{'fraction_non_alphanumeric': 0.027658559847401048, 'fraction_numerical': 0.027849308536003814, 'mean_word_length': 5.662007623888183, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 3, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Clinical features and prevalence of Klinefelter syndrome in transgender individuals: A systematic review

Abstract Objective Previous studies have suggested a higher prevalence of Klinefelter syndrome amongst transgender individuals. We undertook a systematic review to determine the prevalence of Klinefelter syndrome amongst transgender individuals presumed male at birth and summarize the clinical features and potential treatment implications for individuals with Klinefelter syndrome commencing gender‐affirming hormone therapy. Design Using preferred reporting items for systematic review and meta‐analysis guidelines, we searched EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to 31 December 2021. All studies reporting on the prevalence or clinical features of transgender individuals with Klinefelter syndrome were included. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42021227916. Results Our search strategy retrieved 11 cohort studies comprising 1376 transgender individuals. In all, 14 of 1376 (1.02%) individuals were diagnosed with Klinefelter syndrome. Based on the seven studies in which karyotype was undertaken in all individuals, the prevalence is 9/1013 (0.88%; 95% CI, 0.41%−1.68%). Case reports highlight unique treatment considerations in this population, including azoospermia, venous thromboembolism, and monitoring of breast cancer and bone health. Conclusions Compared to the general population, observational studies document a higher prevalence of Klinefelter syndrome amongst transgender individuals, though underdiagnosis in the general population limits conclusions. Routine karyotype in transgender people initiating gender‐affirming hormone therapy is not supported unless clinical features of Klinefelter syndrome, such as small testicular volume, or hypergonadotropic hypogonadism are present. Transgender individuals with Klinefelter syndrome need to manage a unique risk profile if they desire feminizing gender‐affirming hormone therapy.


| INTRODUCTION
Transgender (trans) individuals, including those with a binary and/or non-binary gender identity, represent a growing population with unique healthcare needs. Some trans individuals experience gender dysphoria, which refers to the distress that arises from incongruence between one's gender identity and their sex assigned at birth. 1,2 A complex set of factors determine one's gender identity, 3 and there has been increasing research into the potential genetic basis of gender incongruence. To date, variations in the oestrogen receptor, 4-6 oestrogen receptor coactivators 7 and androgen receptor 8 have been reported in trans individuals. Past studies have also suggested a higher prevalence of Klinefelter syndrome amongst trans individuals presumed male at birth compared to the expected prevalence in the general population. 9,10 Klinefelter syndrome (47,XXY) is the most common sex chromosomal disorder in individuals presumed male at birth, affecting 0.02%−0.22% of the population. [11][12][13] Klinefelter syndrome is a significantly underdiagnosed condition with estimates suggesting only 25%−50% of individuals are diagnosed. 14,15 Diagnosis is frequently made in adulthood during fertility assessment. 14 Individuals with Klinefelter syndrome have a primary testicular failure, with resultant clinical features including small testes, gynaecomastia, sparse male-pattern body hair and eunuchoid proportions. 11,16 Klinefelter syndrome is associated with an increased risk of venous thromboembolism, 17,18 breast cancer [19][20][21] and infertility, 16,22 which could have treatment implications before, and following, initiation of feminizing gender-affirming hormone therapy. Therefore, clinicians should consider investigating for Klinefelter syndrome in individuals with suggestive clinical features, to mitigate potential risk and ensure informed therapeutic decisions.
The aims of this systematic review were to (a) determine the prevalence of Klinefelter syndrome amongst trans individuals presumed male at birth, and (b) summarize the clinical features and potential treatment implications for trans individuals with Klinefelter syndrome commencing feminizing gender-affirming hormone therapy.

| MATERIALS AND METHODS
Preferred reporting items for systematic review and meta-analysis (PRISMA) reporting guidelines were used in the development of this systematic review. 23 This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42021227916.

| Eligibility criteria
Studies that used karyotyping to determine the prevalence of Klinefelter syndrome in cohorts of trans individuals presumed male at birth were included in this review. To assess clinical features, we included case series and case reports of trans individuals with Klinefelter syndrome. Only publications in peer-reviewed journals and in the English language were eligible for inclusion.

| Study selection
Our search strategy is outlined in Table 1

| Role of the funding source
There was no funding source for this study.

