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Clinical practice guidelines for the care of girls and women with Turner syndrome

Clinical practice guidelines for the care of girls and women with Turner syndrome

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting

 

Abstract


Turner syndrome affects 25–50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS.

 

This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy.

 

The guidelines project was initiated by the European Society of Endocrinology and the Pediatric Endocrine Society, in collaboration with the European Society for Paediatric Endocrinology, the Endocrine Society, the European Society of Human Reproduction and Embryology, the American Heart Association, the Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society of Endocrinology, the Pediatric Endocrine Society, the European Society for Paediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.

 

1. Summary of recommendations


The recommendations (R) are worded as recommend (strong recommendation) and suggest (weak recommendation). We formally graded only the evidence underlying recommendations for therapeutic choices. The quality of evidence behind the recommendations is classified as very low (⨁◯◯◯), low (⨁⨁◯◯), moderate (⨁⨁⨁◯) and strong (⨁⨁⨁⨁). See further section ‘Summary of methods used for guideline development’.

 

1.1. Diagnosis and genetics


R 1.1. We recommend considering a diagnosis of TS in phenotypic females with a karyotype containing one X chromosome and complete or partial absence of the second sex chromosome, associated with one or more typical clinical manifestations of TS (⨁⨁⨁⨁).

R 1.2. We recommend against considering a diagnosis of TS in females with one X chromosome and a deletion distal to Xq24 on the other X chromosome, and in women over the age of 50 years with less than 5% 45,X mosaicism (⨁⨁◯◯).

R 1.3. We suggest that the new general surveillance management guideline applies to TS patients with any karyotype (⨁⨁◯◯).

R 1.4. We recommend to consider testing for Turner syndrome (TS) in a female with typical signs (Table 2) (⨁⨁⨁⨁).

R 1.5. We recommend gonadectomy in all female individuals with Y chromosome material identified on standard karyotyping (⨁⨁◯◯).

 

2. Growth and puberty


R 2.1. We recommend initiating growth hormone (GH) treatment early (around 4–6 years of age, and preferably before 12–13 years) in the following circumstances: the child already has evidence of growth failure (e.g., below 50th percentile height velocity (HV) observed over 6 months in the absence of other treatable cause of poor growth), the child is already short or has a strong likelihood of short stature (e.g., short parents and short predicted adult height or already pubertal at the time of diagnosis) (⨁⨁⨁◯).

R 2.2. We recommend using a GH dose of 45–50 µg/kg/day or 1.3–1.5 mg/m2/day (4.0–4.5 IU/m2/day) in most instances, increasing to 68 µg/kg/day (2.0 mg/m2/day) if adult height potential is substantially compromised (⨁⨁⨁⨁).

R 2.3. We recommend monitoring growth-promoting treatment by measurement of height at least every 4–6 months during the first year of treatment and at least every 6 months thereafter (⨁⨁⨁◯).

R 2.4. We recommend monitoring the safety of growth-promoting therapy by measurement of IGF-I at least annually (⨁⨁◯◯).

R 2.5. We suggest that for TS patients treated with GH the measured IGF-I should ideally be no greater than 2 SDS above the mean for age. If an IGF-I value is measured above +3 SDS, a GH dose decrease is warranted. For an IGF-I value between +2 SDS and +3 SDS, clinical judgment should guide further GH dose selection (⨁◯◯◯).

R 2.6. We suggest concomitant treatment with oxandrolone from the age of 10 years or older at 0.03 mg/kg/day and maintained below 0.05 mg/kg/day, if the diagnosis of TS (and therefore GH treatment initiation) is delayed, and/or adult height outcome is likely to be unsatisfactory with the standard GH dose alone (⨁⨁⨁⨁).

R 2.7. We suggest to not routinely add very-low-dose estrogen supplementation in the prepubertal years to further promote growth (⨁⨁◯◯).

R 2.8. We recommend that estrogen replacement should start between 11 and 12 years of age increasing to adult dosing over 2–3 years (⨁⨁⨁◯).

