Amy Herlihy

The psychosocial impact of Klinefelter syndrome and factors influencing quality of life

Purpose: There is considerable information regarding the medical and cognitive aspects of Klinefelter syndrome yet little research regarding its psychosocial impact. This study investigates the personal impact of Klinefelter syndrome and the influence of age at diagnosis, clinical, social, and demographic factors on adult quality of life outcomes.Methods: Men from across Australia, diagnosed with KS at different ages, were recruited through multiple sources. Participants completed a questionnaire assessing subjective well-being, body image, self-esteem, mental health, social support, and general health.Results: Eighty-seven individuals self-completed the questionnaire. All outcomes were much poorer for the study population than for the general male population. Individuals diagnosed later in life reported many of the same symptoms as those diagnosed at younger ages. Employment status, social support, and phenotypic features were the strongest predictors of psychosocial outcomes. Age at diagnosis was not as influential because it did not correlate with phenotypic severity score.Conclusion: This is the first quantitative study to show Klinefelter syndrome has a significant personal impact. Men diagnosed with Klinefelter syndrome later in life reported similar difficulties as those at younger ages, suggesting that they would benefit from early detection and intervention. Understanding factors influencing this can assist in providing adequate services to individuals with Klinefelter syndrome, their partners, families, and the health professionals caring for them.

A qualitative exploration of mothers’ and fathers’ experiences of having a child with Klinefelter syndrome and the process of reaching this diagnosis

Klinefelter syndrome (KS) is a common genetic condition that is currently under-diagnosed. The phenotype is broad, with physical, medical and psychosocial features ranging from mild to severe. When a child is diagnosed with KS, the parents may spend months to years searching for a diagnosis. This study used a qualitative methods approach to explore parents’ experiences of having a child with KS and receiving a diagnosis. Fifteen semistructured one-to-one in-depth interviews were conducted to explore their experiences and views. The interviews were then transcribed, coded and thematically analysed. The interviews revealed that parents had diverse experiences related to: the timing of the diagnosis of their child and reasons why their child was investigated for KS; the information that was provided at the time of diagnosis; the supports that were available and the concerns that parents held for the future of their child. The conclusions from this study were that parents’ experiences of having a child with KS and receiving a diagnosis were complex and multifaceted. This experience was shaped by the timing of when the diagnosis was received, who provided the diagnosis, what information was provided from health-care professionals and that which parents may have encountered on the internet. The long-term experiences for parents were also impacted by the level of support they received. These findings have implications for the process by which KS is recognised by the health-care community and supports available for families.

Postnatal screening for Klinefelter syndrome: is there a rationale?

Diagnosis of Klinefelter syndrome (KS) allows for timely beneficial interventions across the lifespan. Most cases currently remain undiagnosed because of low awareness of KS amongst health professionals, the hesitancy of men to seek medical attention and its variable clinical presentation. Given these barriers, population‐based genetic screening provides an approach to comprehensive and early detection. We examine current evidence regarding risks and benefits of diagnosing KS at different ages.

Fragile X-related element 2 methylation analysis may provide a suitable option for inclusion of fragile X syndrome and/or sex chromosome aneuploidy into newborn screening: a technical validation study

Purpose:We show that a novel fragile X–related epigenetic element 2 FMR1 methylation test can be used along with a test for sex-determining region Y (SRY) to provide the option of combined fragile X syndrome and sex chromosome aneuploidy newborn screening.Methods:Fragile X–related epigenetic element 2, SRY, and FMR1 CGG repeat analyses were performed on blood and saliva DNA, and in adult and newborn blood spots. The cohort consisted of 159 controls (CGG <40), 187 premutation (CGG 56–170), and 242 full-mutation (CGG ~200–2,000) males and females, 106 sex chromosome aneuploidy individuals, and 151 cytogenetically normal controls.Results:At the 0.435 threshold, fragile X–related epigenetic element 2 analysis in males was robust on both blood DNA and newborn blood spots, with specificity and sensitivity of ~100% for full-mutation genotype. In females, the specificity was 99%, whereas half of full-mutation females were above the 0.435 threshold in both blood DNA and newborn blood spots. Furthermore, at this threshold, the test could not differentiate individuals with Klinefelter syndrome from female controls without using the SRY marker. When combined with SRY analysis, the test was consistent with most results for sex chromosome aneuploidies from karyotyping.Conclusion:Setting specific thresholds for fragile X–related epigenetic element 2 analysis and including the SRY marker provides the option to either include or exclude detection of sex chromosome aneuploidies as part of fragile X syndrome newborn screening.Genet Med 2013:15(4):290–298

Assessing the risks and benefits of diagnosing genetic conditions with variable phenotypes through population screening: Klinefelter syndrome as an example

Consideration of postnatal population-based genetic screening programs is becoming increasingly common. Assessing the medical and psychosocial impacts of this can be particularly complex for genetic conditions with variable phenotypes, especially when outcomes may be more related to quality of life rather than reducing physical morbidity and mortality. In this article, we present a framework for assessing these impacts, by comparing diagnosis and non-diagnosis at different age points. We use the example of Klinefelter syndrome, a common yet frequently under-diagnosed genetic condition for which interventions are available. This framework can be used to supplement established screening guidelines and inform decision-making.

