Transition from pediatric to adult care in patients with Turner syndrome in Italy: a consensus statement by the TRAMITI project

The transition process and its timing should be tailored to the unique needs of young adults with TS and should be based on interdisciplinary collaboration between pediatric and adult care specialists [5]. Ideally, transition should occur around the age of 18, as timely integration into an adult clinic is predictive of consistent and stable long-term follow-up (Statement A1) [12].

Early disclosure of TS diagnosis to parents and, subsequently, to the patient around the age of 11–13 years, promotes self-reliance and healthcare autonomy [5, 13]. Developmental age should take precedence over chronological age in determining communication timing (Statement A2) [14].

Since there is currently no validated TS-specific transition readiness assessment tool, the Transition Readiness Assessment Questionnaire (TRAQ) 5.0 could be recommended due to its well-defined structure and ease of use [15] (Statement A3). TRAQ is a validated instrument comprising 20 items designed to evaluate an individual's knowledge and self-assessed competencies in health-related skills [16].

In order to reduce the risk of chronic complications and comorbidities in women with TS, a timely initiation of hormone replacement therapy (HRT) for ovarian dysfunction, continued management of complications that began in childhood and proactive screening for comorbidities that may emerge in adulthood are necessary (Statement A4) [5, 17‐19]. Adolescents with TS should be informed about how their condition is likely to affect their adult lives, about the risk of complications and the need for regular follow-up and preventive care (Statement A5) [5].

Identifying disease-specific knowledge is crucial due to the significance of self-efficacy in behavioral interventions [5, 20]. Before transitioning, a comprehensive review of TS-related issues and future care plans is essential (Statement A6). Transition discussions should encompass the adolescent’s progression into adulthood, including health, independence, education, career and social aspects [5, 7, 12, 17, 21, 22]. Psychological support, educational assistance and engagement with TS support groups are all invaluable in boosting self-esteem and essential skills [5, 7, 12, 17, 21, 22].

Telemedicine can be helpful in enhancing the sharing of information between patients and clinical staff, thus bolstering the effectiveness of consultations and adherence to follow-up appointments (Statement A7). Incorporating telemedicine platforms into transition strategies offers the potential for greater flexibility in scheduling visits and mitigating social and logistical hurdles for both patients and parents [13, 23, 24]. However, it is important to recognize that telemedicine should complement, rather than supplant, in-person visits.

Various models of transition have been proposed, ranging from vertically integrated care within a single hospital to care provided across different sites within the same healthcare system [7, 25]. Ideally, transition should take place in the same hospital where the patient received pediatric care (Statement A8). An essential element of transition is a medical record summary that includes TS-specific clinical information, which should be shared by the pediatric and adult endocrinologists with the patient and their caregivers (Statement A9) [26]. The Endocrine Society offers a specialized tool, the Clinical Summary and Transfer Record for Youth with Turner Syndrome, which can be utilized as a TS-specific transition aid [15].

Both pediatric and adult endocrinologists are regarded as the driving forces within the multidisciplinary care team [13]; the first transition visit should be managed by both specialists (Statement A10).

TS is usually accompanied by hypergonadotropic hypogonadism and amenorrhea [5, 27, 28]. As a result, spontaneous puberty occurs in 21–50% of TS girls and menarche in 15–30% of patients with mosaicism [5, 27, 28]. Thus, pubertal failure is frequent in girls with TS, and most need hormonal replacement therapy (HRT) for induction or completion of puberty, maintenance of secondary sex characteristics, attaining peak bone mass and normalizing uterine growth for potential pregnancies (Statement B1). To mimic physiological initiation and/or progression of puberty, treatment should begin at 11–12 years of age, or whenever pubertal development fails to progress [27].

Although the optimal regimen for estrogen replacement therapy (ERT) in girls with TS has not been established [27], transdermal preparations of estradiol should be the preferred choice (Statement B2). In fact, ERT administered via a systemic route tends to mimic physiological estradiol secretion more closely. In contrast, when given orally estrogen reaches the systemic circulation only after absorption through the portal venous system, thus exposing the liver to a greater amount of estrogen than the rest of the body [27]. However, the oral route might be the preferred choice from the patients’ perspective and often girls ask for an oral estro-progestin pills as maintenance HRT at the end of induction.

