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  1. SEX CHROMOSOMES ANOMALIES

  2. SEX CHROMOSOMES ANOMALIES • 45,X (Turner syndrome) • 47,XXX (XXX female) • 47,XXY (Klinefelter syndrome) • 47,XYY (YY male) • Other polygonosomies

  3. TURNER syndrome • Chromosomal nomenclature: 45,X • Frequency • In 99% of the cases: miscarriage during the first trimester or IUFD • 1/2500 female newborns • Parental age: no increased risk

  4. TURNER syndrome • CLINIC • Prenatal period • IUGR • Thickened nuchal translucency • Other abnormal echographic features

  5. TURNER syndrome

  6. TURNER syndrome • At birth • Bonnevie-Ullrich syndrome • 1. Short stature (mean 46 cm) • 2. Edema with puffy extremities • 3. Thickened neck Complete in 30% of the cases Incomplete in 70% of the cases

  7. TURNER syndrome • Post-natal period • Variable phenotype in term of severity • 1. Short stature (98%) • Present at birth • Worse during childhood (no or delayed puberty) • Mean adult height without any ttt 1,42 m

  8. TURNER syndrome • 2. Gonadal dysgenesis • Atrophy of the gonads: streak gonads • Without any ttt: no development of the secondary sexual characteristics • Primary amenorrhea

  9. TURNER syndrome • 3. Congenital malformations • Congenital heart defect in 30% of the cases: coarctation of the aorta (stenosis of the aorta) • Renal malformation in 50% of the cases: horseshoe kidney, duplicated kidney, renal agenesis

  10. TURNER syndrome • 4. Other features • Internal genitalia present but hypoplastic • Spontaneous puberty not exceptional (10 à 15% of the cases) • Sterility most of the time • Hypo or hyperthyroidy • Obesity

  11. TURNER syndrome • 4. Other features • Pterygium colli • Naevi • No or mild facial dysmorphism

  12. TURNER syndrome • 4. Other features

  13. TURNER syndrome • 4. Other features

  14. TURNER syndrome • 5. Intelligence • Within the normal range • Increased risk of delayed milestones (speech, walk…) • Differences in social cognition ? shyness, immaturity…

  15. TURNER syndrome • CYTOGENETIC • 55%: 45,X (pat post zygotic mitotic origin) • 20% mosaic • Error in meiosis • 3O% structural anomalies

  16. Isochromosome: i(Xq)

  17. TURNER syndrome • Clinical management • Treatment with growth hormone + 10 cm • Estrogen replacement therapy: normal puberty and sexual life

  18. Klinefelter syndrome • Male phenotype 47,XXY • The most frequent sex chromosome aneuploidy 1/500 (XXY) male newborns

  19. Klinefelter syndrome

  20. CLINIC At birth: normal phenotype During childhood Short penis, hypospadias Cryptorchidism Learning disability Delayed milestones Sometimes ? abnormal behavior Klinefelter syndrome

  21. Adolescence Absence or delayed puberty Gynecomastia (breast enlargement) Small testes Adult Sterility: azoospermia with sclerohyalinosis of the semineferous tubes Breast cancer .. Klinefelter syndrome

  22. Gynecomastia

  23. Klinefelter syndrome • Clinical management • Testosterone replacement therapy before puberty • No gynecomastia • Better behavior and skills • Orthophony ….

  24. Females with 47,XXX • 1/1000 of the female newborns • maternal non disjunction in meiosis (90%) • normal female phenotype (with increased stature) • Normal puberty and fertility • Intelligence • Delayed milestones → early treatment • Reduction of 10-20 points in intellectual skills

  25. Males with 47,XYY • 1/1000 of the male newborns • Normal male phenotype (with increased stature) • Normal puberty and fertility • Intelligence • Normal • Sometimes impulsive behavior

  26. 5p monosomy:cri du chat disorder • Clinical diagnosis at birth • Cat-like cry • Microcephaly • Round and flat face • Hypertelorism • Rare congenital malformations • Extremely severe encephalopathy • Long term life

  27. 5p monosomy:cri du chat disorder • Cytogenetic • de novo deletion in 90% of the cases • Rare unbalanced reciprocal translocation

  28. You are following a 14 years old girl with a puberty delay and a short stature (- 3 SD). • Which diagnosis will you suggest ? • Which exam will you ask ? • Which gene explains the short stature ? • Which genetic counseling will you deliver to the couple ?

