Thyroid Function and Structure IN Klinefelter Syndrome

Study Overview
=================
Brief Summary
-----------------
This is a longitudinal retrospective study for the evaluation of thyroid function and structure in patients with Klinefelter syndrome compared to healthy controls and patients affected by chronic lymphocytic thyroiditis.

Detailed Description
-----------------
This is a longitudinal retrospective study for the evaluation of thyroid function and structure in patients with Klinefelter syndrome compared to healthy controls and patients affected by chronic lymphocytic thyroiditis (CLT). The investigators will retrospectively enroll patients with Klinefelter syndrome followed at the host institution and will retrieve data with regards to peripheral hormone levels (thyroid function) and ultrasonographic appearance (thyroid structure) according to pubertal status and gonadal status. Data will be compared with male age- and pubertal stage-matched euthyroid controls, as well as with male patients affected by CLT. The primary outcome will be the thyroid function compared to healthy controls, by the assessment of peripheral blood TSH, free T3 (fT3) and free T4 (fT4) levels according to pubertal status (pre-pubertal, pubertal and adult subjects) as well as according to gonadal status (eugonadal subjects, hypogonadal subjects and subjects receiving testosterone replacement therapy [TRT]). Secondary Outcome Measures will be: Thyroid function indexes (fT3/fT4 ratio, fT4/TSH ratio, TSH*fT4 product) Quantitative ultrasonographic thyroid structure parameters, comprising: thyroid volume and echogenicity index, as well as the echotexture parameters of homogeneity and entropy evaluated by Gray Levels Co-occurrence Matrices (GLCM). In vitro assay of testosterone and estradiol effects on deiodinase type 2 (DIO2) activity in a rat pituitary cell line.

Official Title
-----------------
Thyroid Function and Structure IN Klinefelter Syndrome

Conditions
-----------------
Klinefelter Syndrome, Thyroiditis, Autoimmune, Hypothyroidism

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with a confirmed diagnosis of classic, non-mosaic 47,XXY Klinefelter syndrome based on a peripheral blood 97 karyotype analysis; Availability of thyroid function test results (TSH, fT3, and fT4) and/or thyroid US imaging; Availability of concurrent clinical data. Exclusion Criteria: Presence of other known genetic conditions or chromosomal abnormalities; Use of levothyroxine or other drugs that are either active on the hypothalamic-pituitary-thyroid (HPT) axis or that may interfere with thyroid function tests; History of previous surgery or radiotherapy on the thyroid or pituitary glands; Current or previous T therapy (for the pre-pubertal and pubertal groups).

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
Male

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Klinefelter syndrome<br>Males affected by 47,XXY non-mosaic Klinefelter syndrome. Subgroups according to pubertal stage: pre-pubertal, pubertal and adults. Subgroups according to gonadal status: eugonadal, hypogonadal and receiving testosterone replacement therapy (TRT). | |
| Healthy controls<br>Euthyroid, age- and pubertal stage-matched males Subgroups according to pubertal stage: pre-pubertal, pubertal and adults. | |
| Chronic lymphocytic thyroiditis<br>Adult males affected by chronic lymphocytic thyroiditis | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral blood TSH concentration | Thyroid function will be assessed by peripheral blood TSH levels, taking into account pubertal status (pre-pubertal, pubertal and adult subjects) as well as to gonadal status (eugonadal subjects, hypogonadal subjects and subjects receiving TRT). | Through study completion, an average of 6 years | 
| Peripheral blood fT3 concentration | Thyroid function will be assessed by peripheral blood free T3 (fT3) levels, taking into account pubertal status (pre-pubertal, pubertal and adult subjects) as well as to gonadal status (eugonadal subjects, hypogonadal subjects and subjects receiving TRT). | Through study completion, an average of 6 years | 
| Peripheral blood fT4 concentration | Thyroid function will be assessed by peripheral blood free T4 (fT4) levels, taking into account pubertal status (pre-pubertal, pubertal and adult subjects) as well as to gonadal status (eugonadal subjects, hypogonadal subjects and subjects receiving TRT). | Through study completion, an average of 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral deiodinase 2 (DIO2) activity | The investigators will derive the the fT3/fT4 ratio as a surrogate marker of peripheral deiodinase 2 (DIO2) activity. | Through study completion, an average of 6 years | 
| Pituitary sensitivity sensitivity to thyroid hormones | The investigators will derive the fT4/TSH ratio as surrogate marker of pituitary sensitivity. | Through study completion, an average of 6 years | 
| Thyroid hormone resistance index | The investigators will derive the TSH*fT4 product as a surrogate marker of thyroid hormone resistance. | Through study completion, an average of 6 years | 
| Thyroid volume | The investigators will assess ultrasonography-derived thyroid volume (in mL) by the sum of the left and right lobe volumes, derived by the ellissoid formula (d1 x d2 x d3 x 0,5233). | Through study completion, an average of 6 years | 
| Quantitative thyroid echogenicity | The investigators will assess the ultraonographic thyroid echogenicity index, derived by the histogram mean of thyroid parenchyma in a standardized scan, normalized by the histogram mean of the pre-thyroid muscles. | Through study completion, an average of 6 years | 
| Thyroid echotexture (homogeneity) | The investigators will assess the ultrasonographic thyroid parenchymal echotexture via the analysis of Grey Levels Co-occurrence Matrices (GLCM) second-order parameter homogeneity (or IDM). | Through study completion, an average of 6 years | 
| Thyroid echotexture (entropy) | The investigators will assess the ultrasonographic thyroid parenchymal echotexture via the analysis of Grey Levels Co-occurrence Matrices (GLCM) second-order parameter entropy. | Through study completion, an average of 6 years | 
| In vitro assay of deiodinase type 2 (DIO2) activity | The investigators will assess in vitro modulation of DIO2 activity by sex hormones testosterone and 17-beta estradiol in a rat pituitary cell line (GH4C1) by using a thyroid hormone-responsive artificial promoter (TRE3Tk-Luc). | At study end (May 2022). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Klinefelter syndrome, Hypothyroidism, Thyroiditis, Puberty, Prepuberty, Testosterone