Girls with TS usually have a normal uterus, mandating the addition of progestin after 2 years of ERT or on the occurrence of breakthrough bleeding (Statement B3) [5]. Although a 10-day treatment cycle and natural progesterone preparations are preferred, there is a paucity of evidence to support these options [5, 28].

Fertility is an area of considerable concern for individuals with TS [5], and thus fertility counseling should be undertaken as soon as diagnosis is confirmed. At transition, fertility counseling should be repeated, or conducted if it has not been undertaken before. Those with TS should be counseled that their ability to conceive decreases with age and that spontaneous pregnancies are rare (Statement B4) [5]. A fertility assessment should be performed at transition, even if conducted previously, and periodically thereafter until premature ovarian insufficiency occurs (Statement B5). However, in prepubertal girls with TS a reliable marker predicting absent pubertal ovarian activity and thus indicating the need for precocious fertility preservation is not available, even if some evidence may suggest that undetectable anti-Mullerian hormone levels predict absent pubertal onset [29]. Young women with TS and persistent ovarian function should be counseled that oocyte cryopreservation after controlled ovarian hyperstimulation or embryo cryopreservation are the best options available to preserve fertility (Statement B5) [30, 31]. Ovarian tissue cryopreservation (OTC) is an established option for those undergoing treatments that can damage the ovaries (Statement B5) and may represent the only option for prepubertal TS patients, although it should still be regarded as experimental [32]. To date, two pregnancies have been reported in patients with TS after implantation of ovarian tissue, one following autografting of ovarian tissue donated by her monozygotic twin and, more recently, a clinical pregnancy conceived naturally after re-implantation of cryopreserved ovarian tissue removed soon after spontaneous puberty [33, 34]. In addition to surgical risks and ethical issues, removal of one or part of an ovary may cause earlier premature ovarian insufficiency. All these issues, in the light of current knowledge, should be discussed with the prepubertal adolescent and her family. Since fertility preservation procedures are also invasive, potentially fraught with complications and costly, patients with TS should also be counseled about alternative paths to parenthood.

Osteopenia and osteoporosis affect approximately 50% of women with TS (Statement B6) [35, 36]. Patients with TS have a 25% increased fracture risk compared with the general population, predominantly seen during childhood and after 45 years [37, 38]. Dual-energy X-ray absorptiometry (DXA) is the gold standard for assessment of bone mineral density (BMD), although it has some limitations in TS patients. Areal BMD values obtained by DXA are influenced by bone size and short stature, thus resulting in an underestimation of BMD. Healthy lifestyle advice, including on physical activity and nutrition, should be given to patients with TS, and patients with TS should be screened for vitamin D deficiency between 9 and 11 years of age, and every 2–3 years thereafter [39].

ERT plays a pivotal role in preserving bone health in individuals with TS (Statement B7) [40‐44]. The timing of ERT initiation is crucial in safeguarding bone health in patients with TS [40, 42‐44]. It appears that the use of transdermal estrogens may have a more favorable impact on bone mass compared with oral administration (Statement B8) [45].

There is a lack of studies specifically focusing on cancer risk during the transition age in TS, with existing information primarily derived from large-scale population-based studies, which encompass patients within the transition age range [46‐50]. Standardized incidence ratios range from 0.9 to 1.82, with increased risk of benign central nervous system tumors and skin neoplasms, and a reduced risk for breast cancer [46‐50]. HRT and growth hormone treatments do not seem to affect overall cancer risk, including breast cancer, in females with TS, however, it is important to closely monitor for specific types of tumors such as thyroid carcinoma, meningioma and skin tumors (Statement B9) [49].

