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Studies from the last decade on factors influencing reproductive planning after genetic counselling were reviewed. Increased possibilities of DNA-analysis and prenatal diagnosis might have brought about a shift in the paramountcy of factors influencing reproductive planning after genetic counselling. In contrast to the literature in the seventies, the magnitude of the genetic risk was no longer found to be one of the decisive factors in postcounselling reproductive planning. Instead, the interpretation of the risk as high or low and the desire to have children appeared to be paramount. The impact of new developments in DNA-analysis in prenatal diagnosis and presymptomatic testing will be an important subject for future studies on factors influencing reproductive planning.

To investigate the factors influencing whether or not couples seek genetic counselling, the parents of 37 children with a major congenital anomaly were interviewed at home. All the children had been admitted to the Intensive Care Unit (ICU) of the Department of Paediatric Surgery. After physical examination of the child, the consultant clinical geneticist stated that genetic counselling was indicated for the parents. Whether they sought genetic counselling was left to the parents to decide. Eighteen of the 37 parents had sought genetic counselling. Assessment of the joint influence of a number of factors revealed that two factors were separately paramount in distinguishing between couples who did seek genetic counselling and those who did not: whether parents considered genetic counselling useful in their case shortly after the birth of their affected child, and whether the couple was clearly and correctly informed about the indication for genetic counselling. The intention to have a subsequent pregnancy was not associated with whether or not couples sought genetic counselling. Loss of information was observed: 1/3 of the referrals for genetic counselling mentioned on the written consultation forms were not stated in the discharge letters. This loss of information could have been reduced by a) routinely including the indication for genetic counselling in the discharge letter and b) appointing a coordinating physician to ensure that the parents were informed clearly about the availability of genetic counselling. Resistance to genetic counselling needs to be respected by the physician. Exploring its background might help to reduce this resistance.

A three-generation family with autosomal dominant segregation of a novel NSD1 mutation (6605G --> A, resulting in Cys2202Tyr) is reported. Haploinsufficiency of NSD1 has been identified as the major cause of Sotos syndrome. The overgrowth condition (MIM 117550) is characterized by facial anomalies, macrocephaly, advanced bone age, and learning disabilities. Manifestations in the present family include dramatically increased height, weight, and head circumference together with a long face, large mandible, and large ears, but mental deficiency was absent.

OBJECTIVES: To determine the effectiveness of early fetal anomaly scanning in a population at risk of fetal anomalies. DESIGN: A prospective study in a tertiary center of 101 consecutive fetuses at risk of congenital anomalies at 11-14 weeks of gestation. RESULTS: The principal (93/101 = 92%) reason for referral was having a previously affected infant. Nine (9/101 = 9%) fetuses were shown to have structural anomalies at the 11-14-week scan. In five of nine structurally affected fetuses, the nature of the anomalies was similar to that established in a previously affected pregnancy, four of which had a recurrence of an autosomal recessive syndrome. In two fetuses with a normal 11-14-week scan, anomalies were detected at the 18-21-week (arthrogryposis) or 30-week (cardiomyopathy) scans. CONCLUSIONS: The majority of fetal anomalies can be diagnosed in the late first/early second trimesters of pregnancy. This will be of particular advantage to those women who are at high risk of having affected offspring. However, as fetal anomalies may present at varying gestational ages, the standard 18-21-week scan cannot be abandoned. The effectiveness of the early pregnancy scan depends on the natural history of anomalies (gestational age at onset) and the variable phenotypic expression of anomalies/syndromes.

Jeune syndrome or asphyxiating thoracic dysplasia is an autosomal recessive osteochondrodysplasia. It is one of the six short-rib (polydactyly) syndromes. The disease has a wide spectrum of manifestations, ranging from a latent to a mild or lethal condition. We describe the prenatal sonographic diagnosis of Jeune syndrome at 14 weeks of gestation in a fetus at risk for this condition, and the development of the syndrome throughout the pregnancy.

Mucopolysaccharidosis type VII was diagnosed prenatally during the first pregnancy of a Turkish consanguineous couple, following diagnostic work-up of an increased nuchal translucency detected by ultrasound at 13 weeks of gestation. Mucopolysaccharidosis type VII (MPS VII) or Sly syndrome is a rare autosomal recessive lysosomal storage disease, caused by the deficiency of the enzyme β-glucuronidase. The most severe form of MPS VII manifests itself by non-immune fetal hydrops. Tests for the diagnosis of metabolic disorders, especially lysosomal diseases, are essential when the major causes of hydrops fetalis have been excluded. The presence of a β-glucosidase deficiency, Gaucher's disease, in the infant of the patient's sister emphasizes the importance of a complete family history in consanguineous couples and the risk for several recessive diseases in some families.

