Clinical experience in the evaluation of 30 patients with a prior diagnosis of FG syndrome.

BACKGROUND: FG syndrome (FGS) is an X-linked disorder characterised by mental retardation, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome by Opitz and Kaveggia in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families, including the original family described by Opitz and Kaveggia. The phenotype was highly consistent in all the R961W positive patients. METHODS: In order to determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. RESULTS: The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. CONCLUSION: This report illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.

Escape of the yolk sac: a hypothesis to explain the embryogenesis of gastroschisis.

Gastroschisis is a significant birth defect that in many countries has shown an increased prevalence in recent decades, and the change has affected primarily younger mothers. Despite numerous epidemiological studies no other consistent associated risk factor has been identified. In this paper we review the five main theories related to the pathogenesis of this malformation and outline the reasons why we think none fully explains the embryogenesis of gastroschisis. We briefly present some clinical observations we have made that we consider germane to the pathogenesis and outline a hypothesis that we think can account for the origins of this malformation. Our proposal is that the determining defect in gastroschisis is failure of the yolk sac and related vitelline structures to be incorporated into the umbilical stalk. Otherwise, ventral closure of the lateral abdominal walls occurs normally, thus orphaning the vitelline duct and yolk sac outside both the main body stalk and the abdominal wall. Thus, in addition to the umbilicus, the abdominal wall has a separate perforation through which the midpoint of the gut is attached to the exteriorized vitelline structures. This connection through the ventral wall prevents normal egress of the gut into the umbilical cord during the second month of development and acts as the egress point for the gut resulting in gastroschisis.

Reduction in size of the myotonic dystrophy trinucleotide repeat mutation during transmission.

Myotonic dystrophy (DM) is an autosomal-dominant disorder that affects 1 in 8000 individuals. Amplification of an unstable trinucleotide CTG repeat, located within the 3' untranslated region of a gene, correlates with a more severe DM phenotype. In three cases, the number of CTG repeats was reduced during the transmission of the DM allele; in one of these cases, the number was reduced to within the normal range and correlated at least with a delay in the onset of clinical signs of DM. Haplotype data of six polymorphic markers in the DM gene region indicate that, in this latter case, two stretches of the affected chromosome had been exchanged with that region of the wild-type chromosome.

Genetic services for hereditary breast/ovarian and colorectal cancers - physicians' awareness, use and satisfaction.

OBJECTIVES: In 2000, the Ministry of Health in Ontario, Canada, introduced a publicly funded program to provide genetic services for hereditary breast/ovarian and colorectal cancers. We surveyed physicians to determine their awareness, use and satisfaction with this program. METHODS: A self-administered questionnaire was mailed to a random sample of 25% of Ontario family physicians and all gynecologists, oncologists (radiation, surgical and medical), gastroenterologists and general surgeons. RESULTS: Response rate was 49% (n = 1,427). Awareness of genetic testing for breast/ovarian cancer was high (91%) but less for colorectal cancer (60%). Use of services was associated with physician age of 40 or greater, urban location, confidence in knowledge of referral criteria and core competencies in genetics, and awareness of the program and where to refer. Almost half were dissatisfied with notification about the program. CONCLUSIONS: Ontario physicians are aware of cancer genetics services, and use is associated with increased knowledge of services, and confidence in skills. They would like more timely services and education about hereditary cancers and susceptibility testing.

A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve.

OBJECTIVES: This study sought to determine the rate of familial occurrence of congenital bicuspid aortic valve (BAV) by using echocardiography to screen family members. BACKGROUND: Congenital BAV is a common anomaly that carries with it a significant risk of potential long-term cardiac complications. Despite several reports of the familial occurrence of BAV, the condition is not generally considered to be inherited. METHODS: Thirty consecutive patients with echocardiographically documented congenital BAV were interviewed to construct three-generation family pedigrees. All first-degree relatives were contacted to undergo echocardiography to specifically determine aortic valve morphology. RESULTS: Of the 210 first-degree relatives, 190 (90.5%) agreed to undergo echocardiography. Four members had technically difficult studies. Of the remaining 186 subjects, 17 (9.1%) were identified as having BAV; 11 (36.7%) of the 30 families had at least one additional member with the condition. The male/female ratio of affected members in the 11 families was 1. In one family, two instances of male-to-male transmission were observed. The distribution of BAV in the majority of multiplex families is compatible with autosomal dominant inheritance with reduced penetrance. CONCLUSIONS: We demonstrated a high incidence of familial clustering in congenital BAV. We believe that the high rate of occurrence of the condition in immediate relatives justifies echocardiographic screening of first-degree relatives to anticipate and prevent future complications associated with this common cardiac malformation.

