Klinefelter Syndrome

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Literature Search: 05/24/2024
• Curation Status: Released (1.0.0)

Assertions and Scores

Actionability Assertions

Variant	Condition (MONDO ID)	OMIM ID	Final Assertion
GRCh38 (chrX:?_2782275-155611794_?)x2, GRCh38 (chrY:1-57227415)x1	Klinefelter syndrome (0006823)	N/A	Strong Actionability

Actionability Assertion Rationale

• While the rubric indicated moderate actionability for both outcomes, some experts felt that the ability to address infertility for some patients combined with the endocrinology improvement supported moving to strong actionability.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Infertility / Semen collection or testicular sperm extraction (TESE) and cryopreservation	1	3A	2A	2	8AA
Morbidity from hypogonadism / Surveillance by specialist to guide management including consideration of testosterone supplementation	1	3C	2A	3	9CA

Severity of Outcome

Prevalence of the Genetic Condition

Klinefelter syndrome (KS) is the most frequent sex chromosome disorder in males. The prevalence of KS is estimated at 1-2/1000 according to studies involving systematic screening of male newborns in the 1960s and 1970s.

Clinical Features (Signs / symptoms)

Frequent characteristics of KS are small testes, azoospermia, and primary hypergonadotropic hypogonadism resulting very often in infertility. Additional features can include gynecomastia, sparse body hair, narrow shoulders, broad hips, and extended body length in relation to parentally derived target height. Neurocognitive and psychosocial manifestations can be seen. The cognitive phenotype is often described by impaired performance on measures of language development, visuospatial, and academic abilities. KS is associated with increased fat mass and reduced lean mass. Individuals with KS have an increased risk for cryptorchidism, osteoporosis, metabolic syndrome, type 2 diabetes, cardiovascular disease, deep vein thrombosis and pulmonary embolism. A reduced QTc time has been reported. The risks of developing psychiatric conditions such as schizophrenia, bipolar disorder, depression, anxiety, autism, and ADHD are increased in individuals with KS. Individuals with KS have an increased risk of some forms of neoplasia, especially breast cancer and mediastinal germ cell tumors.

Natural History (Important subgroups & survival / recovery)

The main clinical features are usually not present in infancy and childhood. During early infancy, growth of males with KS is usually within the normal range. By the age of 5-6 years, growth velocity might be accelerated resulting in significantly taller stature than expected on the basis of parental target height. Smaller penile length and lower testicular volume may be observed during childhood. In younger males with KS, a delay in speech development, dyslexia, and scholastic difficulties may be observed, whereas significant deficits in higher aspects of expressive language are more common in adolescents. At the beginning of puberty, which in general occurs at a normal age, testes grow to a minor extent and subsequently shrink. Gonadal dysfunction becomes more marked and may be associated with a failure to progress in puberty. The degeneration of germ and Sertoli cells accelerates during puberty, and extensive fibrosis and hyalinization of the seminiferous tubules occur. From around mid-puberty, testosterone and insulin-like factor 3 (INSL3) concentrations stop to increase and remain in the low-normal range in most individuals. Concomitantly, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations increase to hypergonadotropic levels. Inhibin B increases slightly during puberty and declines markedly within a year of pubertal onset, remaining undetectable from the end of puberty onwards in the vast majority

of individuals with KS. The risk of lower bone mass starts at mid-puberty. Gynecomastia can present during or after puberty. In adulthood, testes are small and firm. Males with KS exhibit an increased morbidity and mortality compared to the general male population, which results in a shortened lifespan (about 2-3 years). A reduced QTc time can lead to sudden cardiac arrest. The mean age of breast cancer in individuals with KS is 58 years, which is younger than the general male population. The high prevalence of adverse cardiovascular, metabolic, and bone-related conditions might explain the increased morbidity/mortality observed in males with KS.

