirmed independent dominant inheritance for elliptocytosis and lipomatosis. BFPSTS appears dominant, but the analysis was inconclusive. No linkages were found between any disease gene and any marker gene. Two female pedigree members with BFPSTS developed systemic lupus erythematosus, a finding in agreement with the previously described association. The analysis did not lead to any conclusions about the causal relationship between the two traits.

Genetic linkage between hereditary hemochromatosis and HLA.

A large Mormon pedigree of a proband with hemochromatosis was studied, using transferrin saturation as the quantitative phenotypic trait. The analysis indicated that the inheritance of hemochromatosis was recessive, with partial expression in some heterozygotes. The lod score of 6.88 (theta = .0) was strongly indicative of linkage between the hemochromatosis locus and the human major histocompatibility (HLA) loci.