Experiences of individuals receiving a sex chromosome multisomy diagnosis

Abstract

Sex chromosome multisomies (SCMs) are genomic conditions with variable phenotypes that range from undetectable to requiring extensive clinical intervention. Currently, many individuals with SCMs are diagnosed in adolescence or adulthood based on physical symptoms related to pubertal development and infertility. Given the expansion of genetic testing in routine clinical practice, the diagnosing clinician is increasingly a primary care or family medicine provider. This study aims to help providers better understand the patient experience of receiving a diagnosis. We conducted a survey of individuals (n = 55) with SCMs using closed and open-ended questions. Open-response questions were qualitatively analyzed and are reported here with the descriptive results of the closed-ended questions. Most participants were diagnosed with 47,XXY (n = 51; 85.0%), identified as White race/ethnicity (n = 46; 88.5%), and were college graduates or higher (n = 29; 54.7%). Many participants reported dissatisfaction with the delivery of the diagnosis, expressing that it was rushed and their provider lacked detailed information about the condition. Participants were frustrated by the general lack of availability of high-quality informational resources from both medical and other sources at the time of diagnosis. Some participants also described the social and psychological impact of the diagnosis and how it was delivered. To the best of our knowledge, this is the largest survey of individuals diagnosed with SCMs, which is notable considering their prevalence and low diagnostic rate. Our findings provide patient-informed insight on how to improve the delivery of SCM diagnoses, especially delivery in a primary care setting, including the provision of up-to-date information and proactive referral to specialty care and counseling services.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12687-022-00604-0.

Introduction

Sex chromosome multisomies (SCMs) make up approximately 1 in every 300–500 live births and collectively are the most prevalent chromosomal conditions in the general population (Milunsky and Milunsky 2015). Common SCMs include Klinefelter syndrome (47,XXY), Triple X (47,XXX), and Jacobs syndrome (47,XYY). Most SCMs are characterized by altered stature, average to lower-than-average intelligence—although lower than in sibling controls—and infertility. Other SCMs, including quadrasomies and pentasomies, are rare and are typically associated with more complex phenotypes (Schoubben et al. 2011; Tartaglia et al. 2011). SCMs can be detected prenatally through the use of cell-free DNA (cfDNA) or other prenatal screening techniques (American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins et al. 2020), but pediatric or adolescent diagnosis continues to be the most common, generally in response to a spectrum of physical, mental, learning, and behavioral symptoms. Because dysmorphic facial features are typically absent, and symptoms may be mild or sub-clinical, many individuals experience misdiagnosis and/or significant diagnostic delays. Young patients are often diagnosed after a long diagnostic odyssey to identify the source of patterns of learning and behavioral symptoms (Visootsak et al. 2013; Berglund et al. 2019). A diagnosis in adolescence may also be prompted by symptoms related to pubertal development. When diagnosed in adulthood, SCMs may be discovered during a workup for reproductive health, or, in males with 47,XXY, during a workup for gynecomastia or breast cancer (Davis et al. 2016; Tartaglia et al. 2010). It is estimated that 75–90% of affected individuals remain undiagnosed during their lifetime (Samango-Sprouse et al. 2016).

As genetic testing is more thoroughly integrated into primary clinical practice, it is increasingly likely that non-genetic providers will be responsible for ordering genetic testing for SCM and delivering the diagnosis of SCM. Primary care providers may also increasingly interact with or participate in the medical management of individuals with known SCM as prenatal diagnoses increase following the use of cfDNA as first- or second-tier prenatal screening for aneuploidy (Howard-Bath et al. 2018). This suggests a growing need for enhanced knowledge of SCM and the support needs of individuals with these conditions. While the literature has described the experiences of parents who received their child’s SCM diagnosis from genetic and non-genetic providers (Jaramillo et al. 2019; Richardson et al. 2021; Riggan et al. 2020, 2021), the experience of individuals with SCMs themselves is not well categorized. We expand upon a qualitative pilot study that explored individual perspectives on receiving the diagnosis of a SCM (Jaramillo et al. 2019) by conducting a survey to categorize the experience of adolescents and adults receiving a SCM diagnosis, including their desired forms of support during and after the diagnosis.