Likelihood of Outcome

Prevalence of Genetic Variants

Classic KS caused by 47,XXY represents approximately 80-90% of individuals. Higher-grade aneuploidies (48,XXXY, 49,XXXXY, or 48,XXYY), mosaicism (mainly 47,XXY/46,XY) and structurally abnormal X chromosomes (47,iXq,Y) account for the remaining 10-20% of individuals.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

A review of clinical data of 130 late-pubertal adolescents with non-mosaic KS age 15–25 years reported spermatozoa (oligozoospermia) were found on semen analysis in 9/130 (7%).

Tier 3

A retrospective observational study of 166 individuals with KS aged 0.3-80.3 years reported the following clinical findings:

• Cryptorchidism: 14%

• Gynecomastia: 44%

• Osteopenia: 44%

• Osteoporosis: 5%

• Azoospermia: 95%

Tier 3

One study that performed a retrospective chart analysis for 98 individuals with KS reported the following clinical signs in pediatric individuals and adults.

Pediatric (<18 years, n=44)

• Neurodevelopmental disorders: 50%

• Small testes: 52%

• Cryptorchidism: 36%

• Gynecomastia: 25%

• Small penis: 14%

Adult (18 years or older, n=54)

• Neurodevelopmental disorders: 22%

• Small testes: 100%

• Infertility: 100%

• Gynecomastia: 31%

• Elevated FSH and LH: 100% and 83%, respectively

• Below normal testosterone: 45%

• Azoospermia: 89%

• Oligozoospermia: 11%

• Osteoporosis: 7%

Tier 3

A study that included 832 individuals with KS in a national register of hospital-admitted patients reported the following discharge diagnoses:

• Undescended testes: 5.2%

• Type 2 diabetes: 3%

• Ischemic heart disease: 8.7%

• Deep vein thrombosis: 1.7%

• Pulmonary embolism: 2.3%

• Cerebrovascular disease: 4.6%

• Osteoporotic fractures: 3.7%

• Gynecomastia: 4.4%

• Breast cancer: 0.4%

• Mediastinal tumors: 0.4%

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

The risk of deep vein thrombosis and pulmonary embolism is elevated in KS, with an overall 3- to 6-fold increased risk as compared to the general population. Individuals with KS have an increased risk of breast cancer with a 4- to 30-fold increased incidence compared with that in males with a karyotype of 46,XY.

Tier 3

Expressivity

Except for small testes, no consistent clinical features or specific abnormalities irrespective of age have been identified. The phenotypic spectrum is extremely wide. The neurocognitive phenotype of individuals with KS is highly variable.

Tier 3

Intervention Effectiveness

Patient Management

Individuals with KS and/or their parents should be offered genetic counseling. Information on fertility issues should be given at a level appropriate to the patient’s age and cognitive level.

Tier 2

Children and adolescents who need pubertal induction or sex hormone replacement to sustain puberty should be treated by a multidisciplinary team including a pediatric endocrinologist, adult endocrinologist, psychologist, urologist, geneticist, surgeon, and nurse specialist depending on the situation and specific requirements.

Tier 2

In childhood and adolescence, careful examination of the testes is recommended. Cryptorchidism in children with KS should be treated as early as possible according to the current treatment guidelines in children without KS. Testicular ultrasound may help to assess testicular development, but testicular palpation may be sufficient.

Tier 2

In cases of micro-penis, serum assessment of LH and testosterone could provide a justification for short term low-dosed systemic testosterone treatment or local application of dihydrotestosterone. Testosterone supplementation is otherwise not recommended during early childhood.

Tier 2

All individuals with KS should be fully informed on their fertility status and possibilities of fertility preservation. After careful information and assessment of the wish of the individual, semen collection and cryopreservation if motile spermatozoa are present is suggested in adolescents and recommended in all adults with a wish for paternity. Testicular biopsy for testicular sperm extraction (TESE) and consequent sperm cryopreservation is suggested for selected adolescents, provided their physical and mental maturity is apt for this decision, and recommended for all adults with confirmed azoospermia and a wish for paternity. Retrieved sperm can then be processed for use in an intracytoplasmic sperm injection (ICSI) program.

Tier 2

Two systematic reviews of TESE outcomes were found.