R 2.9. We suggest that low-dose estradiol (E2) is the preferred estrogen and that it be administered by a systemic route and that the transdermal route is preferred (⨁◯◯◯).

R 2.10. We recommend adding progesterone once breakthrough bleeding occurs, or after 2 years of estrogen treatment (⨁⨁⨁⨁).

 

3. Fertility, assisted reproductive technologies and pregnancy


R 3.1. We recommend counseling females with TS that their probability to conceive spontaneously decrease rapidly with age, if at all present, and consideration should be given to offering fertility treatment at a young age (⨁⨁⨁⨁).

R 3.2. We suggest that young mosaic TS women with persistent ovarian function should be counseled that oocyte cryopreservation after controlled ovarian hyperstimulation is a possible fertility preservation option (⨁◯◯◯).

R 3.3. We recommend against routine oocyte retrieval for fertility preservation of young TS girls before the age of 12 years (⨁◯◯◯).

R 3.4. We recommend considering oocyte donation for fertility, only after thorough screening and appropriate counseling (⨁⨁⨁⨁).

R 3.5. We recommend that management of pregnant women with TS should be undertaken by a multidisciplinary team including maternal–fetal medicine specialists and cardiologists with expertise in managing women with TS (⨁⨁⨁◯).

R 3.6. We suggest that other options for motherhood such as adoption or using a gestational carrier should be mentioned during preconception counseling (⨁◯◯◯).

R 3.7. We suggest that all women with TS should be counseled about the increased cardiovascular risk of pregnancy (⨁◯◯◯).

R 3.8. We recommend imaging of the thoracic aorta and heart with a transthoracic echocardiography (TTE) and CT/cardiac magnetic resonance scan (CMR) within 2 years before planned pregnancy or assisted reproductive therapy (ART) in all women with TS (⨁◯◯◯).

R 3.9. We suggest that ART or spontaneous conception should be avoided in case of an ascending aortic size index (ASI) of >2.5 cm/m2 or an ascending ASI 2.0–2.5 cm/m2 with associated risk factors for aortic dissection (AoD), which include bicuspid aortic valve, elongation of the transverse aorta, coarctation of the aorta and hypertension (⨁◯◯◯).

R 3.10. We suggest that women with a history of AoD should be advised against pregnancy. If already pregnant these women should be followed very closely at a specialist center and deliver by cesarean section (⨁◯◯◯).

R 3.11. We suggest performing TTE in women with TS without aortic dilatation or other risk factors (hypertension, bicuspid aortic valve, coarctation, previous aortic surgery) at least once during pregnancy, at approximately 20 weeks of gestation (⨁◯◯◯).

R 3.12. We suggest that women with TS with an ascending ASI >2.0 cm/m2 or any risk factor (hypertension, bicuspid aortic valve, coarctation, previous AoD or surgery) should be monitored frequently, including TTE at 4- to 8-week intervals during pregnancy and during the first 6 months postpartum (⨁◯◯◯).

R 3.13. We suggest that CMR imaging (without gadolinium) should be performed during pregnancy when there is suspicion of disease of the distal ascending aorta, aortic arch or descending aorta (⨁◯◯◯).

R 3.14. We recommend that blood pressure control is strict (135/85 mmHg) in all pregnant women with TS (⨁◯◯◯).

R 3.15. We suggest that during pregnancy, prophylactic surgery is reasonable in case of a dilated aorta with rapid increase in diameter (⨁◯◯◯).

R 3.16. We suggest that in case of an acute ascending AoD before the fetus is viable, to perform emergency aortic surgery understanding that fetal viability may be at risk. If the fetus is viable, it is reasonable to perform cesarean section first, followed by aortic surgery, which should be performed under near-normothermia, pulsatile perfusion, high pump flow and avoidance of vasoconstrictors (⨁◯◯◯).

R 3.17. We suggest that exercise testing before pregnancy can be useful to reveal exercise induced hypertension, especially in women with coarctation (⨁◯◯◯).

