Teebi hypertelorism syndrome: additional cases

We report on two unrelated Brazilian boys who have craniofacial and digital anomalies resembling those reported with Teebi hypertelorism syndrome. Additional features such as cleft lip and palate, large uvula, atypical chin and abnormal scapulae were observed.     

Teebi hypertelorism syndrome with Tetralogy of Fallot

A 34-month-old boy presented with clinical manifestations of Teebi hypertelorism syndrome including prominent forehead with frontal bossing, hypertelorism, exophthalmos due to shallow orbits, a short and broad nose with anteverted nares, small hands and feet with interdigital webbing, umbilical hernia, and shawl scrotum. In addition, he had previously undescribed manifestations including tetralogy of Fallot, bilateral inguinal testes, and bifid scrotum. His phenotypically normal mother showed splayed labiae majora during her pregnancy, a possible manifestation of the syndrome. Am. J. Med. Genet. 77:345–347, 1998. © 1998 Wiley-Liss, Inc.     

Reluctance to undergo predictive testing: The case of Huntington Disease

The development of a presymptomatic test for Huntington Disease (HD) has enabled some persons at risk to determine whether or not they are gene carriers. The purpose of this study was to explore the reasons why those at risk choose not to be tested in a situation where testing is available and most of the test-associated costs are covered by state funding. Subjects were also asked their levels of knowledge about testing, attitudes towards aspects of the testing protocols, and intentions towards testing once the gene for HD is found. Sixty-six individuals at risk for HD who had chosen not to be tested completed a mailed questionnaire. The most important reasons for not being tested were increased risk to children if one was found to be a gene carrier, absence of an effective cure, potential loss of health insurance, financial costs of testing, and the inability to “unndo” the knowledge. Individuals comprising this sample were quite knowledgeable about predictive testing. Most supported the availability of testing despite the lack of a cure, the need for special counseling prior to testing, and the idea that testing should be a voluntary decision. Most said they would take the test if a treatment was available, if the mechanics of the test were simplified, or if the test was 100% accurate. The risk to relatives, lack of treatment or cure, fear of losing one's health insurance, and the accuracy of the information to be gained from testing are important factors in the decision not to be tested. © 1993 Wiley-Liss, Inc.     

Atrioventricular block and wiry hair in Teebi hypertelorism syndrome

We report on a 4 1/2-year-old girl with clinical features of Teebi hypertelorism syndrome (THS), including a prominent forehead with a widow's peak, heavy and broad eyebrows, hypertelorism, long palpebral fissures, ptosis, a thin upper lip, a grooved chin, and a left preauricular cyst. She required a pacemaker for third degree atrioventricular (AV) block, a finding that has not been previously reported in 36 other patients with THS and for which we were unable to identify other causes. We have reviewed the previous reports of THS and note a characteristic facial appearance with hypertelorism, heavy, broad, and arched eyebrows, a thin upper lip with a long and deep philtrum, and a prominent forehead. Structural cardiac defects were present in five patients, implying that cardiac investigations are warranted in patients with a cardiac murmur and a clinical diagnosis of THS.     

Teebi hypertelorism syndrome: report of a family with previously unrecognized findings

We present a family consisting of a mother, a daughter, and a son with Teebi hypertelorism syndrome, including some previously unrecognized manifestations. The clinical findings include a prominent forehead, arched eyebrows, pronounced hypertelorism, long philtrum, mild interdigital webbing, fifth-finger clinodactyly, umbilical anomalies, and hypotonia. The mother and daughter also had ptosis requiring surgical correction. The daughter has bilateral iridochorioretinal colobomas with high hyperopia and a small umbilical hernia. The son has less striking facial features but was born with a small omphalocele, large ASD secundum, PDA, bilateral cryptorchidism right hydronephrosis, and a cystic left kidney. The mother had an umbilical hernia requiring surgical correction as a child and a history of heart murmur. Both children have normal hearing and mild developmental delay. Their high-resolution karyotypes were normal and the FISH for 22q11 microdeletion was negative in the daughter. We conclude that cardiac defects in Teebi hypertelorism syndrome are not rare findings and that eye colobomas and renal anomalies were previously unrecognized.     