• A systematic review and meta-analysis of sperm recovery outcomes in individuals with KS included 37 trials enrolling a total of 1248 individuals with a mean age of 30.9 ± 5.6 years. Overall, a sperm retrieval rate (SRR) per TESE cycle of 44% was detected. Age and pre-procedure hormone levels did not affect the final SRR. Information on fertility outcome after ICSI were available for 29 trials. A total of 218 biochemical pregnancies after 410 ICSI cycles were observed (pregnancy rate = 43%). Similar results were observed when live birth rate per ICSI cycle was analyzed (43%), with an overall live birth rate of 16% for couples who initiated TESE. There was no influence of age of the individual with KS on pregnancy rate or live birth rate.

• Another systematic review and meta-analysis included 53 studies with 2965 individuals with chromosomal abnormalities who underwent sperm retrieval (2239 individuals with KS; 75.5% of the cohort). Individuals with KS had a positive SRR of 38.6%. A higher testosterone level was a significant predictor for positive SSR using TESE in KS patients (p=0.000). Lower age was significantly associated with positive SSR (p = 0.037).

Tier 1

In a review of 9 studies evaluating sperm preservation for a total of 135 adolescents and young adults with KS, using TESE, the spermatozoa retrieval rate varied between 0% and 70% in different small studies, mostly depending on the age of the participants. In the largest study included in the review, with a study population of 50 adolescents aged 13–19 years, they reported a spermatozoa retrieval rate of 38% (19/50). However, in the subgroup of adolescents aged 13–14 years, the spermatozoa retrieval rate was 10% (1/10), whereas in the subgroup of adolescents aged 15–19 years the spermatozoa retrieval rate was much higher with 45% (18/40).

Tier 2

Testosterone supplementation is recommended in adolescence in case of delayed puberty and/or symptoms of hypogonadism associated with low-normal testosterone and supra-normal LH serum concentrations. Treatment should be individualized. All males who receive pubertal induction therapy should have a structured endocrine assessment at baseline and follow-up. Testosterone substitution is also recommended in adults with low testosterone/hypogonadism, which should be started as soon as the diagnosis is made. Assessment of fertility status and TESE, if desired, should ideally be performed before the start of testosterone substitution. Testosterone substitution should follow established guidelines on hypogonadism.

Tier 2

A systematic review and meta-analysis of testosterone treatment in individuals with KS included 21 observational and 22 interventional studies with a total of 1144 individuals with KS (mean age 31.5 years). In individuals with KS and hypogonadism, testosterone treatment resulted in a significant improvement of body composition (reduction in fat mass and increase in lean mass). A significant increase in lumbar bone mineral density, but not neck, was also observed. There was no difference in BMI, waist circumference, or metabolic parameters including fasting glycemia and cholesterol.

Tier 1

A retrospective cohort analysis included 110 individuals with KS between the ages of 10 to 21 years who received testosterone replacement therapy. Average ± SD treatment duration was 23.2 ± 14.2 months. The most common route of testosterone administration was topical via a gel formulation (104 individuals) which was found to have good clinical efficacy and compliance. No adverse event associated with testosterone therapy was noted in this cohort. Only 6 of 110 (5%) adolescents did not achieve serum testosterone in the therapeutic range using testosterone gel. Average serum testosterone improved from 240 to 650 ng/ml after testosterone supplementation. There was a decrease in the number of obese individuals after the use of hormone therapy, this decrease was not statistically significant (17% vs 11%, p=0.25).

Tier 2

For bone health, adequate vitamin D and calcium supplementation is recommended in children, adolescents, and adults when needed. Weight-bearing exercises and cessation of smoking are recommended. Antiresorptive therapy is recommended in hypogonadal males at high fracture risk.

Tier 2

Suspected neurological or psychiatric deficits should be examined by respective specialists. Psychosexual and psychiatric issues should be considered in all adults with consultation by a specialist if required.

Tier 2

Most individuals identify as male, but gender incongruence has been reported in some studies. Individuals with gender incongruence should attend a respective specialist within a multidisciplinary setting. Interdisciplinary work up with mental health professionals will be mandatory.

Tier 2

Thrombosis prophylaxis is suggested for adults prior to long-term flights or exposure to other risks to attenuate the increased risk for deep vein thrombosis and/or pulmonary embolism.