International guidelines advocate for prophylactic gonadectomy in patients with TS with a Y chromosome (TS + Y) upon diagnosis [5, 51]. However, only one national registry reported an increased risk of gonadoblastoma by the age of 25 in such individuals [47], and the quality of evidence behind this recommendation is rather low. Most of the germ cell tumors in patients with TS + Y described thus far are based on a small number of case reports and case series with likely publication bias, and the optimal strategy for screening and performing gonadectomy in these patients remains unclear. Cases of gonadoblastoma have been described in children (two reports of dysgerminoma at 6 and 10 years old) but generally malignant transformation occurs in older patients in their second decade [51]. A recent multicenter study evaluating 44 patients with TS + Y (19 patients aged ≥ 13 years) found that 42% of girls entered puberty spontaneously and 11% had spontaneous menarche, supporting gonadal function [52]. Gonadoblastoma was identified in seven patients (19%), one patient had in situ germ cell neoplasia and one patient had dysgerminoma (3%) [52]. In addition, a number of reports of spontaneous pregnancies and live births have been published, demonstrating that some women with TS + Y have gonadal function [53‐55]. As fertility preservation methods improve, the potential for fertility in patients with TS + Y needs to be weighed against the risk of gonadal malignancy, and discussions regarding gonadectomy conducted with these patients and their caregivers (Statement B10) [53, 54].

Although historically physicians have often withheld information from patients with sex development disorders (including TS), the current guidelines advocate for patients’ rights to be informed of their diagnosis [5, 56, 57]. Open and transparent communication with physicians is an essential part of transitioning from pediatric to adult care for patients with TS as it promotes self-awareness and identity formation [56]. The Chicago Consensus Statement underscores the importance of gradual disclosure tailored to the patient's cognitive and emotional capacities [57]. Involvement of the patient in their own treatment path is fundamental (Statement C1).

Individuals with TS typically have normal IQ levels but exhibit deficits in visual-spatial reasoning, information processing speed, working memory, executive functions and social cognition, which impact their daily life [58‐60]. These deficits also significantly affect academic performance, social interactions and occupational functioning (Statement C2) [58‐60]. Although HRT can improve some aspects of cognitive functioning, social competencies remain affected [58].

There is an increased prevalence of psychiatric disorders, especially anxiety and depression, in individuals with TS (Statement C3) [61‐64]. Cultural factors, physiological aspects and social interactions influence emotional well-being in adults with TS [65]. Anxiety and depression impair the psychological health and functioning of patients with TS (Statement C4), with anxiety exacerbating attention challenges [3].

Routine neuropsychological assessments and psycho-diagnostic evaluations aimed at detecting and treating critical neurocognitive issues are essential in early identification of psychological and emotional problems (Statement C5), especially in adolescents transitioning to adulthood (Statement C6) [66]. Standardized questionnaires and psychometric tools are recommended for screening symptoms of anxiety and depression, and any detected symptoms should prompt further assessment by mental health specialists [63, 67].

Addressing sexuality-related attitudes and behaviors in adolescents with TS prior to transitioning to adult care is vital for improved psychosocial well-being (Statement C7). Inducing puberty in alignment with physiological norms is crucial, and psychological support is especially important for patients from low socioeconomic backgrounds [68, 69].

Patients with TS often have lower QoL, particularly in psychosocial aspects, despite maintaining a stable socioeconomic status (Statement C8) [70, 71]. Life satisfaction is influenced by personal factors, and attention to self-perception and health-related sentiments is critical for improving QoL [72].

There is an increased prevalence of eating disorders among adolescents with TS, and aspects such as negative self-image, immature behavior, delayed pubertal development and HRT may contribute to their etiology (Statement C9) [73, 74].

Patients with TS frequently have various metabolic, cardiovascular and autoimmune disorders.

TS is associated with an increased incidence and prevalence of diabetes mellitus (DM) [75‐78]. DM in patients with TS is primarily caused by impaired insulin secretion due to autoimmunity or other reasons that are currently unknown [76, 77]. The time-course of insulin, glucose, and insulinogenic index in response to glycemic challenge do not differ between antibody-positive and antibody-negative individuals with DM [79]; therefore, screening for autoimmune diabetes is not recommended until DM is diagnosed. The available evidence indicates that the oral glucose tolerance test (OGTT) is superior to fasting glucose and glycated hemoglobin (HbA1c) in early DM diagnosis [77, 78, 80]. Therefore, an annual HbA1c and fasting glucose screening and a biennial OGTT screening are recommended (Statement D1).

Obesity is common in patients with TS, who have a distinct body fat distribution, characterized by increased visceral fat and reduced subcutaneous fat and lean body mass compared with women without TS [81‐86]. Therefore, body mass index (BMI) is not an effective measure of adiposity in this population and alternative measures, such as waist circumference, waist-to-height ratio and body composition analysis, should be used (Statement D2) [86].