Screening for Klinefelter syndrome.

Purpose of reviewTo examine recently published evidence that may inform the need for population screening of Klinefelter syndrome; by far the most common chromosomal disorder in males, which most often escapes diagnosis throughout the lifespan. Recent findingsResearch regarding the prevalence and characteristics of developmental and learning difficulties in Klinefelter syndrome emphasize the importance of early intervention with likely subsequent psychosocial and other health benefits. Testosterone treatment will always need to be individualized, but there is growing evidence for the benefits of intervention from the time of puberty, and possibly in early childhood. Discussion of fertility options is now essential given the advent of surgical sperm retrieval and intracytoplasmic sperm injection. SummaryDespite increasing knowledge of the natural history of the Klinefelter syndrome spectrum, beneficial interventions and when they should occur, most opportunities are missed due to nondiagnosis. Population screening is arguably the only way of ensuring timely detection of individuals with Klinefelter syndrome. The technologies and structures for such a program already exist. This field now requires a pilot program to further define the risks, benefits and psychosocial and ethical dimensions of screening.

The attitudes of people with sarcoma and their family towards genomics and incidental information arising from genetic research

PurposeThe study aimed to examine attitudes of individuals diagnosed with sarcoma and their family members towards genetics, genomic research and incidental information arising as a result of participating in genetic research.MethodsA questionnaire was administered to 1200 individuals from the International Sarcoma Kindred Study (ISKS). Respondents were divided into three groups: individuals affected with sarcoma (probands), their spouses and family members.ResultsApproximately half of all research participants felt positively towards new discoveries in human genetics. Overall, more were positive in their attitudes towards genetic testing for inherited conditions (60%) but family members were less so. Older participants reported more highly positive attitudes more often than younger participants. Males were less likely to feel positive about new genetic discoveries and more likely to believe they could modify genetic risk by altering lifestyle factors. Almost all ISKS participants believed participants would like to be given ancillary information arising as a result of participating in genetic research.ConclusionsThe only difference between the study groups was the decreased likelihood of family members being highly positive about genetic testing. This may be important if predictive testing for sarcoma becomes available. Generally ISKS research participants supported the notion of returning incidental genetic information to research participants.

Is paternal age playing a role in the changing prevalence of Klinefelter syndrome

We were very interested to read the recent article published by Morris et al suggesting that the prevalence of Klinefelter syndrome (KS), XXY, may be increasing. We are currently carrying out analyses using routinely collected data in Victoria to ascertain an estimate of XXY prevalence in Australia. Studies like these highlight the value in systematic collection of various types of information for public health purposes. Certainly, preliminary analysis of our more recent data (unpublished) suggests a higher prenatal prevalence than has been previously indicated in prenatal studies extending back to 1970. By separating the earlier and later newborn chromosome surveys, Morris et al showed a difference in prevalence of XXY between the two time periods. However, although all three sex trisomies were seen at similar frequencies in the earlier surveys, neither the prevalence of XYY nor XXX changed in the later surveys. The observed increase in the frequency of XXY was supported by data series of prenatal diagnoses, spontaneous abortions and perinatal deaths. On the basis of this finding, the authors hypothesise that the increase in frequency of XXY is due to an increase in non-disjunction at paternal meiosis I, and that this may be caused by the same factors that have been attributed to the falling sperm counts in men. Such factors may include prenatal exposure to environmental chemicals or perinatal exposure to known environmental xeno-oestrogens. The effect of maternal age on KS is well established but would cause a similar increase in the frequency of XXX, which was not seen by Morris et al. However, the authors do not mention paternal age effect as a possible explanation, or at least contributing factor, for the increase in the frequency of XXY conceptions. Increasing paternal age trends in Australia are similar to those seen in the United Kingdom, with the average age of fathers of live births reaching an all time high of 33.1 years in 2006 years, and the number of men in their 50s having children up by around 20% in the last decade. The effect of paternal age on recombination frequency (reduced in XY disomic sperm) and non-disjunction is a controversial area, with not all study findings supporting a relationship, yet there remains a substantial body of evidence that indicates an association between paternal age and the birth of a child with KS. If the increased frequency of XXY that has been observed is due to a paternal age effect acting only at meiosis I, this would explain the lack of corresponding increases in frequencies of XYY and XXX. Finally, we are curious about the lack of reference to the comprehensive study of Bojesen et al in 2003 that utilised the extensive prenatal and postnatal diagnoses Danish databases, and covers a considerable time period. We presume that this was excluded because it only considered karyotypes associated with KS and not the other two sex chromosome trisomies. However, in our organisation, we use this publication as our benchmark for KS prevalence, and would be interested to hear the perspective of Morris et al on how this study compares to theirs in regards to the prevalence of KS. Above all else, the possible increasing frequency of XXY only further highlights the need for increased awareness and detection of males with the condition at an age and stage of development most appropriate for treatment and intervention. The best time to be diagnosed has yet to be determined and there remains a lack of research on the psychosocial impacts of having KS, and how quality of life and life outcomes might be affected by age of diagnosis. If this condition is truly becoming even more common, it is vital that we identify the needs of this group of males.