| Statistical analysis
The prevalence (95% confidence interval) of Klinefelter syndrome in trans and gender diverse individuals presumed male at birth was calculated using STATA version 17.0 software. 24

| RESULTS
There were 451 studies identified using MEDLINE and EMBASE. Based on the seven studies in which karyotype was undertaken in all individuals, the prevalence is 9/1013 (0.88%; 95% CI, Clinical data from 15 individuals reported in case reports or case series are shown in Table 3. All individuals were diagnosed with Klinefelter syndrome at age 16 or older. Of the seven case studies that reported serum testosterone concentration, five (71%) had serum testosterone concentrations below the lower limit of the male reference range. In all, seven articles reported on the prescription of testosterone therapy in nine individuals, 31,37,38,40,41,44,45 three of whom had poor compliance or ceased testosterone following the development of secondary male sex characteristics. 41,44,45 One individual ceased testosterone therapy after days, 38 while another ceased while receiving treatment for prostate cancer. 40 Two individuals reported an improvement in gender incongruence following the commencement of testosterone. 40, 43 Feminizing hormone therapy was prescribed in seven individuals. 31,36,39,41,42,44 Clinical features are shown in Table 3. Pathognomonic small testicular volume was reported in two individuals. 37,44 Two individuals had venous thromboembolic events before the initiation of estradiol. 40, 41 Of the two case reports that reported on semen analysis, both had azoospermia. 37,38 One individual had osteopaenia. 38

| DISCUSSION
We performed a systematic review to determine the prevalence of Klinefelter syndrome in trans and gender-diverse individuals presumed male at birth, and to identify the clinical features of Klinefelter syndrome that may result in treatment considerations in trans people undergoing feminizing gender-affirming hormone therapy. We found a 0.88% prevalence of Klinefelter syndrome, which is higher than previous analyses in the general population.

| Prevalence of Klinefelter syndrome in trans individuals
This review included 11 cohort studies, which consisted of 1376 individuals. Out of the total study population, 14 (1.02%) were identified as having Klinefelter syndrome. Based on the seven studies in which karyotype was undertaken in all individuals, the prevalence is 9/1013 (0.88%; 95% CI, 0.41%−1.68%). In the general population, the prevalence of Klinefelter syndrome is estimated at 0.02%−0.22% or approximately 1/600 people presumed male at birth. 14,27,46 However, it is important to note that Klinefelter syndrome is thought to be underdiagnosed and even when diagnosed, it is usually delayed and post-pubertal. 13,14,46,47 Studies have suggested that 50%−75% of Klinefelter syndrome is not diagnosed. 46,48 Given the underdiagnosis in the general population, pre-natal screening programs can also be considered. Based on pre-natal screening, the prevalence of Klinefelter syndrome is estimated to be 0.21%−0.23%. 46,49 However, a 0.9% prevalence has been reported in a cohort study evaluating the prevalence of 47,XXY karyotype in male blastocysts from trophectoderm biopsies obtained during preimplantation genetic testing cycles during in vitro fertilization. 50 However, several factors need to be considered, including if these blastocysts would have lower implantation rates, higher early miscarriage rates, or if there are higher rates of 47,XXY blastocysts in infertile patients of advanced maternal age. 50 Although the prevalence of Klinefelter syndrome appears to be higher than that observed in the general population and in pre-natal screening, existing literature has not suggested undertaking karyotyping in trans individuals in the absence of suggestive clinical features. 9 Some studies have concluded that there is no link whereas others have identified a higher frequency of cytogenetic alterations in trans individuals. 9 transdermal route of administration would be a consideration to mitigate VTE risk. 57,58 However, notably there are no supportive data in the trans population with no differences in hypercoagulable global coagulation assays seen between transdermal and oral formulations of feminizing hormone therapy. 59 This may be possibly due to relatively higher doses of transdermal estradiol used in genderaffirming hormone therapy relative to menopausal hormone therapy. 59 Furthermore, estradiol dose should also be considered as higher doses have been associated with a higher risk of thromboembolic disease. 58,60 Given the risk profile of Klinefelter syndrome and the evidence of higher

| Limitations
The limitations of this systematic review are selection bias and the biases embedded within the retrospective cohort studies. None of the included studies have a cisgender control group, so the increased prevalence may be due to a higher number of karyotyping analyses.
Controlled studies would allow a comparison of the prevalence of Klinefelter syndrome in the cisgender population. To our knowledge, this is the first systematic review that has sought to determine the LIANG ET AL.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analysed in this study.