Tier 2

In cases of persistent gynecomastia, systematic treatment with anti-estrogens and local treatment with a dihydrotestosterone (DHT) gel could be useful. Percutaneous treatment with DHT has been reported to be effective in small series of non-KS individuals. Surgical treatment is only recommended for patients with long-lasting gynecomastia, which does not regress spontaneously or following medical therapy.

Tier 2

Surveillance

Physical examinations in individuals with KS are recommended, including testis and mammary gland evaluation. Exams should be performed biennially during childhood, annually during puberty/adolescence, and at least annually in adults. In adults, mammary gland ultrasound is recommended, if necessary.

Tier 2

In adolescence, assessment of Tanner stages and pubertal development is recommended, along with measurement of testosterone, sex hormone binding globulin (SHBG), and gonadotropins. Assessment of signs and symptoms of hypogonadism, starting prior to the predicted start of puberty is recommended. Testicular ultrasound is suggested during puberty and every year at follow-up visits. In adults, assessment of serum concentrations of sex steroids and gonadotropins is pivotal to detect possible hypogonadism and fertility issues.

Tier 2

Growth should be monitored during childhood and adolescence assessing height, weight, waist circumference, and body proportions, starting prior to the predicted start of puberty. Whenever possible according to centiles or SDS for the reference ethnic group of the individual. In the case of excessive growth compared to estimated parental-derived target height or abnormal body proportions, bone age should be determined.

Tier 2

Assessment of vitamin D levels is recommended in childhood, adolescence, and adulthood at the first visit and then on an individual basis.

Tier 2

In adulthood, yearly assessment of weight, waist circumference, blood pressure, fasting glucose, HbA1c and lipid profile are recommended.

Tier 2

Speech development, learning abilities, social, and psychosocial problems should be monitored during childhood and adolescence.

Tier 2

An endocrine evaluation is recommended every 12 months in adults who are not on testosterone substitution.

Tier 2

For adults, assessment of 12-lead ECG QTc time at least once is suggested.

Tier 2

Dual-energy x-ray absorptiometry (DXA) analysis at the lumber and femoral levels is recommended for adults at the first visit and then on an individual basis.

Tier 2

Clinical breast and axilla examinations are suggested every two years in adults with KS and eventual mammography and/or mammary gland ultrasonography especially in those with a family history of breast cancer or other reason for suspicion thereof.

Tier 2

Circumstances to Avoid

Information regarding circumstances to avoid was not identified.

Nature of Intervention

Nature of Intervention

TESE is a surgical procedure to retrieve spermatozoa from the testes. Post-operative complications such as hematoma, devascularization, and inflammation have been described, eventually leading to scars and calcification. A decease in serum testosterone levels after a TESE procedure has also been described. A systematic review that included 15 studies (8 studies with data on 54 males with KS) found that males with KS had the strongest decrease in total testosterone levels 6 months after TESE, with a mean decrease of 4.1 nmol/l, which recovered again to baseline levels 26 months after TESE. Serum total testosterone levels decreased after TESE surgery to levels that might be related to symptoms and signs for hypogonadism.

Context: Adult Pediatric

There is a wide range of testosterone preparations available including intramuscular, transdermal, oral, subcutaneous, and intranasal. Randomized and open-label trials in young males with hypogonadism report a low frequency of serious adverse events with testosterone replacement. Common drug-related adverse events included acne, oiliness of skin, and breast tenderness. Erythrocytosis is the most frequent adverse event reported in RCTs of testosterone. Testosterone therapy is associated with a significant but small decrease in HDL cholesterol levels. Testosterone treatment may stimulate the growth of metastatic prostate cancer and breast cancer since these are hormone-dependent cancers.

Context: Adult Pediatric

Chance to Escape Clinical Detection

The main clinical features of KS are not present in infancy and childhood and may not become evident until after the onset of puberty. Phenotypic variability, and especially a presentation with mild clinical features, often leads to diagnostic delay or non-diagnosis. Despite its high incidence, it has been estimated that 50-75% of males with KS never obtain a diagnosis. Diagnosis during childhood is quite rare, representing about 10-12% of all diagnoses, as pre-pubertal clinical signs are not specific for KS. Overall, 21% are diagnosed prenatally, 16% are diagnosed at puberty, and 51% during adulthood.