Detection of skewed X-chromosome inactivation in Fragile X syndrome and X chromosome aneuploidy using quantitative melt analysis.

Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed X-chromosome inactivation (XCI) in fragile X syndrome full mutation (FM: CGG > 200) females. XCI skewing has been also linked to abnormal X-linked gene expression with the broader clinical impact for sex chromosome aneuploidies (SCAs). In this study, 10 FREE2 CpG sites were targeted using methylation specific quantitative melt analysis (MS-QMA), including 3 sites that could not be analysed with previously used EpiTYPER system. The method was applied for detection of skewed XCI in FM females and in different types of SCA. We tested venous blood and saliva DNA collected from 107 controls (CGG < 40), and 148 FM and 90 SCA individuals. MS-QMA identified: (i) most SCAs if combined with a Y chromosome test; (ii) locus-specific XCI skewing towards the hypomethylated state in FM females; and (iii) skewed XCI towards the hypermethylated state in SCA with 3 or more X chromosomes, and in 5% of the 47,XXY individuals. MS-QMA output also showed significant correlation with the EpiTYPER reference method in FM males and females (P < 0.0001) and SCAs (P < 0.05). In conclusion, we demonstrate use of MS-QMA to quantify skewed XCI in two applications with diagnostic utility.

Ethical Issues in Recruiting Prenatally Diagnosed Adults for Research: Klinefelter Syndrome as an Example

genetic information obtained prenatally or in the first few years of life, a topic that has not received much attention. One example that raises substantial ethical issues arising from information obtained during prenatal diagnosis is Klinefelter syndrome (KS). KS is a common, but underdiagnosed, genetic condition caused by an additional X chromosome in males (47,XXY). Symptoms range from azoospermia, small testes, testosterone deficiency and breast development, to varying degrees of learning, behavioural and cognitive difficulties, but can vary greatly between individuals [3] . Recent studies have estimated the prevalence of KS to be as high as 1 in 450 male births [4] , and possibly increasing [5] . However, up to 70% of males are never diagnosed [6] because of low awareness of the condition amongst health professionals, the nonspecificity of symptoms and the reluctance of men to seek medical attention [7] . Many postnatal diagnoses occur in adulthood during fertility investigations, which may be beyond the point of optimal intervention [8] . Due to this lack of detection, many studies of KS suffer from ascertainment bias and small sample size, as research can only be carried out with the diagnosed population. A series of newborn screening surveys in the 1950’s and 1960’s provide the most comprehensive description Since its introduction during the 1970’s, prenatal diagnosis has become more accessible and more accessed, with the number and range of genetic conditions able to be detected increasing as technology advances [1] . For many genetic conditions that can be identified by prenatal diagnostic testing, such as Down syndrome (trisomy 21), a clinical diagnosis would almost always be made at birth due to the obvious phenotype, if the condition was not identified prenatally. However, prenatal diagnosis, and even newborn testing, has opened the doors for the incidental identification of genetic conditions that may not be phenotypically explicit at birth, leading to a diagnosis earlier than one might expect should such testing not have occurred. There are a number of ethical considerations that may arise around prenatal diagnosis and genetic information obtained about an individual prior to adulthood. Much of the current literature focusses on ethical issues confronting the couple or clinician during prenatal diagnostic testing or around the rights and autonomy of children who may undergo genetic testing at an age where informed consent is not possible [2] . The purpose of this article is to highlight the more long-term ethical dilemmas that may arise around issues of disclosure regarding Received: December 9, 2010 Accepted after revision: April 18, 2011 Published online: June 30, 2011