R 3.18. We suggest that women with aortic dilatation, bicuspid aortic valve, elongation of the transverse aorta, coarctation of the aorta and/or hypertension should be advised that pregnancy would carry a high risk of AoD (⨁◯◯◯).

R 3.19. We suggest that vaginal delivery is reasonable in women with TS with an ascending ASI below 2.0 cm/m2 (⨁◯◯◯).

R 3.20. We suggest that in women with TS with an ascending ASI of 2.0–2.5 cm/m2, a vaginal delivery with epidural anesthesia and expedited second stage is preferred or a cesarean section may be considered. In women with TS with an ascending ASI >2.5 cm/m2, a cesarean section is reasonable or a vaginal delivery with epidural anesthesia and expedited second stage may be considered (⨁◯◯◯).

R 3.21. We recommend that in women with TS with a history of AoD, a cesarean section should be performed (⨁◯◯◯).

 

4. Cardiovascular health issues in Turner syndrome


R 4.1. We recommend that an infant or child is examined with transthoracic echocardiography (TTE) at the time of diagnosis, even if the fetal echocardiogram or postnatal cardiac examination was normal (⨁⨁◯◯).

R 4.2. We recommend that girls or women with aortic dilatation and/or bicuspid aortic valve be counseled to seek prompt evaluation if they are experiencing acute symptoms consistent with AoD, such as chest, neck, shoulder, back or flank discomfort, particularly if it is sudden in onset and severe (⨁⨁◯◯).

R 4.3. We recommend that women with TS demonstrating an increase in TS-specific Z-score of 1 in aortic diameter or an increase of >0.5 cm over a one-year period, need an optimization of medical treatment and surgical consultation (⨁⨁◯◯).

R 4.4. We suggest that elective operations for aneurysm of the aortic root and/or ascending aorta are reasonable for women with TS who are ≥16 years of age with an ascending ASI ≥2.5 cm/m2 and associated risk factors for AoD, including bicuspid aortic valve, elongation of the transverse aorta, coarctation of the aorta and/or hypertension according to standard definitions (⨁◯◯◯).

R 4.5. We suggest that elective operations for aneurysm of the aortic root and/or ascending aorta may be considered for women with TS who are ≥16 years of age with an ascending ASI ≥2.5 cm/m2, and no associated risk factors for AoD (⨁◯◯◯).

R 4.6. We suggest that elective operations for aneurysm of the aortic root and/or ascending aorta may be considered for women with TS, who are <16 years of age, and for whom their ascending aorta TS-specific Z-score is ≥4.0, with or without associated risk factors for AoD (i.e., bicuspid aortic valve, elongation of the transverse aorta, coarctation of the aorta and/or hypertension) (⨁◯◯◯).

R 4.7. We recommend that in adolescents and adults TS cardiovascular screening with TTE and CMR at the time of diagnosis is the preferred approach (⨁⨁◯◯).

R 4.8. We recommend that a CMR scan is performed as soon as it is feasible without needing general anesthesia. If an adult or child cannot tolerate a CMR study, a CT scan is a reasonable option (⨁⨁◯◯).

R 4.9. We recommend, in the absence of a bicuspid aortic valve or other significant disease at the initial screening, TTE or CMR surveillance studies should be performed every 5 years in children, every 10 years in adults, or prior to anticipated pregnancy (see R 3.8) to evaluate the aorta based on published guidelines (⨁⨁◯◯).

R 4.10. We recommend that, if TS is highly suspected or has been confirmed prenatally, a fetal echocardiogram should be performed (⨁⨁◯◯).

R 4.11. We recommend that diagnosis of a bicuspid aortic valve or a left-sided obstructive lesion in a female fetus or child should prompt a genetic evaluation for TS (⨁⨁◯◯).

R 4.12. We recommend referral to a pediatric cardiologist when congenital heart disease is detected prenatally in a fetus with TS to provide counseling regarding the anatomy and physiology of the specific defect, recommended site and mode of delivery and postnatal multidisciplinary management plan (⨁⨁◯◯).