Outcome of the routine assessment of patients with mental retardation in a genetics clinic.

This study reviewed hospital and genetics clinic records of 411 patients evaluated in our department from 1986 to 1997 inclusive. Major objectives were to establish how often and under what circumstances a specific genetic/syndrome diagnosis was made and to determine the value of laboratory tests in the hope of gaining a more selective approach to referral, evaluation, and use of the laboratory. A specific genetic/syndrome diagnosis was made in 19.9% of cases, and in a further 4.4% the referring diagnosis was eliminated but no new diagnosis made. There was a significant excess of affected males (277:134) and of affected male sib pairs over expectation, suggesting an additional, potentially important, contribution from nonspecific X-linked mental retardation (MR). Factors associated with making a diagnosis included referral from a pediatrician or neurologist, absence of cerebral palsy, presence of more than three minor anomalies and/or an unusual appearance, a recognizable Gestalt or key anomaly. There was a linear relationship between the likelihood of making a diagnosis and the number of minor anomalies. Factors not associated with making a diagnosis included the year when the patient was seen, degree of MR, number of prior specialists seen, presence of a major malformation, occurrence of seizures, and a head circumference either <3rd or >97th centile. Although chromosome studies were somewhat less likely to be ordered in patients with less severe MR, the positive rate was unaffected by the severity of the MR. The rate of abnormal results was positively correlated with the presence of minor anomalies and/or an unusual appearance. None of 134 studies carried out on patients with 60% when ordered by a clinical geneticist compared with 0% when ordered by other physicians. Results showed that use of the laboratory was inconsistent and not clearly based on the findings in a particular child. Significant changes in patterns of referral and the evaluation process could be made that would result in significant economies of time and laboratory use and a minimum level of missed diagnoses.

Neural tube defects in Eastern Ontario and Western Quebec: demography and family data.

This paper reports the results of a study of families in the Eastern Ontario/Western Quebec region who had a child born with a neural tube defect during the years 1969-1981. As in several other geographic areas, the prevalence of neural tube defects at birth has fallen from previous levels. However, there was no evidence of further decline during the period of study. Socioeconomic and ethnic influences were noted, but there was no evidence of seasonal variation or any correlation with maternal age or parity. There was support for a causative role of maternal fever in some cases. The rates of miscarriage varied between pregnancies before and those after the proband, and there was an excess of males born prior to the proband. Family studies showed a 2.4% risk for sibs born after the proband and an excess of affected relatives on the maternal side. Knowledge of rates of occurrence in relatives is useful for counseling and the interpretation of the results of alpha-fetoprotein screening.

Some psychosocial aspects of nonlethal chondrodysplasias: II. Depression and anxiety.

Individuals with chondrodysplasias may have disproportionate short stature and in some cases a distinctive facial appearance. These physical signs have the potential of affecting parent-child interactions and those of the dwarfed person with broader society. Depression and anxiety are two psychological symptoms with potential for a major impact on a person's functioning within society. In this study depression and anxiety were assessed using the Beck Depression Inventories and the Spielberger State-Trait Anxiety Inventories. While in general depression did not appear more likely in dwarfs than in the general population, comparison of adult patients with their unaffected sibs did raise some concern. Also, having an unaffected parent or spouse appeared to be associated with higher depression scores. Adult trait anxiety levels appeared higher, especially among women, than normally expected in the general population and when compared with their unaffected sibs.

Some psychosocial aspects of nonlethal chondrodysplasias: I. Assessment using a Life-Styles Questionnaire.