Context: Adult Pediatric

Tier 3

It is common to diagnose KS in individuals when they are seeking medical care for hypogonadism, infertility, and/or sexual dysfunction.

Context: Adult Pediatric

Tier 3

Knowledge about KS diagnosis is uneven among physicians.

Context: Adult Pediatric

Tier 4

The fact that symptoms of KS rarely present simultaneously can make diagnosis more difficult.

Context: Adult Pediatric

Tier 4

Variant Condition Association

Variant Info			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			GRCh38 (chrX:?_2782275-155611794_?)x2, GRCh38 (chrY:1-57227415)x1 (CACN36920366, CACN52853040) 47,XXY			N/A	0006823

References List

Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA. (2018) Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 103(1945-7197):1715-1744.

Corona G, Pizzocaro A, Lanfranco F, Garolla A, Pelliccione F, Vignozzi L, Ferlin A, Foresta C, Jannini EA, Maggi M, Lenzi A, Pasquali D, Francavilla S, Klinefelter ItaliaN Group (KING). (2017) Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta-analysis. Human reproduction update. 23(1460-2369):265-275.

Eliveld J, van Wely M, Meißner A, Repping S, van der Veen F, van Pelt AMM. (2018) The risk of TESE-induced hypogonadism: a systematic review and meta-analysis. Human reproduction update. 24(1460-2369):442-454.

Jarvi K, Lo K, Fischer A, Grantmyre J, Zini A, Chow V, Mak V. (2010) CUA Guideline: The workup of azoospermic males. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 4(1920-1214):163-7.

Kanakis GA, Nordkap L, Bang AK, Calogero AE, Bártfai G, Corona G, Forti G, Toppari J, Goulis DG, Jørgensen N. (2019) EAA clinical practice guidelines-gynecomastia evaluation and management. Andrology. 7(2047-2927):778-793.

Majzoub A, Arafa M, Clemens H, Imperial J, Leisegang K, Khalafalla K, Agarwal A, Henkel R, Elbardisi H. (2022) A systemic review and meta-analysis exploring the predictors of sperm retrieval in patients with non-obstructive azoospermia and chromosomal abnormalities. Andrologia. 54(1439-0272):e14303.

Nordenström A, Ahmed SF, van den Akker E, Blair J, Bonomi M, Brachet C, Broersen LHA, Claahsen-van der Grinten HL, Dessens AB, Gawlik A, Gravholt CH, Juul A, Krausz C, Raivio T, Smyth A, Touraine P, Vitali D, Dekkers OM. (2022) Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline. European journal of endocrinology. 186(1479-683X):G9-G49.

Pizzocaro A, Vena W, Condorelli R, Radicioni A, Rastrelli G, Pasquali D, Selice R, Ferlin A, Foresta C, Jannini EA, Maggi M, Lenzi A, Pivonello R, Isidori AM, Garolla A, Francavilla S, Corona G, King, Klinefelter ItaliaN Group. (2020) Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis. Journal of endocrinological investigation. 43(1720-8386):1675-1687.

Radicioni AF, Ferlin A, Balercia G, Pasquali D, Vignozzi L, Maggi M, Foresta C, Lenzi A. (2010) Consensus statement on diagnosis and clinical management of Klinefelter syndrome. Journal of endocrinological investigation. 33(1720-8386):839-50.

Rochira V, Antonio L, Vanderschueren D. (2018) EAA clinical guideline on management of bone health in the andrological outpatient clinic. Andrology. 6(2047-2927):272-285.

Zitzmann M, Aksglaede L, Corona G, Isidori AM, Juul A, T'Sjoen G, Kliesch S, D'Hauwers K, Toppari J, Słowikowska-Hilczer J, Tüttelmann F, Ferlin A. (2021) European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology. Andrology. 9(2047-2927):145-167.