  29. You are following a 14 years old girl with a puberty delay and a short stature (- 3 SD) without any other features. • Which diagnosis will you suggest ?

  30. TURNER syndrome • Post-natal period • Variable phenotype in term of severity • 1. Short stature (98%) • Present at birth • Worse during childhood (no or delayed puberty) • Mean adult height without any ttt 1,42 m

  31. TURNER syndrome • 2. Gonadal dysgenesis • Atrophy of the gonads: streak gonads • Without any ttt: no development of the secondary sexual characteristics • Primary amenorrhea

  32. TURNER syndrome • 3. Congenital malformations • Congenital heart defect in 30% of the cases: coarctation of the aorta (stenosis of the aorta) • Renal malformation in 50% of the cases: horseshoe kidney, duplicated kidney, renal agenesis

  33. TURNER syndrome • 4. Other features • Internal genitalia present but hypoplastic • Spontaneous puberty not exceptional (10 à 15% of the cases) • Sterility most of the time • Hypo or hyperthyroidy • Obesity

  34. TURNER syndrome • 4. Other features • Pterygium colli • Naevi • No or mild facial dysmorphism

  35. TURNER syndrome • 4. Other features

  36. TURNER syndrome • 4. Other features

  37. TURNER syndrome • 5. Intelligence • Within the normal range • Increased risk of delayed milestones (speech, walk…) • Differences in social cognition ? shyness, immaturity…

  38. You are following a 14 years old girl with a puberty delay and a short stature (- 3 SD). • Which diagnosis will you suggest ? • Which exam will you ask ?

  39. TURNER syndrome • Karyotyping • 55%: 45,X (pat post zygotic mitotic origin) • 20% mosaic • Error in meiosis • 3O% structural anomalies

  40. You are following a 14 years old girl with a puberty delay and a short stature (- 3 SD). • Which diagnosis will you suggest ? • Which exam will you ask ? • Which gene explains the short stature ? The SHOX gene located on the pseudo-autosomal region

  41. PGPL, SHOX, ANT3, ASTML, Tramp, MIC2, XG GSISX, STS, KAL1 ZFX, EIF2 UBE1, TIMP1, UTX, SMCX/XE169X XIST, RPS4X IL9R PAR: pseudo-autosomal region(s)

  42. You are following a 14 years old girl with a puberty delay and a short stature (- 3 SD). • Which diagnosis will you suggest ? • Which exam will you ask ? • Which gene explains the short stature ? • Which genetic counseling will you deliver to the couple ? There is no increased risk with the parental age. The recurrence risk is low.

  43. You are following a pregnant woman who is at 11 weeks gestation. The ultrasound examination shows a thick nuchal translucency (6 mm). • Which exam will you ask for ? Which result are you expecting ?

  44. You are following a pregnant woman who is at 11 weeks gestation. The ultrasound examination shows a thick nuchal translucency (6 mm). • Which exam will you ask for ? Which result are you expecting ? Standard karyotyping performed following a chorionic villus sample. 11-13 WG

  45. Chorionic villus sample • Miscarriage : 1-3 % • Risk of infection • Short term culture : 24-48 h • Long term culture : 2-3 weeks

  46. You are following a pregnant woman who is at 11 weeks gestation. The ultrasound examination shows a thick nuchal translucency (6 mm). • Which exam will you ask for ? Which result are you expecting ? Standard karyotyping performed following a chorionic villus sample. We expect a chromosomal anomaly, such as a Down syndrome or a Turner syndrome

  47. You are following a pregnant woman who is at 11 weeks gestation. The ultrasound examination shows a thick nuchal translucency (6 mm). • Which exam will you ask for ? Which result are you expecting ? • Karyotyping shows a Turner syndrome. The couple decide to continue the pregnancy. What could be the clinical presentation of the newborn ? Please, detail.