Credits

• Section Writer: Dr. Om J Lakhani
• Section Editor: Dr. Om J Lakhani

Q. How common is Klinefelter syndrome (KS) ?

• 1:1000 live births

Q. Can 46 XX have KS?

• Yes
• It could be because of translocation of testis determining factor on the X chromosome

Q.  What is the difference in terms of timing of non-disjunction in 46 XXY vs. Mosaic Klinefelter's?

• 46 XXY occurs because of non-disjunction of either parent during meiosis
• Mosaicism occurs due to non-disjunction during mitotic division

Q. What is the typical psychosocial manifestation of Klinefelter's?

• Poor insight
• Lack of judgment
• Inability to learn from past adverse experiences

Q. What happens to linguistic abilities in Klienfetler's?

• Higher linguistic capacity is lost
• Sparing of vocabulary and understanding of language

Q. What happens to attention span on KS?

• Inability to sustain attention
• But no impulsivity

Q. What other systems are involved in KS?

• Pulmonary involvement- increase risk of bronchiectasis, emphysema, and chronic bronchitis
• Increased risk of germ cell tumors – including extragonadal germ cell tumors
• Increased risk of breast cancer
• Increased risk of NHL
• Increased risk of varicose veins
• SLE
• Diabetes mellitus

Q. Mortality from which cancer is reduced in Klinefelter's?

• Mortality from Prostate cancer is reduced

Q. What is the importance of CAG repeats in KS?

• The more the CAG repeats- the less the transactivation of androgen receptors
• Longer CAG repeats in KS- more tall stature, lesser BMD, and more severe the hypogonadism

Q. Enlist the essential clinical features of Klinefelter's syndrome?

• Adults
  • Infertility
  • Azoospermia
  • Pulmonary involvement- Broncheactesis etc
  • Small testis
  • Gynecomastia
  • Mitral valve prolapse
  • Osteoporosis and fracture
  • Increase the risk of cancer- breast, NHL, germ cell tumors
  • Type 2 diabetes and metabolic syndrome
• Children
  • Behavioural problems
  • Tall stature
  • Delayed puberty or pubertal arrest
  • Delayed speech
  • Cryptorchidism
  • Mediastinal cancers
  • Congenital malformation- cleft lip, cleft palate

Q. Which gene is thought to influence the phenotype in KS?

• It is probably SHOX located in XP
• This is the opposite of what is seen in Turner's, where there is SHOX haploinsufficiency

Q. What are the transcriptional targets of SHOX?

• Brain natriuretic peptide
• FGFR3

Q. Do patients with KS have a shorter lifespan?

• Yes, reduced by 1.5-2 years compared to peers

Q. Which cancers are increased in KS?

• Breast cancer- 50 times increase risk
• NHL
• Lung cancer
• Extragonadal germ cell tumors – especially mediastinal germinomas

Q. Do patients with KS have more criminal intent?

• Yes
• They have an increased likelihood to perform sexual crimes and arson
• And lesser likelihood to perform traffic offenses and drug-related crimes

Q. What is the typical testicular biopsy finding in KS?

• Hyalinization of the seminiferous tubule with Leydig cell hyperplasia

Q. When does the hyalinization of the seminiferous tubules start?

• It starts are around mid puberty when the testicular volume is around 6 ml
• Hence patients with KS have normal pubertal development till the TV of 6 ml and then arrest without further increases in the size of the testis or further pubertal development

Q. What happens to the hormones in KS patients compared to controls?

• Testosterone – lower
• Estradiol- same as control
• FSH and LH- higher
• SHBG- same as controls
• Inhibin B-, AMH- lower

Q. Do patients with KS have a higher risk of metabolic syndrome and Diabetes mellitus?

• Yes
• And this probably starts at puberty
• It is probably because of lower testosterone

Q. What is a difference in body composition in KS patients compared to controls?

• KS patients are taller and have more abdominal fat compared to peer
• BMI may be the same, but more central adiposity

Q. What is the impact on bones?

• Patients with KS have lower BMD and increase fracture risk compared to peers
• Easy to understand with lower testosterone

Q. Which neurocognitive domain is most impaired in KS patients?

• They have defective verbal communications
• They have delayed the development of speech
• They are not able to understand non-verbal cues
• Difficulty in reading and spelling
• Difficulty in syntax

Q. What about IQ?

• It is similar to controls

Q. What about arithmetic?

• Similar to control

Q. Does testosterone therapy improve neurocognitive impairments?

• Results are mixed

Q. Do patients with kS have more psychiatric problems?

• Yes
• There is more likelihood of being referred to psychiatric care in KS patients
• Patients with Schizophrenia are more likely to have KS

Management of patients with Klinefelter syndrome

Q. When is BMD-DEXA done in a patient with Kleinfeter's?

• At baseline
• Then every 2 years

Q. What care must be taken while managing children with KS?

• They must be referred to speech therapists

Q. When should testosterone be started in boys with KS?

• Must be started close to puberty
• Helps improve the androgenic status and also BMD

Q. How long should they be treated?

• They must be treated lifelong

Q. Which cancers are increased in KS?

• Breast cancer- 50 times increase risk
• NHL
• Lung cancer
• Extragonadal germ cell tumors – especially mediastinal germinomas

Q. When does the hyalinization of the seminiferous tubules start?

• It starts are around mid puberty when the testicular volume is an around 6 ml
• Hence patients with KS have normal pubertal development till the TV of 6 ml and then arrest without further increases in the size of the testis or further pubertal development

Q. When should testosterone be started in boys with KS?

• Must be started close to puberty
• Helps improve the androgenic status and also BMD

Q. How long should they be treated?

• They must be treated lifelong

Q. What should be the target while treating patients with KS?

• Bring testosterone in mid-normal range
• Mid LH in mid-normal range
• However, normalization of LH may not be feasible in all cases because of its effect on hematocrit

Q. Can patients with Klinefelter syndrome have normal Total Testosterone levels?

• Yes
• Klinefelter syndrome leads to an increase of SHBG
• Because of this, some of the patients may have low normal Total testosterone levels
• However, the free testosterone levels are surely elevated
• This is especially true for mosaic Klinefelter's

Q. Is FSH higher in Klinefelter syndrome or LH is more elevated?

• Either can be higher
• There is no fixed pattern

Q. Is the FSH value affected by biotin?

• Just like the thyroid function test, the FSH value is also often affected by a high intake of biotin (usually given for hair loss)
• FSH levels tend to be lower in patients on high biotin intake when the test is done using sandwich biotin-streptavidin capture assay