Methods

Study design

Two researchers with expertise in SCMs and survey design developed a questionnaire to explore individual (Appendix) and parent/caregiver experiences receiving a genetic diagnosis of SCM (Riggan et al. 2020). This questionnaire was adapted from one that was previously developed by Skotko et al. for the Down syndrome community (Skotko 2005). In contrast to the more extensive literature on Turner syndrome (45,X), limited studies have explored SCM patient experiences. In response to the recommendation of the SCM patient community, the questionnaire was designed to capture the experiences of multisomy conditions only. The questionnaire contained fixed yes/no, single answer, and multiple-choice questions. Open-ended responses were included to elicit patient narratives on the delivery of the diagnosis and to provide additional context for respondents’ fixed answers. A 7-point Likert scale measured agreement/disagreement with statements on receiving the diagnosis and materials received at the time of diagnosis. The study was approved by the institutional review board of Mayo Clinic, which declared it to be minimal risk (#17–008,618).

Data collection

An invitation to complete the anonymous questionnaire was distributed through the Association for X and Y Chromosome Variations’ (AXYS) social media platforms and email listserv. AXYS is a patient support organization for over 7000 individuals and families with a SCM diagnosis across the USA and with a global outreach. The questionnaire was fielded through REDCap, a secure HIPAA-compliant web application for survey collection and data management. The survey was open to both parents of individuals with SCMs and individuals themselves who were 16 years of age or older and English-speaking. Respondents were informed that by continuing with the survey, they consented to have their results used for research. The IRB waived assent for 16- to 17-year-old participants since the information was collected anonymously. The survey was open from September 6 to October 31, 2018, when new completions stopped. Due to social media distribution, it is unknown how many individuals viewed the invitation and thus a response rate cannot be determined (McRobert et al. 2018).

Data analysis

Analysis of parent responses is reported separately (Riggan et al. 2020, 2021). This analysis focuses on the experiences of individuals with a diagnosis of SCMs. All completed questionnaires were included for quantitative analysis. Fixed responses were analyzed via descriptive statistics. For the Likert scales, means over neutral value of 4 were considered agreement, and under 4, disagreement, with the corresponding statement. Completion rates varied for each question. All questionnaires with at least one response to an open-ended question were included for qualitative analysis. Two researchers (JR and NA) conducted an inductive, qualitative analysis of open-ended questions and developed a codebook based on recurrent thematic content in accordance with standard qualitative methodology (Saldana 2016). A spreadsheet was used to code responses. Responses from 10 participants (18.2%) were coded to consensus to validate the codebook with additional codebook refinement. Remaining responses were divided equally with an additional 10 responses consensus coded to maintain coding consistency. Any discrepancies were resolved by mutual agreement with trends and codes checked weekly to maintain research vigor. In accordance with the Standards for Reporting Qualitative Research, direct quotes from participant responses are included here and have been minimally edited for readability (O’Brien et al. 2014).

Results

Demographics and survey data

Of the n = 61 questionnaires completed by individuals who identified as having an SCM, 55 respondents answered at least one open-ended question. Most participants were diagnosed with 47,XXY (n = 51; 85.0%), identified as White race/ethnicity (n = 46; 88.5%), and were college graduates or higher (n = 29; 54.7%) (Table 1).

Table 1.

