Psychiatric disorders and comorbidity in women with Turner Syndrome: a retrospective national cohort study

Turner syndrome (TS) is the most common chromosomal aneuploidy in females (≈1:2,500 live female births) resulting from complete or partial absence of one X chromosome, often with mosaicism. About half of individuals have 45,X monosomy; others present mosaic karyotypes (45,X/46,XX; 45,X/46,XY; 45,X/47,XXX; or X structural abnormalities). TS is sometimes classified among disorders of sex development and is associated with a characteristic neurocognitive profile. Genetic factors may influence risk for neuropsychiatric disorders (e.g., anxiety, depression), and case reports suggest associations with schizophrenia or psychosis. Given known sex differences in depression and anxiety prevalence and prior small, heterogeneous TS studies, robust data on psychiatric morbidity in TS are limited. The study’s purpose was to determine the presence and frequency of psychiatric diagnoses in adult women with TS over 25 years and to compare with age-matched female population data from Sweden.

Existing literature suggests women have higher prevalence of depression and anxiety than men. Prior small studies and case reports in TS have reported elevated lifetime depression (36–65% vs ≈21% community rates) and occasional associations with schizophrenia/schizoaffective disorder; the prevalence of bipolar disorder in TS remains unclear. Neurocognitive features in TS include difficulties in visual-spatial reasoning, attention, executive function, and motor skills, with suggested increased risk of ADHD and ASD in girls with TS. Biological contributors to mood/anxiety include hormonal fluctuations and neuroactive steroids; TS involves estrogen and androgen deficiency due to gonadal dysgenesis, potentially influencing mood. Autoimmune conditions are more prevalent in sex chromosome aneuploidies and have been linked to neuropsychiatric outcomes, though findings in TS vary. Overall, published evidence is sparse, often based on small cohorts or case reports, underscoring the need for population-based, longitudinal data.

Study design: Retrospective national cohort study with longitudinal clinical follow-up over up to 25 years, using linkage to national health registries for psychiatric diagnoses. Participants: 487 women with cytogenetically verified Turner syndrome (age ≥16 years; 16–84 years) in Sweden were recruited via Turner Centers, hospital referrals, pediatric clinic transitions, colleagues, or the national patient society. Informed consent was obtained. Approximately one third had prior growth hormone therapy; about 80% were on menopausal hormone therapy (estrogen plus progesterone, no androgen supplementation). Follow-up and clinical assessments: Participants were monitored every 5 years per national and international TS guidelines, including medical history (e.g., parity, medications), physical examinations by endocrinologists and gynecologists, blood pressure, anthropometry, blood tests, audiometry, bone mineral density, and echocardiography. Ascertainment of psychiatric diagnoses: Personal identification numbers linked participants to the Swedish National Inpatient and Outpatient Registers and the National Board of Health and Welfare databases (1994–2021). Diagnostic coding followed ICD systems: ICD-9 (codes 290–319, E950–E959) and ICD-10 (F10–F99, X60–X84). Diagnostic groupings included substance use disorders (F10–F19), schizophrenia and related (F20–F29), mood disorders (F30–F39), anxiety disorders (F40–F48), eating disorders (F50), personality disorders (F60–F62, F69), intellectual disability (F70–F79), ASD (F84), ADHD (F90), suicide attempts (X60–X84). Each registry individual is unique; duplicates across diagnostic categories were handled via ICD coding. Comparators: Age-matched female population data from Sweden (public health authority reports) served as reference prevalence estimates for psychiatric diagnoses. Statistical analysis: Means ± SD for continuous variables; Student’s t-test for continuous data; Chi-square tests for categorical variables. Two-sided p<0.05 considered significant. Software: SPSS v24.0 and SAS v9.4.