Objective The aim of this study was to analyze fetuses with prenatally diagnosed microcephaly including the nature of associated anomalies and the genetic-diagnostic implications. Design Retrospective study design. Methods A total of 30 fetuses with reliable dates and with prenatally diagnosed microcephaly as a common feature were analyzed. Results Microcephaly was diagnosed at a mean gestational age of 28 weeks. More than half of the fetuses were also small for gestational age. Five subsets of microcephaly emerged from this study: (1) isolated microcephaly (16.7%); (2) microcephaly due to holoprosencephaly (16.7%); (3) microcephaly associated with chromosomal disorders (23.3%); (4) microcephaly as part of a genetic syndrome (20.0%); and (5) microcephaly as part of multiple anomalies (23.3%). Conclusions In 25 out of 30 infants microcephaly proved to be part of a complex problem, emphasizing the need of a meticulous search for structural anomalies and fetal karyotyping when biometric data are not according to gestational age. The etiologic heterogeneity and variability of microcephaly in genetic syndromes are among the more difficult issues in prenatal ultrasound in pregnancies either with an incidental finding of this anomaly, or in cases with a recurrence risk. The complex situations described in this study demonstrate the importance of follow up, post-mortem investigation and careful genetic counseling. Copyright © 2000 International Society of Ultrasound in Obstetrics and Gynecology

Several mutations in the tau gene have been found in families with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17). This study is the first attempt to correlate genotype and phenotype in six families with FTDP-17 with mutations in the tau gene (DK280, G272V, P301L, and R406W). We have investigated tau pathology in 1 P301L and 1 R406W patient. The R406W family showed a significantly higher age at onset (59.2 6 5.5 years) and longer duration of illness (12.7 6 1.5 years) than the families with the other mutations. The six families showed considerable variation in clinical presentation, but none of them had early parkinsonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W family was less severe than in the P301L and DK280 families. The P301L brain contained many pretangles in the frontal and temporal cortex, and the dentate gyrus of hippocampus, showing three tau bands (64, 68, and 72 kd) of extracted tau from the frontal cortex. The presence of many neurofibrillary tangles, many diffuse and classic neuritic plaques in the temporal and parietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl-insoluble (60, 64, 68, and 72 kd) tau bands. The coexistence of characteristic P301L and Alzheimer pathology in the same brain needs further explanation. The R406W brain showed abundant neurofibrillary tangles in several brain regions, and four tau bands (60, 64, 68, and 72 kd) of extracted tau from these regions. The slower progression of the disease in the R406W family might be explained by the microtubule-binding properties of the mutant protein.

Blomstrand chondrodysplasia is a rare lethal skeletal dysplasia with presumed autosomal-recessive inheritance. A family with 2 affected fetuses was studied. One fetus demonstrated a severe skeletal dysplasia at routine transabdominal ultrasound examination at 18.5 weeks of gestation. The pregnancy was terminated and the diagnosis of Blomstrand chondrodysplasia was made at autopsy. A second affected fetus was identified by first-trimester transvaginal ultrasound at 12 weeks of gestation. In this case the diagnosis was confirmed by posttermination radiography and histopathology. From these observations, Blomstrand chondrodysplasia seems like a lethal rhizo/mesomelic short-limb, early-onset dysplasia with autosomal-recessive inheritance. Easy detectability by transvaginal ultrasound is demonstrated, but general applicability awaits further studies on the intra- and interfamilial variability of this disorder. Am. J. Med. Genet. 73:345–350, 1997. © 1997 Wiley-Liss, Inc.

The attitudes of 1020 Dutch GP's towards presymptomatic and prenatal testing for Huntington disease (HD) were studied by means of a postal questionnaire. The questionnaire contained questions about: approval of presymptomatic DNA-testing, informing individuals at-risk who do not request predictive testing, referral to a clinical genetics center, and opinions about different strategies of informing and supporting individuals at-risk. The response rate was 62%. More than two-thirds of the GP's considered post-test counselling and support as their responsibility. Twenty-six per cent were of the opinion that the test results should be disclosed by the GP. Fifty-nine per cent of GP's who had an individual at-risk in their practice were familiar with the test. The attitudes of GP's towards giving support and giving test results were independent of familiarity with the test and the incidence of HD-patients or at-risk individuals in the practice. Although GP's were willing to play an important role in presymptomatic DNA-testing procedures, there is a risk that they might underestimate the difficulties in communicating genetic information and the psychosocial effects of DNA-testing. Hence, we favor the premise that extensive pretest counselling and test disclosure should remain the prime responsibility of the clinical geneticist. Increasing involvement of GP's should, however, be encouraged and combined with appropriate postgraduate education about predictive DNA-testing in general.