Demographics

	n (%)
Age (n = 55)	45.3 mean (range 18–74)
SCM (n = 60)
47,XXY	51 (85.0)
47,XXX	5 (8.3)
47,XYY	1 (1.7)
48,XXXY	1 (1.7)
48,XXYY	1 (1.7)
49,XXXXY	1 (1.7)
Biologic sex (n = 61)
Male	56 (91.8)
Female	5 (8.2)
Gender identity (n = 61)
Male	52 (85.2)
Female	7 (11.5)
Nonbinary	2 (3.3)
Race/ethnicity (n = 52)
White	46 (88.5)
Hispanic or Latino	4 (7.7)
Asian	1 (1.9)
Multiracial	1 (1.9)
Education (n = 53)
Less than 8th grade	2 (3.8)
Graduated 8th grade	2 (3.8)
High school diploma	20 (37.7)
College graduate	21 (39.6)
Master’s degree	6 (11.3)
Doctorate degree	2 (3.8)

Delivery of diagnosis

Most participants (n = 49; 81.7%) received their diagnosis directly from a healthcare provider (HCP), while others were told about the diagnosis from a family member (n = 9; 15.0%) or other mechanisms (n = 2; 3.3%). Of the 49 individuals who received the news from a HCP, 19 indicated the specialty of the provider. Only 1 individual stated that they received the diagnosis from a genetic specialist in adolescence or adulthood (Table 2). Half of the sample (n = 30, 50.0%) did not specify the specialty of the diagnosing provider, although some indicated in their written comments that the diagnosis was first delivered by a primary care provider before they were referred to specialty care. Many participants recalled the way their clinician delivered a diagnosis as having a substantive impact on their diagnostic experience and understanding of their SCM.

Table 2.

Characteristics of diagnosis delivery

	N (%)
Delivered the diagnosis (n = 60)
Family member	9 (15.0)
Mother	5 (8.3)
Father	1 (1.7)
Both parents	2 (3.3)
Aunt	1 (1.7)
Healthcare provider	49 (81.7)
Endocrinology	10 (16.7)
Urology	5 (8.3)
Rheumatology	1 (1.7)
Genetics	1 (1.7)
Pediatrics	1 (1.7)
Family medicine	1 (1.7)
Specialty not provided	30 (50.0)
Other	2 (3.3)
Age at diagnosis (n = 61)
Early childhood (0–6 yrs)	1 (1.6)
Middle/late childhood (7–12 yrs)	5 (8.2)
Adolescence (13–17 yrs)	9 (14.8)
Early adulthood (18–25 yrs)	10 (16.4)
Adulthood
25–35	18 (29.5)
36–45	12 (19.7)
46–55	4 (6.6)
56 +	2 (3.3)
Time since diagnosis (n = 55)
One year or less	10 (18.2)
2–5 yrs	5 (9.1)
5–10 yrs	8 (14.5)
11–20 yrs	9 (16.4)
21–30 yrs	13 (23.6)
31–40	5 (9.1)
41 +	5 (9.1)

Participants were also asked to rate the extent to which they agreed or disagreed with statements on the experience of receiving a diagnosis. Agreement is indicated by a mean score over the neutral mark of 4 with disagreement indicated by a mean score under 4. Participants’ fixed responses indicated that those who received their diagnosis from a HCP disagreed that the experience was as a positive event (mean: 3.6, STD: 2.2); disagreed that positive aspects of SCM were emphasized (mean: 2.8, STD 2.2); and agreed that negative aspects of their condition were emphasized (mean: 4.7, STD 2.0) (Table 3).

Table 3.

Mean responses on participant reactions to the diagnosis

Statement	Diagnosis delivered by family member (mean ± STD)*	Diagnosis delivered by provider (mean ± STD)*
Learning of my X/Y Chromosome Variation was a positive experience	5.6 (1.6)	3.6 (2.2)
The person who told me of my diagnosis emphasized the positive aspects of X/Y Chromosome Variations	5.7 (1.7)	2.8 (2.2)
The person who told me of my diagnosis emphasized the negative aspects of X/Y Chromosome Variations	4.4 (2.2)	4.7 (2.0)
The person who told me of my diagnosis provided contact information for other persons who have X/Y Chromosome Variations	3.1 (2.1)	1.9 (1.9)
When I learned that I had an X/Y Chromosome Variation, I was depressed	3.6 (2.4)	4.8 (2.2)
When I learned that I had an X/Y Chromosome Variation, I was anxious	3.4 (2.1)	4.6 (2.2)
When I learned that I had an X/Y Chromosome Variation, I was relieved	2.8 (2.2)	3.4 (2.1)
When I learned that I had an X/Y Chromosome Variation, I felt positive	3.8 (1.9)	2.9 (2.0)
When I learned that I had an X/Y Chromosome Variation, I had no prior knowledge about this genetic condition	5.4 (2.5)	6.2 (1.9)

