Turner And Klinefelter Treatment Target Study
Turner And Klinefelter Treatment Target Study
Rationale: Health related Quality of life (HRQoL) is impaired in patients with Turner and
 Klinefelter syndrome (TS and KS). It is unknown what the optimal endocrine treatment target
 values are that maximize HRQoL in patients with these syndromes. Therefore the relation
 between HRQoL and biochemical parameters will be studied in large cohorts of patients with TS
 and KS. This information will give essential insight that will help to improve endocrine
 treatment and HRQoL in these patients.

 Research objectives: To explore the relationship between biochemical parameters and HRQoL in
 patients with TS and KS.

 Hypothesis: Biochemical parameters are related to HRQoL in patients with TS and KS.

 Study design: Cross-sectional, observational, multicentre study Study population: Patients
 with KS or TS, 18 years or older Methods and procedures: To measure fatigue the Checklist
 Individual Strength (CIS-20) will be used, for QoL the 5-level EQ-5D (EQ-5D-L5) will be used
 and for stress the Perceived Stress Scale (PSS) and hair cortisol levels. For patients with
 KS the anxiety scale from the Liebowitz social anxiety scale (LSAS) will be used to measure
 social anxiety. To measure the long-term exposure to testosterone in KS patients,
 testosterone concentrations in hair will be measured. For patients with KS, all questions
 from the questionnaires will be discussed orally during a visit to the outpatients clinic.
 One extra tube of blood and a strand of hair will be collected during routine blood
 withdrawal. All other variables are already part of the standard patient care and are
 available in patient records. For patients with TS all information including the
 questionnaires and laboratory values is already available and will be collected from clinical
 records.

 Main study parameters/endpoints: The relationship between different hormonal parameters and
 HRQoL as measured by questionnaires. The main hormonal parameter that will be investigated in
 KS is testosterone in hair. For patients with Turner syndrome, free thyroxine (FT4), thyroid
 stimulating hormone (TSH) and liver enzymes, which have already been collected, will be
 investigated. The relationships between the EQ-5D-L5 score and testosterone in hair (in
 patients with KS) and thyroid hormone status (in patients with TS) are the primary outcomes.
Rationale: Health related Quality of life (HRQoL) is impaired in patients with Turner and
 Klinefelter syndrome (TS and KS). It is unknown what the optimal endocrine treatment target
 values are that maximize HRQoL in patients with these syndromes. Therefore the relation
 between HRQoL and biochemical parameters will be studied in large cohorts of patients with TS
 and KS. This information will give essential insight that will help to improve endocrine
 treatment and HRQoL in these patients.

 Research objectives: To explore the relationship between biochemical parameters and HRQoL in
 patients with TS and KS.

 Hypothesis: Biochemical parameters are related to HRQoL in patients with TS and KS.

 Study design: Cross-sectional, observational, multicentre study

 Study population: Patients with KS or TS, 18 years or older Methods and procedures: To
 measure fatigue the Checklist Individual Strength (CIS-20) will be used, for QoL the 5-level
 EQ-5D (EQ-5D-L5) will be used and for stress the Perceived Stress Scale (PSS) and hair
 cortisol levels. For patients with KS the anxiety scale from the Liebowitz social anxiety
 scale (LSAS) will be used to measure social anxiety. To measure the long-term exposure to
 testosterone in KS patients, testosterone concentrations in hair will be measured. For
 patients with KS, all questions from the questionnaires will be discussed orally during a
 visit to the outpatients clinic. One extra tube of blood and a strand of hair will be
 collected during routine blood withdrawal. All other variables are already part of the
 standard patient care and are available in patient records. For patients with TS all
 information including the questionnaires and laboratory values is already available and will
 be collected from clinical records.

 Main study parameters/endpoints: The relationship between different hormonal parameters and
 HRQoL as measured by questionnaires. The main hormonal parameter that will be investigated in
 KS is testosterone in hair. For patients with Turner syndrome, free thyroxine (FT4), thyroid
 stimulating hormone (TSH) and liver enzymes, which have already been collected, will be
 investigated. The relationships between the EQ-5D-L5 score and testosterone in hair (in
 patients with KS) and thyroid hormone status (in patients with TS) are the primary outcomes.

