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Klinefelter Syndrome KRISTIN CLEMENS PGY 5 ENDOCRINE ROUNDS JANUARY 30, 2013 Case 20 year old male Presents to new family doctor for physical No known medical conditions Inguinal hernia repair No medications, no significant family history Puberty at age 13, tall compared peers Development seemed to slow Learning disability, behavioural problems Didn’t finish high school Living at home Physical Exam Tall, long legs, BMI 30 kg/m2 Normal cardiac, respiratory and abdominal exams Scant facial and chest hair Bilaterally small testicles – 4mL Klinefelter syndrome? Objectives To learn about the origin of Klinefelter syndrome and understand it’s genetics To review its many clinical manifestations and associated medical co morbidities To learn how to optimally manage patients with the condition Klinefelter Syndrome Most common sex chromosome aneuploidy seen in clinical practice 1 in 500 live male births Increased maternal age ?Association with paternal age First described by Klinefelter in 1942 Reports of 9 men with gynecomastia, sparse facial and body hair, small testes and an inability to produce sperm Genetics Extra X chromosome first documented in 1959 Classically 47 XXY – 89% 48 XXXY among other variants Non-disjunction – abnormal partitioning of chromosomes Non-disjunction: Meiosis Abnormal partitioning of chromosomes during meiosis such that the resultant haploid gametes have too many or too few chromosomes Meiosis Meiotic non-disjunction Meiosis I Meiosis II genetics.thetech.org 53% result from 1st paternal meiotic non disjunction 34% from 1st maternal meiotic non disjunction 9% 2nd meiotic division Non disjunction: Mitosis Mosaic 47 XXY Mitotic non disjunction within the zygote 10% of cases Variable phenotype Typically less severe Depends on the specific tissues in which an extra X chromosome is present If normal karyotype in the testis may have intact spermatogenesis and fertility Pathogenesis: Extra X Chromosome(s) Genes of X chromosome play an important role in the sex development in males and females at the level of the gonad More than 100 X chromosome genes are expressed in the testes Genes on extra X chromosome: Testicular failure - progressive loss of germ cells, seminiferous tubule hyalinization and fibrosis Low testosterone Progressive hypogonadism Furthermore… Androgen receptor gene on X chromosome Variable CAG repeats on exon 1 Length of the highly polymorphic CAG repeat inversely related to AR activity Short lengths more stable with more marked effect of androgens Longer lengths less stable- androgen insensitivity In Klinefelter’s, at least 2 X chromosomes Shortest CAG repeat is preferentially inactivated – non-random X chromosome inactivation Less effective androgen receptor Further contributes to the phenotype Clinical Manifestations Infancy and Childhood Micropenis Small testes Normal surge of testosterone over 1-6 months Early gonadal dysfunction and decreased fetal testosterone in utero Hypospadias Cryptochordism Hypotonia Cleft palate Inguinal hernia Hypertelorism Elbow dysplasia Clinodactyly High arched palate Journal of Pediatrics Delayed developmental progress Delayed gross and fine motor skills Adjustment disorders Deficits in language and executive function Dyslexia ADHD Emotional difficulties Pre-puberty may see disproportionate lower component compared with upper Tall stature for familial size Unfused growth plates secondary to androgen deficiency Narrow shoulders, broad hips Puberty Normal onset of puberty with rise in testosterone, LH, FSH until about 13 to 14 years or Tanner stage 3 puberty Slow progression or arrest of pubertal changes Impaired Leydig cell reserve and low testosterone levels Testicles fail to increase in size and become firm due to a progressive loss of germ cells and seminiferous tubule hyalinization and fibrosis Incomplete virilization with AR instability Gynecomastia Gynecomastia 15% of estrogen secreted by testes as estradiol or estrone Rest from peripheral conversion from testosterone 95% from the testicles Adipose tissue has P450 aromatase activity important for transforming androstenedione into estrone Conversion increases with age and obesity Science Direct Breast tissue development Balance between estrogen and testosterone Estrogen stimulates the growth and differentiation of breast epithelium Androgens inhibit the growth and development of breast tissue Why gynecomastia in Klinefelter’s? High circulating LH levels stimulate aromatase activity in Leydig cells leading to higher levels of estradiol relative to testosterone Low testosterone Alteration in estrogen to androgen ratio from high estrogen or low androgen concentrations Breast tissue enlargement Adulthood Signs/symptoms of hypogonadism Infertility Gonadal failure and loss of germ cells from tubule hyalinization and fibrosis of seminiferous tubules There’s more! Osteoporosis Decreased bone mass in 20-50% of patients and osteoporosis in up to 15% Low testosterone? Testosterone aromatized to estrogen which decreases bone resorption Also effects osteoblasts directly through the androgen receptor Promotes periosteal bone formation and reduces bone resorption through adult life Need testosterone to achieve peak bone mass Ferlin et al 2011 Cross-sectional cohort study 112 treatment naïve KS XXY and 50 aged matched controls 43% of KS patients had low bone mass No significant relationship between testosterone, bone markers (calcium, phosphate, albumin, PTH, 25 hydroxyvitamin D) and bone mass CAG repeats not different in those with normal and low bone mass Likely multifactorial Other contributors may include abnormal androgen receptor, X chromosome inactivation, increase fat mass and reduced muscle mass, low vitamin D levels Low insulin like factor 3 levels produced by Leydig cells Lung pathology Bronchitis Bronchiectasis Unknown pathophysiology Malignancies Germ cell tumours Mediastinal tumours in 8% (50x expected rate) Relative risk of 67 in cancer