When access is an issue: exploring barriers to predictive testing for Huntington disease in British Columbia,Canada

Predictive testing (PT) for Huntington disease (HD) requires several in-person appointments. This requirement may be a barrier to testing so that at risk individuals do not realize the potential benefits of PT. To understand the obstacles to PT in terms of the accessibility of services, as well as exploring mechanisms by which this issue may be addressed, we conducted an interview study of individuals at risk for HD throughout British Columbia, Canada. Results reveal that the accessibility of PT can be a barrier for two major reasons: distance and the inflexibility of the testing process. Distance is a structural barrier, and relates to the time and travel required to access PT, the financial and other opportunity costs associated with taking time away from work and family to attend appointments and the stress of navigating urban centers. The inflexibility of the testing process barrier relates to the emotional and psychological accessibility of PT. The results of the interview study reveal that there are access barriers to PT that deter individuals from receiving the support, information and counseling they require. What makes accessibility of PT services important is not just that it may result in differences in quality of life and care, but because these differences may be addressed with creative and adaptable solutions in the delivery of genetic services. The study findings underscore the need for us to rethink and personalize the way we deliver such services to improve access issues to prevent inequities in the health care system.     

Providing predictive testing for Huntington disease via telehealth: results of a pilot study in British Columbia,Canada

Predictive testing (PT) for Huntington disease (HD) usually requires several in‐person appointments which acts as a barrier to testing for those from remote regions. This pilot study reports the use of telehealth PT to examine whether such telehealth testing improves access to HD PT while maintaining quality of care and support. Individuals underwent PT via the telehealth protocol or standard in‐person protocol and were asked to complete surveys regarding their experience. Results reveal no significant differences between the in‐person‐tested and telehealth‐tested groups with respect to quality of care, information, counselling and support. The majority of participants in both groups stated that pre‐test counselling had provided them with sufficient knowledge about the advantages and disadvantages of undergoing testing, the opportunity to ask questions, and the ability to make an informed decision. The majority of participants in both groups were satisfied by the manner in which results were delivered and stated they had received sufficient information regarding the implications of these results. This study reveals that telehealth PT improves access while maintaining quality of care and support.     

Evidence‐based genetic counselling implications for Huntington disease intermediate allele predictive test results

Intermediate alleles (IAs) for Huntington disease (HD) contain 27–35 CAG repeats, a range that falls just below the disease threshold of 36 repeats. While there is no firm evidence that IAs confer the HD phenotype, they are prone to germline CAG repeat instability, particularly repeat expansion when paternally transmitted. Consequently, offspring may inherit a new mutation and develop the disease later in life. Over the last 5 years there has been a renewed interest in IAs. This article provides an overview of the latest research on IAs, including their clinical implications, frequency, haplotype, and likelihood of CAG repeat expansion, as well as patient understanding and current genetic counselling practices. The implications of this growing evidence base for clinical practice are also highlighted. These evidence‐based genetic counselling implications may help ensure individuals with an IA predictive test result receive appropriate support, education, and counselling.     

Predictive testing for Huntington disease in Canada: Adverse effects and unexpected results in those receiving a decreased risk

By January 1, 1991 a total of 388 persons had enrolled in the Canadian collaborative study of predictive testing for Huntington disease (HD). Of these participants, 105 persons have been given a decreased risk result. Contrary to expectations, approximately 10% of persons with a decreased risk result have had psychological difficulties coping with their new status. Here, we describe the individual responses of 6 such persons and experiential themes emerging after following these persons for up to 2 years. Individuals who are more likely to suffer an adverse reaction to a decreased risk result include those persons who have made irreversible decisions based on the belief they would develop HD or those who had unrealistic overoptimistic expectations of the positive effects of a decreased risk result. In contrast to those receiving an increased risk result, the most vulnerable time for persons receiving a decreased risk result is between 2 and 12 months after learning the outcome. The need for assessment and counselling of participants in predictive testing programs, even when there is a decreased risk result, is emphasized.     

Predictive testing for Huntington disease: social characteristics and knowledge of applicants, attitudes to the test procedure and decisions made after testing

An investigation has been made of the social characteristics and knowledge and experience of Huntington disease (HD) for the first 80 individuals considering presymptomatic testing (applicants) at the medical genetics centres in Edinburgh and Glasgow and of attitudes to the test procedure and decisions made after testing for those who received a result. Sixty-one percent of applicants were female and 31% were over 40 years old. Almost all had a symptomatic parent but 38% did not know HD was in their family until they were over 25 years old and 48% had never received genetic counselling. Thirty-eight percent of applicants first heard of the test at the genetic clinic, 20% from a relative and 20% from the media, but none had received information from their GP. Thirty-one applicants did not have the test because they voluntarily withdrew (17 individuals), their family structure was unsuitable or no informative result was possible (11 individuals), or they were diagnosed clinically as being affected (3 individuals). Those who voluntarily withdrew did not differ significantly from the 49 who received a result in social characteristics or knowledge and experience of HD. Twenty-two individuals were found to be at increased risk (IR) (>50% of becoming affected) and 27 to be at decreased risk (DR) (< 50% of becoming affected). There was a median period of 9 months between entering the test procedure and receiving a result and the main criticism of the procedure was that it took too long to complete and several individuals experienced considerable anxiety while awaiting their result. One year after receiving their result, almost 40% of individuals had made major life decisions, mainly in the areas of personal relationships, career and financial matters and over a third of fecund individuals in both IR and DR groups had changed their decision about future childbearing. Eighty-five percent of the IR group and 53% of the DR group requested continued follow up after the 1-year follow-up visit. The majority wanted follow up by the genetic clinician, but we have found that in practice many individuals do not attend when offered clinic appointments after this time.     