^*Based on a 7-point Likert scale. Means over the neutral mark of 4 indicate agreement, and under 4, disagreement

Participants were also asked to provide additional detail on the diagnosis delivery in response to open-ended questions designed to prompt reflections about their experience. Most comments focused on areas of the diagnosis experience they found to be personally upsetting. Several participants recounted that the HCP shared the news apathetically or impersonally. Some explicitly expressed dissatisfaction about receiving the diagnosis over phone rather than in-person.

He looked out the window when he told me instead of looking at me. (47,XXY, diagnosed age 32, age 32)

The doctor told me I had 47,XXY chromosomal disorder and hung up. I do hope this doctor learned that his actions and accountability was poor! (47,XXY, diagnosed age 43, age 47)

Participants also stated a perception that their HCP did not provide appropriate clinical guidance during the initial diagnosis conversation, leading to the expression of feelings of provider abandonment. Some recalled their appointments feeling rushed or that there was no opportunity to ask questions about their diagnosis.

I saw a urologist [about] why I couldn’t have kids and found out that way, it wasn't really explained to me until I spoke to my doctor. (47,XXY, diagnosed age 26, age 37)

Very brief- thankfully I received my lab results prior to his awful explanation, he only told me of a couple of the major symptoms. (47,XXY, diagnosed age 32, age 32)

Several participants also reported a perception that the diagnosis was delivered in an insensitive or inappropriate manner, especially in the context of infertility diagnoses. Participants expressed two levels of disappointment in such encounters: that the diagnosis was unexpected and that the news of infertility was delivered without sensitivity to the great emotional impact it could have.

I was initially there for fertility testing and that came back as no sperm, absolute zero. Not only was I kind of rushed out of there but also I was told, you can’t have kids. My wife and I had been trying for over a year. This is borderline patient abandonment in my view. (47,XXY, diagnosed age 37, age 38)

The doctor who told me had no knowledge of XXY and said ‘you will never have kids.’ (47,XXY, diagnosed age 15, age 26)

Some participants also objected to the ways in which HCPs objectified their genitals during the clinical encounter, reporting that healthcare providers expressed fascination and scrutiny and displayed their genitals to other medical colleagues. Participants reported feeling humiliated and uncomfortable by these interactions.

They had not seen this before and another doctor was called in the room so they could see how small my testicles were - that's what they said when they came in the room. It was horrifying. (47,XXY, diagnosed age 37, age 38)

I was told with 3 doctors male and female with them measuring my testicles. Very embarrassing!! (47,XXY, diagnosed age 22, age 40)

Some participants reported that clinicians made comments relating an SCM diagnosis to their gender expression. This included references to different levels of masculinity or femininity in people with SCMs compared to the typical population.

Told me there were drugs that would change me to more of a man. (47,XXY, diagnosed age 30, age 71)

[They] explained that if I didn't start taking the medicine I would start looking like a girl. (47,XXY, diagnosed age 18, age 47)

By contrast, participants who indicated that they had opportunity to discuss the diagnosis with a HCP that was knowledgeable about the condition and was able to explain the genetics of the diagnosis generally reported a more positive diagnostic experience. Some described aspects of their encounter or diagnostic explanation that they found helpful and comforting. These include the use of clear and accessible language, inclusion or referral to a genetic counselor, and the opportunity to ask questions.