Hepatic abnormalities, including architectural changes, alterations in liver enzymes and hepatic steatosis, are common in TS [87‐91]. Their cause remains uncertain, but congenital vascular disorders, metabolic syndrome and estrogen deficiency, environmental influences, lifestyle, genetic and epigenetic factors, may play a role [89, 91]. In addition, biliary conditions, including sclerosing cholangitis, primary biliary cholangitis, biliary atresia and a paucity of bile ducts, can develop, primarily as a result of primary hepatic vascular abnormalities [89, 92]. Liver function should be assessed annually in patients with TS and an ultrasound should be performed in case of significant and consistent abnormalities (Statement D3). Discontinuation of HRT is unwarranted as it does not cause deterioration of liver function [89, 91].

Patients with TS often have hypertension, affecting up to 25% of adolescents and between 13 and 58% of adults, and influenced greatly by factors such as race and lifestyle [93‐97]. Hypertension in TS is predominantly characterized by an elevated systolic pressure and the absence of the typical circadian variation, with abnormal nocturnal dips observed as early as infancy [93, 97]. Patients with TS should undergo at least one ambulatory blood pressure assessment annually (Statement D4). Upon an initial diagnosis of hypertension, secondary causes should be meticulously investigated and ruled out. Beta-blockers, angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACE-I) are recommended as first-line treatment for hypertension in patients with TS, while losartan can be used to reduce the growth rate of the aorta (Statement D5).

Approximately, 30% of patients with TS have congenital cardiac anomalies, with the most common being a bicuspid aortic valve and coarctation of the aorta [94, 98‐100]. These anomalies are observed more frequently in those with 45X monosomy compared with those with mosaicism and often contribute to early mortality even after surgical or percutaneous intervention [98, 99, 101, 102]. In patients with TS, electrocardiogram (ECG) abnormalities such as QT interval prolongation have been reported starting from childhood, although they are generally mild in severity [94, 103].

Aortic dilation in TS is serious and often leads to fatal dissections [94, 104‐106]. Typically originating in the ascending aorta, aortic dissections account for 2–8% of deaths in patients with TS [94, 107]. The condition occurs at an average age of 35 in those with TS, as opposed to 68 in the general population [94, 104, 108]. Aortic size index (ASI) is the primary parameter for assessing the risk of dissection [109]. During the transition phase, it is imperative for patients with TS to undergo trans-thoracic echocardiography (TTE) or cardiac magnetic resonance (CMR) assessments, as these methods provide high accuracy in measuring aortic size (Statement D6) [100, 110]. Educating affected patients about the risks of aortic dissections and the importance of early symptom recognition is essential (Statement D7). For those with TS aged ≥ 15 years, it is advisable to undertake surgical intervention for the aortic root and ascending aorta if ascending ASI is ≥ 25 mm/m², irrespective of the presence of risk factors for aortic dissection (Statement D8).

Autoimmune disorders are also prevalent in TS due to complex genetic and environmental interactions [111‐113]. Hashimoto’s thyroiditis is common, affecting approximately 50% of individuals with TS [111‐113]. Moreover, a Danish study revealed that 57% women with TS had at least one type of autoantibody, most commonly anti-thyroid peroxidase antibodies (TPO), which is significantly higher than in the general population [111]. The annual evaluation of anti-TPO antibodies is advisable for all patients with TS until positive results are obtained. Thyroid-stimulating hormone (TSH) and possibly free thyroxine (FT4) should be annually measured regardless of the presence of Hashimoto’s thyroiditis (Statement D9). In the presence of thyroid nodules and/or goiter, an ultrasound should be conducted annually (Statement D10). Screening for celiac disease should be performed every 3 years, while screening for other autoimmune diseases should be conducted in the presence of clinical indications (Statement D11).

Furthermore, it is imperative to conduct regular audiologic and sensorineural assessments for all patients to keep track of hearing loss and related complications. These assessments are crucial for ensuring psychosocial integration and enhancing QoL (Statement D12).

Reassuringly, HRT does not appear to adversely affect the risk of DM, liver enzyme abnormalities or autoimmune conditions [114‐116].