Long-term impact of Huntington disease linkage testing

We performed a long-term follow-up of Huntington disease (HD) predictive testing (an average of 6 years post-test) for 16 of 20 people who received informative linkage test results. Although no pre-test or baseline psychological differences were noted between those with an increased versus a decreased risk of HD, the long-term impact was dramatically different in these two groups. The low-risk group reported less uncertainty, anxiety or worry, fear, and worry about children's risk, whereas the high-risk group reported either the same or increased concern in these areas. Those at low risk also acknowledged an increased sense of control and self-esteem, whereas those at high risk reported decreases or no changes. One high-risk individual reported chronic depression that had occurred since the testing. Additionally, those at low risk reported greater reliance and faith in spiritual or religious beliefs than those at high risk. The emotional impact of HD genetic testing justifies the continued utilization of pre- and post-test counseling protocols. Pre-test counseling should include discussion of the known risks and benefits of predictive testing, with special emphasis on the participant's expectations for future change and improvement. Although the psychological impact appears mostly favorable for those with decreased risk, there is risk for a decline in psychological well-being over time for those with an increased risk for HD. Am J. Med. Genet. 70:365–370, 1997. © 1997 Wiley-Liss, Inc.     

Reactions to predictive testing in Huntington disease: Case reports of coping with a new genetic status

A predictive testing program for Huntington disease has been available in Stockholm, Sweden since October 1990. Psychosocial assessments were performed throughout the testing program to evaluate the impact of the risk situation itself and the effect of predictive testing, and to identify those individuals who were most vulnerable to severe stress and anxiety reactions. All subjects underwent neurological, neuropsychological, and psychiatric examinations. Individuals undergoing predictive testing were assessed twice by a genetic counsellor before receiving their results, and at 10 days (gene carriers only) and then 2, 6, 12, and 24 months after receiving the results. The process of coping with the test results and the psychological adjustment to knowledge about new genetic status have been shown to vary considerably. In this report, we describe the results obtained from two gene carriers and two noncarriers. The four persons chosen represent different ways of coping with the outcome of the test and of integrating knowledge about their genetic status into everyday life. These cases illustrate common themes and recurrent problems often surfacing during the counselling and testing process. The longitudinal evaluations provide information about the impact, adaptation, and long-term effects of living with a new genetic status. Am. J. Med. Genet. 73:356–365, 1997. © 1997 Wiley-Liss, Inc.     

The choice not to undergo genetic testing for Huntington disease: Results from the PHAROS study

Rates of genetic testing in Huntington disease (HD) are lower than was predicted before direct DNA testing became available. Clinicians often do not have in-depth conversations with people at risk who chose not to test. We queried 733 research subjects who chose not to learn their HD gene status when enrolling in the Prospective Huntington At-Risk Observational Study, carried out between 1999 and 2008. Lack of an effective cure or treatment (66% of subjects) and inability to undo knowledge (66%) were the major reasons cited for choosing not to undergo HD DNA testing. Most subjects were not concerned about the length or burden of the testing process (61% and 59%, respectively). Subjects were optimistic that a treatment to improve symptoms or postpone onset would be developed within the next 10 years (56% and 53%, respectively), but they had less certainty about the prospects to prevent HD onset (36%). This is the first large, systematic study of why people at risk for HD choose not to undergo genetic testing. Attitudes about how people at risk for HD approach this life-altering choice should be reassessed as new treatments develop, and as clinical trials now require genetic testing at entry.     

Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at‐risk observational study (PHAROS)

Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine–adenine–guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG < 37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support.     