At a private appointment over an hour and a half. Genetic counselor came in first and then the genetics came in. He had case studies in front of him. (47,XXX, diagnosed age 44, age 44)

She drew out how the XXY comes to be and why I don’t produce enough testosterone. (47,XXY, diagnosed age 15, age 15)

Participants recounted that the most helpful aspect of the diagnosis was connection to appropriate specialty care, such as referral to an endocrinologist to provide specific therapeutic options (e.g., testosterone) and medical management.

The endocrinologist said I have an extra chromosome and briefly went over the condition. Treatment was started up within 1 month with starting on taking two 2.5 mg patches. Within a few weeks I felt different and better all around. (47,XXY, diagnosed age 16, age 41)

Gave me a list of physicians who know how to treat me. (47,XXY, diagnosed age 22, age 40)

Information needs

Table 4 presents responses to statements about the materials provided by their HCP, including specialists, primary care providers, and HCPs, otherwise not specified. Only 14 respondents (28.6% of 49) indicated in their fixed response that they received any printed materials and 6 (6.9% of 47) online materials on the SCM. Of those who received materials, respondents agreed that these materials emphasized the negative aspects of the condition (printed: mean 4.9, STD 1.9; online: mean 5.2, STD 2.3).

Table 4.

Mean responses on materials on SCM received from provider

Statement	n (%)
The person who told me of my diagnosis gave me printed materials about X/Y Chromosome Variations (n = 49)
Yes	14 (28.6)
No	35 (71.4)
	(mean ± STD)*
The person who told me of my diagnosis provided me with enough up-to-date printed material on X/Y Chromosome Variations	4.5 (2.3)
The printed materials that I received emphasized the positive aspects of having X/Y Chromosome Variations	3.8 (2.6)
The printed materials that I received emphasized the negative aspects of having X/Y Chromosome Variations	4.9 (1.9)
The printed materials that I received provided an equal mix about the positive and negative aspects of X/Y Chromosome Variations	4.0 (2.1)
	n (%)
The person who told me of my diagnosis told me about websites or other online places to learn about my diagnosis (n = 47)
Yes	6 (12.8)
No	41 (87.2)
	(mean ± STD)*
The online materials that I saw emphasized the positive aspects of having X/Y Chromosome Variations	4.5 (2.1)
The online materials that I saw emphasized the negative aspects of having X/Y Chromosome Variations	5.2 (2.3)
The online materials that I saw provided an equal mix about the positive and negative aspects of X/Y Chromosome Variations	5.7 (1.4)
The online materials were helpful in understanding X/Y Chromosome Variations	4.7 (2.9)

^*Based on a 7-point Likert scale. Means over the neutral mark of 4 indicate agreement, and under 4, disagreement

In participant’s written comments, a shared concern was the lack of clear, high-quality information about SCM and its implications. Participants reported that this information deficit often started with HCPs, who were unable to answer questions or give correct explanations of the diagnosis as they were delivering it.

It was actually the specialist’s assistant that figured out that I have it and the so-called specialist referred to Wikipedia in front of us for details on the condition (Wikipedia was wrong at the time as well). (47,XXY, diagnosed age 39, age 46)

Medical doctors need more education related to chromosomal disorders. We now know more about these disorders and many of us could have a more positive experience when being diagnosed. (47,XXY, diagnosed age 43, age 47)

Participants also frequently requested connections to reputable resources to further educate themselves. These resources were often envisioned as printed resources in the provider’s office or reputable websites.

Having the blood tests waiting for the results was painstaking, having leaflets & more information to hand to read would have been more helpful to me. (47,XXY, diagnosed age 45, age 45)

Have a written or type[d] information, of all the FAQ’s, have a doctor who knows the problem that can answer all questions. Direct patients to websites, that have other people that have the same problem. (49 XXXXY, diagnosed age 20, age 60)

Participants offered recommendations on the type of information that would have been helpful to receive at time of diagnosis. Specifically, many participants wanted to know how the SCM would impact them over the life course.

