Transcript Klinefelter Syndrome

Turner Syndrome
Based on:
BRS, Big Picture, First Aid, Secrets,
Rapid Review, Essentials of Rubin’s
Genetics
• MC sex chromosome abnormality in females
• Complete or partial X monosomy
– Distribution is roughly half-and-half
• Usually a mosaic of 45,X/46,XX karyotype
– Missing X is usually father’s
– Less common mosaic: 45,X/46,XY
• Risk of gonadoblastoma
Genetics
• Less commonly caused by:
– 45,XO karyotype
• 99% miscarriage rate
• Note: no extra chromosomes  no Barr body
– Chromosome structure abnormalities
• 1 in 5000 live births
• No correlation with maternal age
• SHOX growth gene stays active on both
chromosomes  deletion = short stature
Pathophysiology
• Decreased estrogen & progesterone
• Increased pituitary gonadotropins
– 2/2 loss of feedback inhibition
• Normal GH and IGF-1
Findings
• Lots!!!
• Streaked ovaries
– 2/2 accelerated loss of oocytes
• by age 2  all gone
– Leads to amenorrhea (Turner = MC cause of)
• Menopause before menarche
– most common initial complaint
Findings
• Ovarian dysgerminoma
– Recall that Klinefelter males can get seminomas
– Gross and microscopic appearance of ovarian
dysgerminoma is very similar to seminoma
Findings
• Short stature (95%)
– 2/2 SHOX gene deletion
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Shield chest
Widely spaced nipples
Wide carrying angle
Low posterior hairline
Findings
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Lymphedema
Cystic hygroma
Webbed neck
Multiple pigmented nevi
Nail dysplasia
Findings
• Small mandible
• Prominent ears
• Epicanthal folds
Findings
• Kidney abnormalities
– Horseshoe kidney
– Malrotation
Findings
• Heart abnormalities (50%)
– Hypoplastic left heart
• Major cause of infant death
– Coarctation of the aorta
– Bicuspid aortic valve
• 1/3 of patients
Findings
• Congenital pyloric stenosis
– Projectile nonbilious vomiting
– Olive-shaped mass
• Autoimmune hypOthyroidism
Recap - Findings
• Sexual infantilism
– Amenorrhea, sterility, dysgerminoma
• MSK/derm
– Dwarfism, cubitus valgus, facial anomalies, nevi
• Lymphatic
– Lymphedema, webbed neck, cystric hygroma
• Heart
– Hypoplastic L heart, coarctation of/bicuspid aorta
• Kidney
– Horseshoe, malrotation
• Others: pyloric stenosis, Hashimoto thyroiditis
Prognosis
• Excellent when treated with GH, estrogen
• Usually normal intelligence
• Mosaic forms cause milder symptoms and
may even be fertile
• Risk of primary hypertension
– associated with aortic dissection  death
A thousand more words…
Klinefelter Syndrome
Genetics
• 2 or more X chromosomes
– Inactive X chromosome is called Barr body
• 1 or more Y chromosomes
– Guarantees male phenotype
• 82% of cases are 47,XXY
– 50% miscarriage rate
• 1 in 500 live births
• Associated with increased maternal age
Genetics
• Usually caused by maternal nondysjunction
– Occurs during meiosis I of oogenesis
– 47 chromosomes
– XXY karyotype
• Less commonly due to mosaicism
– 46,XY
– 47,XXY
Pathophysiology
• The X chromosome carries genes for:
– Androgen receptors
• Used by testosterone
– Testis function
– Brain development
– Growth
• The androgen receptor (AR) gene contains
CAG trinucleotide repeats
Pathophysiology
• Recall that testosterone mediates its
function through the androgen receptor
– Testosterone interacts best with ARs that have
the least CAG repeats
– More CAG repeats = less testosterone action
• KS causes inactivation of the X chromosome
with the shortest CAG repeats
– All you have left are the bad androgen receptors
Pathophysiology
• Result: hypogonadism
– Decreased testosterone
– Increased FSH
• and other pituitary gonadotropins
• Mechanism
– Dysgenesis of seminiferous tubules
–  decreased inhibin
–  increased FSH
Pathogenesis
• Testicular volume decreases at puberty
• Histology
– Fibrosis of seminiferous tubules
– Absence of spermatogenesis
– Loss of Sertoli cells
– Prominence of Leydig cells
• Decreased Sertoli cells leads to  FSH
– Increased FSH increases aromatase
• Aromatase converts testosterone  estradiol
Findings
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Usually undiagnosed until puberty
Developmental delay
Eunuchoid body shape
Atrophic testes
Sterility
Findings
• Long legs
– 2/2 delayed fusion of epiphyses
• Gynecomastia
• Decreased body hair
– Female hair distribution
• Hair does not extend from mons to umbilicus
Findings
• Cardiovascular abnormalities
– Mitral valve prolapse
• 50% of adults
• Endocrine abnormalities
– Increased risk of type 2 DM
• Higher risk of metabolic syndrome
Lab findings
Prognosis
• Intelligence is usually low-normal
– if not, mental retardation is proportional to
number of X chromosomes
• Higher chance of autoimmune disease
– SLE, rheumatoid arthritis, Sjögren, osteoporosis
Prognosis
• Testosterone tx virilizes but still no fertility
• Higher risk of testicular neoplasms
• 20x increased risk of breast cancer
A thousand more words…