Problems assessing uptake of Huntington disease predictive testing and a proposed solution

The uptake of predictive testing for Huntington disease informs our understanding of decision making by those at risk and assists with planning for service provision. Uptake figures have been reported from several centers based on the total number of people who have undertaken predictive testing as a percentage of those estimated to be at 50% risk in the region. This method produced a figure of 35% from our own service, much higher than observation of the local pedigrees indicated, and higher than other published reports. We have identified some errors in the commonly used formula. The major errors are the use of the cumulative total of those who have had testing with a static denominator of those at 50% risk, and the failure to exclude from the at-risk group those who are too young and therefore ineligible to test.We report data from the Huntington Disease Register of Victoria and estimate the prevalence to be 8 per 100,000 in 1999. Additional data on individuals at risk were collated. We found that for every diagnosed person there were 4.2 individuals at 50% risk, a lower ratio than one to five hypothesized in the literature. We examined these ratios in the context of uptake.Significantly, we provide a solution to the calculation of uptake with a formula that factors in a dynamic denominator and corrects for the number of years testing has been offered. Using this formula, we calculated an uptake of 13.0-15.4% for the state of Victoria, Australia. This formula can be used to compare uptake across different centers.     

Uptake of Huntington disease predictive testing in a complete population

Using the Northern Ireland Huntington disease (HD) register, the number of prospectively recorded predictive tests was analysed over a 20-year period. Two hundred and twelve patients completed predictive testing. Ninety-two (43%) received mutation-positive results and 119 (56%) mutation negative. There was one intermediate allele result. There was no significant gender difference. One hundred and eighty affected cases confirmed by molecular genetic testing were alive on 1 January 2001. The uptake of predictive testing in the entire HD 50% at-risk population in 2001 was calculated by three methods giving a range of 12.3-14.6%. Uptake after 20 years was estimated to be 14.7%. The minimum prevalence of affected HD cases was calculated as 10.6/100,000 in 2001. The total uptake of predictive testing was calculated and it suggests that a substantial number of at-risk patients do not come forward for testing until symptomatic. Pre-symptomatic testing for this late-onset condition with no present treatment, and limited management options, still presents challenges for families.     

Predictive and pre-natal testing for Huntington Disease in Australia: results and challenges encountered during a 10-year period (1994-2003)

This study summarizes 10-years' experience of predictive and pre-natal testing and pre-implantation genetic diagnosis (PGD) for Huntington disease (HD) in Australia. Results are presented from 2036 direct mutation predictive tests conducted between January 1994 and December 2003. Thirty-eight per cent of results (776/2036) were positive, 56% (1140/2036) were negative, and 6% (120/2036)) were in the mutable normal (27-35 CAG repeats) or in the reduced penetrance (36-39 CAG repeats) ranges. Ninety-four per cent (1908/2036) and 6% (128/2036) of those tested had prior genetic risks of 50% and 25%, respectively. Twenty-seven per cent (34/128) of those at 25% risk had their genetic status changed to positive, thus revealing the positive status of their at-risk parent. During this period, 63 pre-natal tests were also conducted, and 13 children were born following PGD for HD. Social workers specializing in predictive testing counselling over this 10-year period across Australia identified and summarized particularly challenging counselling issues. These included the interpretation of mutable normal and reduced penetrance range test results, potential conflicts of interest between family members regarding testing decisions, unanticipated consequences of both predictive and pre-natal testing decisions, the importance of following protocols for predictive testing to facilitate long-term adjustment to results, and the potential for genetic discrimination. The identified issues highlight the importance of the protocols for predictive testing and indicate that extension of the international guidelines published in 1994 may be timely.     

A novel SPECC1L mutation causing Teebi hypertelorism syndrome: Expanding phenotypic and genetic spectrum

Only eleven SPECC1L mutations have been reported worldwide which were associated with autosomal dominant oblique facial clefts, Opitz G/BBB Syndrome and Teebi hypertelorism syndrome. In this study, we reported the first Chinese patient with Teebi hypertelorism syndrome. Utilizing whole exome sequencing and Sanger sequencing, we identified a de novo missense mutation NM_015330.3: c.1249A > C, p.(Thr417Pro) in SPECC1L gene. With common manifestations in Teebi hypertelorism syndrome such as special facial appearance, umbilical malformations and congenital heart defects, the patient also had unusual symptoms including recurrent infections, febrile seizures and widely opened anterior fontanelle. Furthermore, all the recorded SPECC1L mutations were analyzed by in silico analysis. Coiled-coil domain 2 was the most frequently mutated domain and positions e and g might be more important than other positions. This paper expanded the phenotypic spectrum of Teebi hypertelorism syndrome and elaborated molecular characteristics of SPECC1L mutations.