A full explanation, with an understanding that my life is going to completely change, and then offering resources and genetic counseling would have helped. (47,XXY, diagnosed age 32, age 32)

Just that wasn’t enough info. To understand what bearing it would have on my life. (49,XXXXY, diagnosed age 32, age 32)

In their open-ended responses, participants indicated that the information provided by HCPs overmedicalized and emphasized only the negative aspects of SCMs. In the clinic, this often took the form of HCPs speaking about the diagnosis in an apologetic way. Many participants stated that there are positive aspects to having an SCM that they believe should be presented at the diagnosis and in support resources.

Ask plenty of questions and ask about the benefits of living with the variation because they will emphasize the negative health hazards as of warnings but skip over the positive. (47,XXY, diagnosed age 16, age 27)

I don’t know exactly. But he just kept telling me about my negativity is all the stuff that has been plaguing me over my time. And now we know why. (47,XXY, diagnosed age 29, age 39)

While many participants called for increased or improved information about SCMs, there was a shared sense that the available information has improved in recent years. This was particularly true among individuals who were diagnosed many years ago and recalled not having any available research or ability to access information.

My doctor just gave me a name to look up, at the time the internet did not exist and the only information available was in library books, that were inadequate. (47,XXY, diagnosed age 17, age 60)

There was no information. 40 years ago research was limited. (49,XXXXY, diagnosed age 20, age 60)

Finally, participants expressed that other people who had been previously diagnosed were a valuable source of information about their lived experience and a source of support. Some participants who had been connected to support groups or patient advocacy organizations found these resources helpful in processing the diagnosis.

A panel that is led and or has participants that have experienced Klinefelter’s. Either directly or indirectly. (47,XXY, diagnosed age 37, age 38)

I’m not sure that it could have been better, but if I were 8 years old, and it was present day, I think it would be important to see examples of successful men with this condition. (47,XXY, diagnosed age 8, age 36)

Emotional and personal impact

Receiving the SCM diagnosis was an emotional experience for many participants, though coping mechanisms varied. Several participants diagnosed as adults expressed that the diagnosis explained perceived differences between themselves and others. These included physical differences, behavioral and learning challenges, and issues with socialization.

The doc gave me some printed material. Reading over the material shed a lot of light on several issues I had in school and problems with socializing with others. (47,XXY, diagnosed age 16, age 41)

My parent said I was born with another chromosome and that it could explain some of the things I did as a child and some things I do now. (47,XXX, diagnosed age 18, age 23)

Participants reported that a diagnosis of SCM negatively impacted their self-understanding. In some instances, participants reported already having a lower self-image, which the diagnosis reinforced. However, some participants seemed to indicate that their self-image was negatively impacted by receiving the diagnosis itself.

It helped me understand all the reasons why I have social problems, learning disabilities and physical issues. Actually, I wish I was never born. (47,XXY, diagnosed age 37, age 66)

It answered a lot of questions that I had about why I am not as good as other people and why I am not normal. (47,XXY, diagnosed age 40, age 43)

One of the most challenging aspects participants reported was coping with infertility. Many of the participants were diagnosed during a fertility workup and were actively trying to conceive. However, even some participants that were not currently attempting to have children struggled with the idea that they would not be able to in the future.

That I wouldn’t ever have a family of my own. because of the extra chromosome I was born sterile. That there wouldn’t be a chance. (48,XXXY, diagnosed age 30, age 50)

It was a pity to find out that I could not have children. (47,XXY, diagnosed age 40, age 43)

Because of this, many participants believed it would have been beneficial to receive their diagnosis earlier in life so they could have appropriately planed future family building. This included tempering expectations of biological parenthood at an early age and avoiding painful infertility journeys.