Presymptomatic DNA-testing for Huntington's disease has made it possible to predict whether or not at-risk individuals are gene-carriers with a reliability of about 98%. In our retrospective study of 18 tested individuals, most of the newly identified carriers function apparently well. They use avoidance and repression of affect as psychological defense strategies. However, 8 out of 9 non-carriers do not experience the expected relief about their test results. They experience survivor guilt and emotional numbness and find it difficult to cope with the effects of the test results on the family system. The partners of gene-carriers are at risk of becoming emotionally isolated by putting aside their own feelings for fear of seeming self-centered. Appreciation of these effects on tested individuals is important and professional support is needed to prevent post-traumatic stress disorders. Whatever the test result may be, the working through process may take years rather than months. These findings have important implications for patient care and necessitate an extended period of observation after presymptomatic testing. © 1992 Wiley-Liss, Inc.

textabstractAt 20 weeks of gestation, a typical combination of a massive enlargement of the right fetal leg and multiple cystic lesions was detected at ultrasound examination. Color‐coded Doppler examination revealed no arteriovenous fistulae. These findings allowed an in utero diagnosis of the Klippel‐Trenaunay‐Weber syndrome, which was confirmed after subsequent termination of the pregnancy. The severe malformation involved the upper and lower right leg. No arteriovenous fistulae were found. Copyright

The intragenic (FMR-1) probe pE5.1 was used for DNA analysis in fragile X families. With this probe fragments of altered size can be detected in female carriers, affected individuals and transmitting males. The length of the altered fragments was found to vary from one generation to another as well as between sibs. This instability of the DNA detected by pE5.1 was also seen in peripheral blood within single individuals. These phenomena are illustrated by 4 exemplary families segregating the fragile X syndrome. We demonstrate the diagnostic contribution of intragenic analysis to carrier detection as well as the identification of normal transmitting males carrying premutations. One of the families illustrates the passage of a premutation to a male through 2 generations.

An in-depth, recorded interview of 30 couples 2-3 years after genetic counseling explored the characteristics of the postcounseling decision-making process, including the role of guilt feelings towards the proband. The study concerned couples with an affected child, sib, or spouse. Results were evaluated by 2 to 4 judges. In contrast to other studies, a generally unstructured decision-making process was found whereby guilt feelings played a significant role in more than half the couples. Guilt feelings were more predominant in couples with an affected sib than in those with an affected spouse. Lack of structure did not seem to complicate the decision-making process. Therefore, authors do not advocate promotion of structuring the decision-making process. Genetic counselors might focus on understanding counselees' feelings concerning the reproductive decision. Acceptance of apparently irrational considerations is particularly important, because these feelings indicate the influence of unconscious motives. Another important aspect of supporting counselees is to understand the role played by guilt feelings toward parents or an affected sib.

To assess the identifiability of reproductive planning after genetic counseling, a model was designed to study 8 relevant factors influencing reproductive decisions after genetic counseling. Altogether, 164 couples were interviewed at home 2 to 3 years after genetic counseling. The factors were arranged in a flow chart distinguishing 3 groups: reproductive outcome prior to genetic counseling, desire to have children, and interpretation of information gained from genetic counseling. The model based upon these retrospective data showed that reproductive decisions were identified correctly in 91% of the cases. The model consisted of 8 factors and documented the urgency of the desire to have children and the interpretation of the genetic risk. In addition, linear discriminant analysis of the 8 relevant factors enabled identification of the reproductive decision in 96% of the cases. This model may prove helpful to counselors and counselees by showing what other couples have decided in comparable circumstances and for which reasons.

Here we report a follow-up study involving interviews with 164 couples 2-3 years after genetic counseling to assess the influence of various factors on their reproductive planning. The results show that the desire to have children and the absence of personal experience with the disorder (no close relative being affected) are important single factors for the decision to opt for having children after genetic counseling. The magnitude of the genetic risk is of relative importance in reproductive planning. Seventy percent of the couples with a high genetic risk (greater than 15%) opted for having children. When the disorder was perceived as severe and the risk was interpreted as high, 72% opted for having children. The availability of prenatal diagnosis became important only in combination with a high genetic risk (greater than 15%). Forty-seven percent of the couples with a high genetic risk refrained from having children when prenatal diagnosis was not available. In the absence of prenatal diagnosis, couples who had an affected child were more cautious about trying again than those who did not--50% versus 14% decided to abstain. This study has provided some insight into the complexity of reproductive decision-making after genetic counseling. The findings may help genetic counselors and clinical geneticists understand and support counselees in their decision-making process, which is "multi-factorial."

Brachydactyly can occur as an isolated malformation or as part of numerous syndromes. Prenatal assessment of brachydactyly may be especially helpful in multiple anomaly syndromes associated with hand and/or finger anomalies. In isolated type A1 brachydactyly, which is an autosomal dominant disorder, all middle phalanges of the fingers and toes are affected. We present a fetus with type A1 brachydactyly inherited from the mother and grandmother.

The original article to which this Erratum refers was published in American Journal of Medical Genetics (2002) 111(4) 443–445.

Prenatal monitoring of three pregnancies at risk of Morquio's disease type A by determination of N-acetylgalactosamine 6-sulphate sulphatase activity in cultured amniotic cells is reported. In one pregnancy prenatal diagnosis of one affected fetus was made. Enzyme determinations in tissues of the aborted fetus confirmed the prenatal diagnosis.