 Objectives:

 Primary Objective:

 To explore the relationship between thyroid hormone status* and QoL as measured by the
 EQ-5D-5L in patients with TS.

 To explore the relationship between testosterone concentrations in hair and QoL as measured
 by the EQ-5D-5L in patients with KS.

 Secondary Objective(s):

 For TS:

 The relationship between thyroid hormone status* and the CIS-20 and PSS scores. The
 relationship between liver enzymes** and the EQ-5D-5L, CIS-20 and PSS scores.

 The relationship between hair cortisol levels and the EQ-5D-5L, CIS-20 and PSS scores.

 For KS:

 The relationship between testosterone concentrations in hair and the CIS-20, LSAS and PSS
 scores.

 The relationship between hair cortisol levels and the EQ-5D-5L, CIS-20, LSAS and PSS scores.

 *Variable that consists of the following 6 categories:

 -  Overt hyperthyroidism (FT4>25pmol/L and TSH<0,4mU/L)

 -  Overt hypothyroidism (FT4 <11 pmol/L and TSH >4,3 mU/L)

 -  Subclinical hypothyroidism with TSH <10mU/L (FT4 11-25 pmol/L and TSH 4,3-10mU/L)

 -  Subclinical hypothyroidism with TSH >10mU/L (FT4 11-25 pmol/L and TSH > 10mU/L)

 -  Subclinical hyperthyroidism (FT4 11-25 pmol/L and TSH <0,4 mU/L)

 -  Euthyroidism (FT4 11-25 pmol/L and TSH 0,4- 4,3 mU/L)

 -  aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline
 phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), bilirubin, lactate
 dehydrogenase (LDH)

 Study design:

 2. STUDY DESIGN This is study is a multicentre cross-sectional cohort study with the Erasmus
 Medical Centre (EMC), the VU University Medical Centre (VUmc) and the Amsterdam Medical
 Centre (AMC) as contributing centres. The duration of the study is 26 months.

 The following data will be collected: laboratory values, fatigue scores, HRQoL scores,
 stress-scores, date of birth, age at diagnosis, height, weight, use of medication, genetic
 background, comorbidities. All information is already available in clinical records for
 patients with TS. For patients with KS information on HRQoL, fatigue and stress scores needs
 to be collected. A strand of hair to measure long-term testosterone and cortisol levels in
 hair and an extra tube of blood for storage will also be collected. This tube of blood could
 later be used to determine CAGn polymorphism in the androgen receptor, see paragraph below.
 Patients with KS visit an endocrinologist at the outpatients clinic of the AMC, VUmc or the
 EMC every one or two years and will be asked all questions of the questionnaires right after
 their appointment with the endocrinologist. The executive researcher will be present at the
 outpatients clinic to obtain informed consent and ask all questions. All laboratory values
 needed are routinely assessed at every visit for standard patient care and will be collected
 from clinical records afterwards.

 2.1 Laboratory values

 Laboratory outcomes:

 For KS: luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone in blood
 and testosterone and cortisol levels in hair.

 For TS: thyroid stimulating hormone (TSH), free T4 (fT4) and liver enzymes: aspartate
 aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase (ALP),
 gamma-glutamyl transpeptidase (GGT), bilirubin, lactate dehydrogenase (LDH) and cortisol
 levels in hair.

 2.2 Genotype The classic form of KS, which is present in the 80-90 % of the cases, is defined
 by a 47,XXY karyotype. Higher-grade aneuploidies (e.g. 48,XXXY or 48,XXYY), structurally
 abnormal X chromosome (e.g. 47,iXq,Y) or mosaicisms (e.g. 47,XXY/46,XY) make up the remaining
 10-20 % of cases.

 The most common genetic background in TS patients is a 45,X karyotype, which is present in
 approximately 60% of TS patients. Around 20% of cases of TS are caused by a mosaicism
 45X/46,XX and structural abnormalities chromosome X explain the last 20%. (26) As genetic
 background influences phenotype, information on karyotype from clinical records will be
 collected.