Knowing about all of this when I was younger, perhaps 6 years old. It might have saved a marriage, had I known. (47,XXY, diagnosed age 53, age 71)

I believe the key is being able to be diagnosed from birth or at a young age. Depending on the person especially when you’re in a marriage and trying to have kids isn’t a positive time to find out you can’t father a child. The earlier the better to be diagnosed is the best. (47,XXY, diagnosed age 16, age 41)

A few participants also suggested that proactive referrals to counseling and mental healthcare by their provider at the time of diagnosis would have been helpful in coping with the diagnosis.

A counselor would have strongly benefited me. I try to see counselors on it now but find myself educating them instead of receiving care. (47,XXY, diagnosed age 37, age 38)

It would’ve been nicer if you were to of [sic] sent me of someone who is a therapist to have really talk me [through] it. (47,XXY, diagnosed age 29, age 39)

Discussion

The experiences of patients—both positive and negative—can inform HCPs on how to deliver a SCM diagnosis in a manner that is experienced by patients as supportive and facilitates healthy adaptation. Participants who were able to access up-to-date information, supportive resources, and specialty care reported being more able to emotionally process, adapt, and develop resiliency following their diagnosis. The present shortage of genetic counselors (Hoskovec et al. 2018), as well as the increasing use of genetic testing in routine clinical care (Hull et al. 2020), means that primary care, internal medicine, and other non-genetic specialists will be increasingly likely to deliver an SCM diagnosis to adolescent and adult patients. The manner and informational content of a diagnosis delivery of SCM has a lasting impact on patient acceptance of the diagnosis, coping, and resilience (Jaramillo et al. 2019; Riggan et al. 2020, 2021). Receipt of a genetic diagnosis has been described in other contexts as a “flashbulb moment” that individuals remember for the rest of their life (May et al. 2020; Skotko 2005). It is essential that both primary care and specialty providers are equipped to deliver a genetic diagnosis.

Mode of delivery

While some participants reported that an HCP with genetic knowledge communicated the diagnosis in a manner that was sensitive to their concerns, others described experiences they perceived to be insensitive and unhelpful. This was also reflected in their fixed responses, which indicate that for most respondents, the experience was negative. While some participants described experiences that occurred decades ago, many patients with more recent diagnoses also expressed the diagnosis experience could be improved. Participants called for HCPs to provide better information and written materials regarding a diagnosis. HCPs should be aware that older and less reputable materials may reference studies from the mid-twentieth century that erroneously concluded that SCMs predisposed individuals to criminal behavior among other negative traits (Abdullah et al. 1969; Melnyk et al. 1969; Tsuboi 1970). By contrast, more recent studies among prenatally diagnosed cohorts have expanded the phenotype, including in-depth characterization of neurocognitive symptoms, and have also characterized positive attributes of SCMs (Thompson et al. 2022). Participants recommended that this more recent information, including symptom management of their particular SCM and counseling on its individual impact, is presented at the time of diagnosis.

While some patient-facing materials have been developed (Association for X and Y Chromosome Variations; Meredith 2020), few materials are tailored specifically for newly diagnosed adolescents and adults. This present gap should be met through active collaboration with the SCM patient community. Improved patient materials may also facilitate diagnosis delivery and meet the call of respondents for materials that present both the positive and negative aspects of their condition and help set expectations regarding future fertility and medical needs across the life course. In order to minimize patient distress and facilitate adaptation, HCPs should be prepared to deliver accurate information and respond to patient questions to show investment in how their patients process the diagnosis. Several comprehensive reviews on individual SCM conditions have been published in the literature (Tartaglia et al. 2010, 2011; Close et al. 2017; Davis et al. 2016), but succinct guidance on the best practices for the delivery of a SCM diagnosis has yet to be developed.