R 4.13. We suggest that a resting electrocardiogram (ECG) with QTc measurement should be done in every individual with TS at the time of diagnosis and that Hodge’s may be preferred over Bazett’s formula to estimate QTc (⨁⨁◯◯).

R 4.14. We suggest that 24-h Holter monitoring and exercise testing be considered for risk estimation in women with TS with QTc interval prolongation (QTc >460 ms) (⨁◯◯◯).

R 4.15. We suggest that, in individuals with prolonged QTc, drugs that prolong the QTc should be avoided. If they are deemed necessary, ECG should be performed 1–2 weeks after initiation of QT-prolonging drugs (⨁◯◯◯).

R 4.16. We recommend that the function of the aortic valve and the presence of any other congenital heart disease and/or hypertension should be considered in determining participation recommendations for the athlete with TS and aortic dilation (⨁◯◯◯).

R 4.17. We suggest that, for girls and women with TS ≥16 years with a moderately dilated aorta (ascending ASI ≥2.0 cm/m2), avoidance of intense weight-training should be advised (⨁◯◯◯).

R 4.18. We suggest that, for girls and women with normal aortic size (age <16 years; TS-specific Z-score of <2.5 or age ≥16 years and ASI <2.0 cm/m2), it is reasonable to participate in all sports (⨁◯◯◯).

R 4.19. We suggest that, for girls and women with a mild to moderately dilated aorta (age <16 years old (TS-specific Z-score of 2.5–3), or age ≥16 years (ASI 2.0–2.3 cm/m2)), participation in low and moderate static and dynamic competitive sports may be advised (⨁◯◯◯).

R 4.20. We suggest that girls and women with a moderately to severely dilated aorta, age <16 years (TS-specific Z-score of >3) or age ≥16 years (ASI >2.3 cm/m2) should be advised not to participate in any competitive sports (⨁◯◯◯).

R 4.21. We recommend that in individuals without structural heart disease, annual assessment of blood pressure should be performed and medical treatment thereof should be considered if hypertension is present. We suggest medical treatment to include a beta-blocker, an angiotensin receptor blocker or both to reduce the risk for AoD in women with TS who are ≥16 years of age for whom their ascending ASI is ≥2.3 cm/m2 (⨁⨁◯◯).

R 4.22. We suggest that medical treatment, including a beta-blocker, an angiotensin receptor blocker or both, to reduce dilatation of an enlarged aortic root and/or ascending aorta may be considered for girls with TS who are ≤16 years of age for whom their ascending aorta TS-specific Z-score is ≥3.0 (⨁◯◯◯).

 

5. Transition from pediatric to adult care


R 5.1. We recommend that the pediatric endocrinologist (or any other TS care provider/coordinator) implements a planned and staged transition process in early adolescence for their patients with TS (⨁⨁◯◯).

R 5.2. We suggest that the pediatric endocrinology team uses or adapts available transition tools to track and document the core elements of transition (⨁⨁◯◯).

R 5.3. We suggest that, irrespective of the health care delivery system, the pediatric and adult health care teams establish a workflow to support a coordinated transition process (⨁⨁◯◯).

R 5.4. We suggest that pediatric endocrinologists and their care teams encourage peer-to-peer (and parent-to-parent) contact with TS support and advocacy organizations to enhance knowledge and confidence, reduce stress and distress and promote the reciprocal sharing of experiences (⨁⨁◯◯).

 

6. Health surveillance for comorbidities throughout the lifespan


R 6.1. We recommend a formal audiometric evaluation every 5 years regardless of the initial age at diagnosis, initial hearing threshold levels, karyotype and/or presence of a mid-frequency sensorineural hearing loss, to assure early and adequate technical and other rehabilitative measures (⨁⨁◯◯).

R 6.2. We recommend aggressive treatment of middle-ear disease and otitis media (OM) with antibiotics and placement of myringotomy tubes as indicated (⨁⨁◯◯).

R 6.3. We recommend screening for hypothyroidism at diagnosis and then annually with (free) T4 and TSH measurements beginning in early childhood and throughout the lifespan (⨁⨁◯◯).