Studies concerning the psychosocial aspects of skeletal dysplasias that cause disproportionate short stature have been few and have usually involved small numbers of patients. As part of a study involving patients with chondrodysplasias and their families, an assessment battery of standardised instruments designed to measure depression, anxiety, self-esteem, personal support networks, marital adjustment, and family structure were completed by patients and, in many cases, their sibs, spouses, and/or parents. This first in a series of six papers reports the results of a Life-Styles Questionnaire which provides some insights into the levels of satisfaction with various aspects of life, including friendships, employment, the use of some substances and services, and the impact of the skeletal dysplasia on career, marriage, and childbearing. Results are presented for patients and the unaffected parents of patients. Overall, the study has shown a high level of satisfaction with many aspects of life. However, there are important differences in attitudes between the married and unmarried patients, and in some cases the unaffected parents, in a number of areas including health, overall satisfaction with life, and concerns surrounding child bearing and employment.

Some psychosocial aspects of nonlethal chondrodysplasias: III. Self-esteem in children and adults.

Self-esteem is considered one of the most important personality attributes. It correlates with physical and mental health and the ability to cope with stress. The attitudes of others, and the experiences of interacting with them, are considered as playing a major role in the development of self-esteem. Thus, those patients with disproportionate short stature due to a chondrodysplasia can reasonably be considered to be at risk of developing low self-esteem. In this study, self-concept and self-esteem were measured in 159 children and adults with various chondrodysplasias and disproportionate short stature. The results from the children did not suggest that they had a lower concept of self than did their unaffected sibs or a sample of average-size persons. By contrast, although the adults did not differ significantly from a population sample, they scored significantly below their unaffected sibs. There also appeared to be a trend to lower scores among women, patients who had had an unaffected parent, and those who were married to an unaffected spouse, although none of those differences were statistically significant.

Some psychosocial aspects of nonlethal chondrodysplasias: IV. Dyadic scale of marital adjustment.

This article examines marital adjustment of couples who have had a child with dwarfism due to a skeletal dysplasia, and of couples where one or both members are dwarfs. The instrument used was the Dyadic Adjustment Scale developed by Spanier [1976: Marriage Family 38:15-38]. The reasons for examining this psychosocial aspect of dwarfism were that the birth of a dwarfed child to average-size parents might be expected to cause stress in the relationship, and because several authors had raised concerns about the nature and/or quality of marriages involving dwarfs. This study provides evidence of a decrease in the level of marital adjustment for the average-size parents of affected children, gives tentative reassurance about marriages where both individuals are dwarfs, but raises some concerns about couples where only one member is a dwarf.

Some psychosocial aspects of nonlethal chondrodysplasias: V. Assessment of personal social support using the Personal Resource Questionnaire.

Social support has been shown to be an important influence on how an individual copes with a number of stresses, including acute and chronic illness, psychiatric morbidity, and life events. It can be thought of as a dynamic process consisting of a network of persons who are available to provide support, and the level of support that is perceived to be available from those persons. Patients with disproportionate short stature due to a chondrodysplasia might be expected to face greater challenges in developing a social support network. This study assessed social support among a group of dwarfed patients using the Personal Resource Questionnaire (PRQ85). The overall extent and functioning of social support appears comparable to that in the general population, but there are some differences when unmarried patients are compared with married patients and when those who have affected spouses are compared with those whose spouses are of average stature.

Some psychosocial aspects of nonlethal chondrodysplasias: VI. Assessment of family interaction using the FACES II Questionnaire.

Intrafamilial dynamics, including those between parents, and between parents and their children, have an important influence on the ultimate success or failure of a child's becoming a well adapted and socially integrated individual. Disability and/or birth defects, such as dwarfism, may alter family functioning, either because of the psychological impact or the day-to-day functional demands or both. Family cohesiveness and adaptability and communication have been identified as key variables that define how a family interacts. The Circumplex Model of Family Systems defines the role of these factors in the family dynamic and the FACES II scale provides a standardised assessment of their level of function within the family. Thus families can be classified by their degree of cohesion, adaptability, and the combination of the two. This article reports on the results of the FACES II assessment that was completed by 107 patients with disproportionate short stature due to a chondrodysplasia, as well as by a variable number of their parents, sibs, or spouses.

Craniofacial anthropometric analysis in several types of chondrodysplasia.