registries Need to consider in those with known Klinefelter’s and precocious puberty Non-Hodgkins lymphoma Acute leukemia Breast cancer 20 fold increase in breast cancer Denmark cohort of 832 KS found that 3.7 to 7.5% had BC Brinton et al studied 4.5 million men in US Veterans Affairs and noted 3518 cases of male breast cancer with 642 in Klinefelters RR 16.83 (6.81-41.62) Alteration in endogenous hormone ratios, genetic predisposition, presence of gynecomastia Autoimmune conditions SLE RA Cardiovascular anomalies Mitral valve prolapse Aortic valvular disease Berry aneurysms Varicose vein Ulcers Danish registry Thromobophlebitis and venous thrombosis HR 5.29 (3.29-8.5) PE HR 3.6 (1.92-6.74) CAD HR 1.71 (1.28-2.29) Abnormalities in plasminogen 1, clotting factors, obesity Endocrine Graves disease Thyroiditis Dyslipidemia DMII DMII Jiang-Feng et al Retrospective longitudinal study of 39 men with Klinefelter’s and 40 with idiopathic hypogonadotropic hypogonadism Prevalence of diabetes in KS group was 20.5% and in the IHH group 5% Testosterone effect on insulin sensitivity IM testosterone (approximately 4 years) to keep total levels <10 nmol/L ?Testosterone effect doesn’t explain whole story Extra copy of X chromosome leads to decreased insulin sensitivity or insulin resistance Autoimmune disease? Metabolic syndrome, increased weight Increased truncal fat and waist measurements during childhood, adolescence and adulthood Variable presentation Genetics – the more X chromosomes, the more severe CAG length CAG lengths Those with short CAG repeat lengths found to have more stable relationships, higher educational levels, greater responses to testosterone treatment If long CAG and reduced AR activity, have longer arms and legs, smaller testes, lower BMD, greater degree of gynecomastia Diagnosis Important as under-diagnosed condition Only 10% diagnosed prior to puberty Under diagnosed Variable phenotype Limited awareness of condition Reduced physical observations in teens Diagnosis Can be informed of the diagnosis by prenatal screening usually for the detection of Down syndrome Karyotype or FISH for an extra X chromosome Cultured peripheral blood lymphocytes, skin fibroblasts, testicular tissue if mosaicism is suspected Other supportive tests See Barr body (X inactivation) Subject to false positives and negatives In adolescence/adulthood Increased FSH/LH in 80-90% Hypergonadotropic hypogonadism Elevated estrogen to testosterone ratio Low testosterone in 50-75% May be normal if have increased SHBG Inhibin B and AMH Low inhibin B and anti-mullerian hormone Both Sertoli cell products Inhibin B is produced the the Sertoli cell in response to FSH stimulation Markers of testicular function, may reflect loss of Sertoli cells Patient management Multidisciplinary Increased mortality and morbidity because of concomitant diseases Gynecomastia Consideration of breast reduction surgery ?Testosterone therapy may lead to regression Little data on the benefit of aromatase inhibitors and anti-estrogens on reversal of breast enlargement Learning Disabilities, Developmental Delay Social work Psychology Speech and behavioural therapy Physical and occupational therapy Hypogonadism Testosterone Topical for infants with micropenis Testosterone therapy When LH and FSH start to rise and low testosterone documented Goal of increasing linear growth, secondary sex characteristics, muscle mass BMD, libido, energy, body composition Goal to normalize LH and keep testosterone in normal range Life long therapy Adulthood? Nielson 1988 Adult KS patients treated with testosterone for 3 years – treatment naive 77% had subjective benefit from therapy Improved mood, irritability, energy and drive, better sleep and relationships with others Bone Health Other Annual breast exam CXR/CT Echocardiogram Fertility Germ cells are depleted at an accelerated rate after puberty Maturation arrest of spermatogenesis, clumping of Leydig cells Early diagnosis important Van Saen et al 7 patients with 47 XXY Followed testosterone, FSH, inhibin B, spermaturia Testicular biopsy when no increase in testicular volume, increased FSH or decreased inhibin 6/7 with extensive fibrosis and hyalinization Spermatogonia in seminiferous tubules with normal architecture in the youngest men with normal FSH and inhibin B Limited experience in banking as <10% diagnosed prior to puberty Testicular sperm extraction and ICSI TSE and ICSI TSE permits identification of the relatively few seminiferous tubules that contain active spermatogenesis and harvesting of sperm from the small testes of men with Klinefelter’s for use in ICSI More than 60 cases of success worldwide Reported pregnancy rates of 50% Risk of sex chromosome aneuploidy Genetic counseling Guidelines? Take home messages Most common sex chromosome aneuploidy Be aware of the diagnosis – patients with KS will present to different physicians at different ages and for different reasons Look for associated conditions Used team based, multi-disciplinary management References Bojesen et al. Klinefelter’s syndrome, DMII and the metabolic syndrome. Molecular Human Reproduction 2010; 16: 396-401. Bojesen et al. Klinefelter syndrome. Nature Clinical Practice 2007; 4: 192203. Endo EXPO Meet the Professor Handbook Ferlin et al. Bone mass in patients with Klinefelter’s syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism Ferlin et al. Osteoporosis in Klinefelter’s syndrome. Molecular Human Reproduction 2010; 16: 402-410. Groth et al. Klinefelter’s syndrome: an update. JCEM 2013; 98: 20-30 Jiang-Feng et al. Prevalence and risk factors of diabetes in patients with Klinefelter’s syndrome. Fertility and Sterility 2012; 98: 1331-1335. Sokol et al. It’s not all about the testes: medical issues in patients with Klinefelter’s syndrome. Fertility and Sterility 2012; 98: 261-265 Van Saen et al. Can pubertal boys with Klinefelter’s benefit from sperm banking? Human Reproduction 2012; 27: 322-330. Williams Textbook of Endocrinology Thank you!