• Cohort: 487 women with TS; 71 (14.6%) had at least one psychiatric diagnosis; 416 (85.4%) had none.
• No differences between TS groups with vs without psychiatric diagnoses in age, age at TS diagnosis, karyotype distribution (monosomy/mosaic/isochromosome/Y), spontaneous puberty, cardiovascular disease, endocrine conditions (e.g., hypothyroidism, diabetes), partnership, or childbirth.
• Most common diagnoses in TS: mood disorders (47/487; 9.9%) and anxiety disorders (36/487; 7.4%).
• Comorbidity: Among 47 mood disorder cases, 30 had an additional psychiatric diagnosis. Overall, 65% of TS women with any psychiatric disease had comorbid psychiatric conditions; 35% had a single diagnosis.
• Substance use disorders: 7/487 (1.4%) vs 20–30% in the female population; p<0.00001.
• Schizophrenia and related disorders: 3/487 (0.6%) vs 0.4% in the population; p<0.00001. Total psychosis cases in TS: 5 (2 linked to bipolar disorder; 1 with developmental disorder; 1 with generalized anxiety disorder; only 1 had hypothyroidism).
• Mood disorders: 47/487 (9.9%) vs 36% in the population; p<0.00001.
• Anxiety disorders: 36/487 (7.4%) vs 11% severe and 41% moderate–mild in the population; p=0.11–0.0001.
• Eating disorders (anorexia nervosa): 2/487 (0.4%) vs 2.4% in the population; p=0.004.
• Personality disorders: 8/487 (1.6%) vs 5%; p=0.0006.
• Intellectual disability: 3/487 (0.6%) vs 0.5–1%; p=0.717–0.395.
• ASD: 3/487 (0.6%) vs 1%; p=0.395. Two ASD cases had comorbid schizophrenia (both 45,X karyotype).
• ADHD: 5/487 (1.0%) vs 7–10%; p<0.00001.
• Suicide attempts: 2/487 (0.4%) vs ≈0.3% per year; p=0.572. Suicide: 1/487 (0.2%) vs ≈0.3% per year; p=0.630.
• Alcohol-related problems in TS were associated with psychiatric comorbidity; individuals required repeated hospital care for intoxication/delirium tremens.
• Temporal trends and associations: No increase in psychiatric diagnoses over time; no associations with specific karyotypes, congenital heart disease, hypothyroidism, hormone therapy, or childbirth.
• Overall, except for schizophrenia (slightly higher in TS), most psychiatric diagnoses were less prevalent or similar in TS compared with population estimates.

Contrary to expectations from smaller studies and known risk factors (female sex, infertility, hormonal deficiencies, possible autoimmunity), women with TS in this national cohort exhibited lower prevalence of most psychiatric diagnoses than age-matched women in the general population. Mood and anxiety disorders were the most frequent in TS but remained well below population estimates. Schizophrenia spectrum disorders were the only category nominally more prevalent in TS than in the general population. Psychiatric comorbidity was common among those affected. No links were found between psychiatric morbidity and TS karyotype, cardiovascular/endocrine comorbidities, spontaneous puberty, or reproductive history. The findings may reflect effective, regular multidisciplinary follow-up and universal access to care that support overall health and well-being in TS. Despite biological and psychosocial challenges (e.g., infertility, neurocognitive profile, potential autoimmune conditions), the data do not indicate an overrepresentation of diagnosed psychiatric illness in adult women with TS. Nonetheless, psychological support during adolescence and interventions addressing self-esteem, body image, and daily-life challenges remain important, given reported social skill difficulties in TS and the burden of psychiatric comorbidity when present.

Over more than two decades of follow-up, women with Turner syndrome did not have an overrepresentation of psychiatric diagnoses compared with the general female population in Sweden. Most common psychiatric conditions (mood and anxiety disorders) were less prevalent in TS than population estimates, and no associations were observed with TS karyotype or somatic comorbidities. Further investigations are warranted to clarify psychiatric risks without overburdening women with TS with unnecessary diagnostic labels and to optimize support and treatment strategies.

• No data on family history of psychiatric diseases among women with TS.
• No clinical data available for the population-based comparator group.
• Fatigue was not systematically recorded in this cohort, limiting assessment of that symptom domain.