R 6.4. We suggest counseling on healthy nutrition and physical activity starting in early childhood (⨁⨁◯◯).

R 6.5. We recommend lifelong annual measurement of HbA1c with or without fasting plasma glucose starting at age of 10 years (⨁⨁◯◯).

R 6.6. We recommend that a lipid profile be performed in individuals who have at least one risk factor for cardiovascular disease starting at age 18 years (⨁⨁◯◯).

R 6.7. We recommend that, while peripheral edema mostly resolves by 2 years of age without therapy, any serious compromise of fingernails, toenails or extremity skin at any age be assessed and treated by a professional edema therapist (⨁◯◯◯).

R 6.8. We recommend dental/orthodontic evaluation at diagnosis if no previous dental/orthodontic care was established. Future management and follow-up should be based on the standard of dental/orthodontic care, individual clinical findings and patient needs (⨁◯◯◯).

R 6.9. We recommend a comprehensive ophthalmolo­gical examination between 12 and 18 months of age or at the time of diagnosis, if at an older age, with emphasis on early correction of refractive errors (⨁◯◯◯).

R 6.10. We recommend clinical evaluation for scoliosis every 6 months during GH therapy or otherwise annually until growth is completed (⨁◯◯◯).

R 6.11. We suggest treatment with GH be coordinated with orthopedic care if spine abnormalities are present at the start of therapy or if they develop during therapy (⨁◯◯◯).

R 6.12. We recommend that all patients should be counseled on healthy lifestyle measures, and on the role of estrogen replacement in bone health (⨁⨁◯◯).

R 6.13. We recommend that dietary intake of calcium and vitamin D follow region-specific recommendations (⨁⨁◯◯).

R 6.14. We suggest screening for vitamin D deficiency with a serum 25-hydroxyvitamin D measurement between 9 and 11 years of age and every 2–3 years thereafter throughout the lifespan and treating with inactive vitamin D (ergocalciferol) as necessary (⨁◯◯◯).

R 6.15.  We suggest using dual energy X-ray absorptiometry (DXA) scans to monitor bone mineral density after adult hormone replacement therapy has been instituted (⨁⨁◯◯).

R 6.16. We recommend using DXA scans to monitor bone mineral density in all women when considering discontinuation of estrogen therapy (simulating menopause) (⨁⨁◯◯).

R 6.17. We recommend screening for celiac disease by measurement of transglutaminase antibodies beginning at 2–3 years of age at a frequency of every 2 years throughout childhood and with suggestive symptoms in adulthood (⨁◯◯◯).

R 6.18. We recommend monitoring liver function tests (including AST, ALT, GGT and alkaline phosphatase) yearly throughout the lifespan starting at age 10 years (⨁⨁◯◯).

R 6.19. We recommend appropriate timing (see R 2.8) for the initiation of female hormone replacement therapy for improvement of liver function (⨁⨁◯◯).

R 6.20. We recommend a renal ultrasound at the time of diagnosis (⨁⨁⨁⨁).

R 6.21. We recommend that girls and women with TS attend specialist interdisciplinary or multidisciplinary clinics for health surveillance (⨁⨁◯◯).

 

7. Neurocognitive and behavioral aspects


R 7.1. We recommend that neuropsychology and allied behavioral health services is integrated into the care for girls and women with TS (⨁⨁⨁◯).

R 7.2. We recommend annual developmental and behavioral screenings until adulthood with referrals as indicated (⨁⨁⨁◯).

R 7.3. We suggest conducting neuropsychological assessments at key transitional stages in schooling (⨁⨁◯◯).

R 7.4. We recommend academic and occupational adjustments if indicated, to accommodate learning/performance issues (⨁⨁⨁◯).

R 7.5. We recommend aiming for on-time puberty and aggressive management of predictors of hearing impairment to facilitate positive psychosocial and psychosexual adaptation (⨁⨁◯◯).

R 7.6. We suggest that evidence-based interventions for cognitive or psychosocial problems in other populations may be adapted to meet the needs of girls/women with TS (⨁◯◯◯).

 

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