Craniofacial anthropometric analysis is a generally accessible technique that potentially offers an objective tool to reduce the subjectivity of syndrome diagnosis and to aid in differential diagnosis. The chondrodysplasias might seem an unlikely target for this technique in that they mainly cause disproportionate growth and are subject to radiographic diagnoses. However, the diagnosis of skeletal dysplasias remains challenged by subjectivity of radiologic assessment, and specific radiologic signs may appear only with age or may no longer be present at the time of examination. Thus patients continue to defy diagnosis, have their diagnosis changed, and/or be misdiagnosed, even in specialized centers. Certain chondrodysplasias have obvious craniofacial involvement while others appear to share a specific gestalt. This paper reports craniofacial anthropometric analysis for several of the more common chondrodysplasias and confirms that some do display a characteristic pattern that is in keeping with what might be expected. Furthermore, the concurrent assessment of several different conditions by a single observer has emphasized the importance of considering the possibility of systematic measurement error in any such studies.

Mental retardation and osteosclerosis.

We report a girl with profound mental retardation who, at 3 years of age, began to show a progressive osteosclerosis on bone roentgenograms. The bony changes were slightly suggestive of osteopetrosis from which they differed by a number of unusual features.

Follow-up study of patients with Wiedemann-Beckwith syndrome with emphasis on the change in facial appearance over time.

We have carried out a follow-up study of 13 children with Wiedemann-Beckwith syndrome (WBS) using a standard protocol which included facial anthropometric measurements. We confirm that most patients with WBS do well and that their clinical abnormalities become less apparent with age. We suggest that there is a characteristic neonatal appearance in WBS and that the expected pattern of facial growth generally results in a normal appearance by mid- to late childhood. We tentatively propose that there is a distinct facial anthropometric pattern profile in WBS.

Implications of malformations not due to amniotic bands in the amniotic band sequence.

It is widely accepted that the primary event in the amniotic band sequence (ABS) is early rupture of the amnion, and that the development of the fetus is then disrupted by entanglement and abrasion. The mechanism of the initial rupture is unknown. An argument raised in favor of this theory has been the apparent absence of non-band-derived malformations in the ABS. Here we report on four infants with ABS and additional malformations that are not readily explainable on the basis of band disruptions. These infants, together with some additional observations in the literature, and a growing number of reports of familial ABS, raise the question as to whether the formation of bands and other "non-disruption" abnormalities may have a common primary etiology in some cases. The primary mechanism could operate through disturbing the vascular system, and the factors involved might be both extrinsic or intrinsic, and some instances might date to an abnormality of the germ disk.

Familial renal-hepatic-pancreatic dysplasia and Dandy-Walker cyst: a distinct syndrome?

Ivemark et al. first described sibs with renal-hepatic-pancreatic dysplasia (RHPD) (Ivemark BI, Oldfelt V, Zetterström R (1959): Acta Pediatr Scand 48: 1-11). Subsequent reports of affected individuals have described additional malformations and syndromes associated with RHPD. In this paper we describe 2 sibs with RHPD in association with Dandy-Walker cyst (DW). Through an examination of the pattern of associated malformations seen in RHPD we argue that RHPD-DW is a distinct monogenetic syndrome, and not an association.

Characteristic craniofacial appearance and brachytelephalangy in a mother and son with Kallman syndrome in the son.

We report on a mother and son with a similar facies characterized by a square forehead, small nose, telecanthus, and thin upper lip. They both had a similar metacarpal-phalangeal profile characterized by marked brachytelephalangy. They were both short in comparison to other family members, and the son had hypogonadotropic-hypogonadism and anosmia. We favor the hypothesis of a single autosomal dominant gene with variable expression of the hypogonadism and anosmia, although there are alternative explanations for the combination.

Ethical, legal, and practical concerns about recontacting patients to inform them of new information: the case in medical genetics.

There is a consensus among medical geneticists that it is desirable to recontact patients as new information becomes available. Furthermore, some have suggested that there are legal arguments to support an obligation, creating a duty to recontact. Thus far much of the discussion among medical geneticists has focused on the practical concerns of implementing such a policy. However, we think that any such policy raises a number of important ethical concerns that must first be considered. Furthermore, there has not been a careful evaluation of the legal precedents that may reflect on a hypothetical duty to recontact. In this paper we first present an analysis of the scope of approaches and issues to be addressed in the development of ethical policy on this question. Secondly, we examine whether there is a legal obligation to recontact former patients about advances in genetics, as well as the legal implications if such a policy were to be adopted. Finally, we consider some of the functional and resource implications of adopting a policy of recontact. Our goal is to provide a framework for further discussion of this question and to stimulate further debate and research.