Need for support

Our participants also called for more compassionate psychosocial support at the time of diagnosis to prevent unnecessary distress. Recommendations include requests that physicians delivering the diagnosis foster a supportive and caring environment; address the complex feelings associated with learning about the diagnosis; and provide referrals to specialized counseling with professionals who were familiar with their SCM and the impact it may have on their life. The emotional and psychosocial impact of receiving a personal genetic diagnosis is well documented in the literature (Broadstock et al. 2000; Heshka et al. 2008; McAllister et al. 2007). Additionally, people with disorders of sexual development, including some SCMs, have increased psychological comorbidities, including depression, anxiety, autism spectrum disorder, and attention deficit/hyperactivity disorder (van Rijn 2019). Patients with Klinefelter syndrome are especially at risk (de Vries et al. 2019). These risks, combined with participants’ reported desires for improved emotional support, suggest a need to improve counseling services during and after genetic diagnoses to minimize long-term psychosocial impacts.

Sensitivity to stigma

A recurring aspect of the diagnostic experience that patients found particularly upsetting was insensitivity towards issues of gender and sexuality, suggesting that physicians need to be especially attuned to the impact an SCM diagnosis may have on these facets of a patient’s life and deliver the diagnosis with sensitivity to avoid patient embarrassment or discomfort. Limited evidence has shown that people with 47,XXY genotypes may be more likely to report that they do not fit within a gender binary than the general population (Herlihy et al. 2011; Herlihy and Gillam 2011). Previous studies have shown that issues related to gender have negatively impacted the psychosocial wellbeing of individual’s with Klinefelter syndrome (Herlihy et al. 2011; Turriff et al. 2017). Evolving views on gender in medicine point to approaching the topic of gender and sexuality with sensitivity and understanding during the diagnosis disclosure conversation. Participants’ experiences suggest that this effect can begin with, or be amplified by, physician attitudes and framing of the SCM. As diagnosis of SCM may also have implications for planned reproduction, physicians should recognize the dual impact of an SCM diagnosis in terms of infertility and self-identity. Infertility-related emotional distress is prevalent in general infertility diagnoses; fertility-focused psychological counseling may also be of benefit to SCM patients as well (Thorn 2009).

Strengths and limitations

This study represents the first and largest exploration of patient experiences receiving a SCM diagnosis. While small, the sample size relative to the low diagnostic rate of SCM is substantive for this population, although it skewed towards a high representation of 47,XXY compared to other diagnostic groups. However, this was expected given the higher prevalence and diagnostic rates of this condition. Additionally, participants reported variable time distances between time of diagnosis and when the questionnaire was completed. Selection bias is also a limitation as participants were recruited via the social media platforms of a national advocacy association and thus may have had a more impactful diagnosis experience or were more involved in patient support networks. Their experiences may not be reflective of underserved individuals or more ethnically diverse populations. Due to the size of this sample and the relative lack of parallel literature, findings are not generalizable and comparative statistical analyses could not be accomplished. However, the rich qualitative portion of the study provides much needed patient-centered information that may inform the development of new information and future interventions to improve care for persons with a SCM.

Conclusions

Primary care and other non-genetic providers will be increasingly called upon to deliver the diagnosis and support patients with SCM conditions as genetic evaluation becomes a more routine approach to explore symptoms with unclear etiology. Tailoring delivery of the diagnosis to reflect the different life contexts of individual patients, including comprehensive discussion with sensitivity towards their implications on gender identity/sexuality and reproduction, provision of up-to-date materials, and anticipatory guidance and specialty referral will promote adaptation and improved support of patients newly diagnosed with SCM.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contribution

Megan A. Allyse and Sharron Close conceptualized and designed the study. Data collection was conducted by Kirsten A. Riggan. Data analysis was performed by Jordan P. Richardson and Nivedita Ahlawat. Jordan P. Richardson drafted the manuscript and all authors provided feedback on earlier versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by Mayo Clinic’s Center for Individualized Medicine.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval

This study was reviewed and determined to be minimal risk by Mayo Clinic’s Institutional Review Board. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 its later amendments. This article does not contain any studies with animal subjects performed by the any of the authors.

Consent to participate

Implied informed consent was obtained for all individuals who voluntarily completed the online survey.

Consent for publication

Participants consented to have their anonymous results used for research.

Conflict of interest

The authors declare no competing interests.