 2.3 Questionnaires Checklist Individual Strength (CIS-20) To measure fatigue the Checklist
 Individual Strength (CIS-20) will be used. The CIS-20 consists of 20 questions that measure
 the amount of fatigue experienced by the subject during the last two weeks. The subject has
 to indicate on a 7 point Likertscale to what extent each statement applies to him or her. The
 CIS-20 consists of 4 subscales: subjective fatigue (8 questions), concentration (5
 questions), motivation (4 questions) and activity (3 questions). The CIS-20 questionnaire has
 been validated in several populations and has proven to be a valid and reliable questionnaire
 for the assessment of fatigue. Utilization of the CIS-20 questionnaire is free, as long a
 reference to two articles is included in the publication.

 5-level EQ-5D (EQ-5D-L5) To assess HRQoL the EQ-5D-L5 questionnaire will be used. This
 questionnaire consists of two components: the EQ-5D descriptive system and the EQ visual
 analogue scale (EQ VAS). In the descriptive system the patient is asked to rate how many
 problems he or she experiences in the following five dimensions: mobility, self-care, usual
 activities, pain/discomfort and anxiety/depression. The scores for these five dimensions can
 be combined to get a number that describes the health state of the respondent. The EQ VAS is
 also a measure of health outcome. The patient is asked to indicate on a visual analogue scale
 how good he or she thinks his or her health is. References values for the Dutch general
 population are available.

 Perceived Stress Scale (PSS) To measure stress the PSS questionnaire will be used. The PSS
 consists of 10 questions that measure the degree of stress experienced by a subject after or
 during certain events during the preceding month. The PSS has proven to be a valid measure
 for perceived stress with good psychometric properties.

 Liebowitz social anxiety scale (LSAS) To measure social anxiety in patients with Klinefelter
 syndrome, the LSAS will be used. The LSAS is widely used to measure social anxiety. It
 consists of two subscales: the scale for anxiety and for avoidance. Respondents are asked to
 rate their level of fear and avoidance in 24 social situations. Research shows good
 psychometric properties. Only the scale for anxiety will be used to minimize the burden for
 the patient.

 2.4 Androgen receptor CAGn polymorphism A study by Zitzmann et al. showed an association
 between androgen receptor CAG repeats and androgen action. KS men with a shorter CAGn length
 seem to have less gynecomastia, bigger testis and higher bone density. When KS men with a
 shorter CAGn length receive testosterone replacement therapy, they show a better suppression
 of LH levels, prostate growth and higher haemoglobin concentrations. However, a more recent
 study by Valente et al. showed no relevant clinical differences in KS patients due to CAGn
 length variation on the androgen receptor. Therefore it is currently unclear whether CAG
 repeats are of clinical importance. Blood samples (buffy coat) will be collected and stored
 to be able to measure androgen receptor CAG repeats when the role of these CAGn polymorphisms
 has been clarified.

 Nature and extent of the burden and risks associated with participation, benefit and group
 relatedness:

 For patients with KS: There are no risks associated with participation. All measurements will
 take place right after a planned visit at the outpatients clinic. All subjects with KS need
 to answer questions from four questionnaires, which will take about 30 minutes (including
 collection of informed consent). The biochemical parameters measured are already routinely
 assessed during the visits to the outpatients clinic. Only one extra tube of blood will be
 collected and stored. Blood will be collected during blood withdrawal for the assessment of
 laboratory values needed for standard care. One strand of hair will also be collected.The
 burden is therefore minimal.

 For patients with TS: For patients with TS all information is already available. Therefore
 there will not be any burden or risk.

 There is no direct benefit for the participants, but all patients with KS and TS could
 benefit from better hormonal treatment in the future due to the results of this study. When
 the questionnaires indicate severe psychological problems, psychological care will be
 offered.
Inclusion Criteria:

 -  Klinefelter or Turner syndrome as confirmed by genetic testing

 -  Sufficient knowledge of the Dutch language to complete the questionnaires

 -  At least 18 years old

 Exclusion Criteria:

 -  KS: Patients not under treatment in the EMC, AMC or VUmc or no planned visits during
 the study period

 -  TS: No laboratory values or no questionnaires available in patient records

 -  Severe psychiatric or neurologic disorders or other reasons for inability to complete
 the questionnaires as assessed by the treating physician.

 -  Failure to obtain informed consent