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염색체질환 Chromosome Disorders
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  1. 염색체질환Chromosome Disorders

  2. 인류유전학Human Genetics • 임상유전학 (clinical genetics) • = 유전의학 (medical genetics) • 세포유전학 (cytogenetics) • 분자유전학 (molecular genetics) • 약리유전학 (pharmacogenetics) • 집단유전학 (population genetics) • 인종유전학 (racial genetics) • 생리유전학 (physiological genetics) • 유전생화학 (biochemical genetics) • 방사선유전학 (radiation genetics)

  3. Genetic Disorders • Cytogenetic Disorders • Cytogenetic disorders involving autosomes • Cytogenetic disorders involving sex chromosomes • Mendelian Disorders • Autosomal dominant disorders • Autosomal recessive disorders • Sex-linked (X-linked) disorders • Disorders with Multifactorial Inheritance • Disorders with Variable Genetic Backgrounds • Congenital malformations • Ehlers-Danlos syndromes(EDS) • Neoplasm

  4. Clinically Important Autosomal Abnormalities • Trisomy: 21, 18, 13, 8, 22, 9, • mosaicism for trisomic and normal cells • Partial Trisomy (duplication): 1q, 13q, 9p, 4p, 10q, • 11q, 7q, 14q, 1q, 3p, 4q, 8q, 10p, 11p, 15q, 20p • Monosomy: 21, 22 • Partial Monosomy (deletion of part): 5p, 13q, 4p, 18p, • 18q, 11q, 7p, 9p, 12p • Polyploidy : Triploidy, Tetraploidy • Chromosome breakage: Fanconi anemia, Bloom syndrome, Ataxia telangiectasia, Xeroderma pigmentosa

  5. Down Syndrome (Trisomy 21) Examples of Incidence Maternal Karyotype age • Trisomy 21 type 47,XX,+21 95% Increased • Translocation type • 46,XX,der(14;21)(q10;q10),+21 4-5% Normal 46,XX,+21,der(21;22)(q10;q10) • Mosaic type 47,XX,+21/46,XX 1% Normal • Clinical Features (1 in 1000 births) • Mental retardation, Flat facial profile, Oblique palpabral fissure, Muscle hypotonia, Hyperflexibility, Lack of Moro reflex, Abundant neck skin, Broad and short trunk, Dysplastic ears, Horizontal palmar crease, Dysplastic pelvis, • Dysplastic middle pharynx, Epicanthic folds, Acute leukemias

  6. Nondisjunctional phenomenon on meiosis

  7. 47,XY,+21 46,XY,der(21)t(21;21),+21

  8. Wide “sandal” gap Down syndrome with downslanting palpebral fissures and a slightly protruding tongue.

  9. Prominent epicanthal fold Light smudgy opaque pupil, called a Brushfield spot. Simian crease (bilateral single palmar crease)

  10. Patau Syndrome (Trisomy 13) • Karyotype Incidence • Trisomy 13 type 47,XX,+13 >80% • Translocation 46,XX,der(Dq;13q),+13 10% • Mosaic type 47,XX,+13/46,XX 5% • Clinical Features (1 in 6000 births) • Microcephaly and mental retardation, Scalp defect, Microphthalmia, Cleft palate, Polydactyly, • Rocket-botton feet, Abnormal ears, • Apneic spells and myotonic seizures, • Cardiac dextroposition and VSD, • Extensive visceral defects

  11. cleft palate, atrial septal defect, inguinal hernia, and postaxial polydactyly of the left hand. polydactyly, particularly of all extremities, strongly suggests trisomy 13.

  12. Edwards Syndrome (Trisomy 18) Karyotype Incidence • Trisomy 18 type 47,XX,+18 90% • Translocation type • 46,XX,der(Dq;18q),+18 rare • Mosaic type 47,XX,+18/46,XX 10% • Clinical feature (1 in 5000 births) • Mental retardation, failure to thrive, • prominent occiput, micrognathia and low-set ears, hypertonicity, flection of fingers, cardiac, renal and intestinal defects, short sternum and small pelvis, abduction deformity of hip

  13. mental retardation, failure to thrive, prominent occiput, micrognathia and low-set ears, hypertonicity, overlapping fingers (clenched fist) cardiac, renal and intestinal defects, short sternum and small pelvis, abduction deformity of hip

  14. A child with multiple congenital anomalies with small face, micrognathia small chest & low-set ear

  15. Cri du Chat (Cat-cry) Syndrome • Karyotype : 46,XX,5p- 46,XY,5p- • Incidence : 1 in 50,000 births • Maternal age : Normal • Clinical features • Mental retardation • Microcephaly and round facies • Mewing cry • Epicanthic folds

  16. Cri du Chat (Cat-cry) Syndrome hypertelorism, epicanthus, retrognathia Phenotype-karyotype map, based on array CGH analysis of del(5p)

  17. Wolf-Hirschhorn Syndrome chromosome deletion 4p syndrome, • Karyotype : 46,XX (XY),4p- • Incidence : 1 in 50,000 births • Maternal age : Normal • Clinical features • Mental retardation, Microcephaly and abnormal facies. Cardiac, renal, and genital abnormalities. • Most are stillborn or die in infancy wide-spaced eyes and repaired cleft lip

  18. 46,XY,del(4)(p16)

  19. Wolf-Hirschhorn Syndrome de novo deletion (WHSC1, WHSC2) ----- 87% WHSC1=Wolf-Hirschhorn syndrome candidate 1 Translocation of 4p ------ 13%

  20. Prader-Willi syndrome • Definetion: a syndrome characterized by infantile • hypotonia, hypogonadism, and obesity • Epdermiology: • incidence: 1/10,000 - 1/25,000 live births • age of onset: newborn • risk factors: paternal chromosomal damage

  21. PWS : hypotonia, feeding difficuty, developmental delay, hypogonadism, hyperphagia and obesity, dysmorphic face, hypopigmentation, intellectual disability, short status AS (Angelman Syndrome) : developmental delay, mental retardation, dysmorphic face, happy and puppet syndrome, easily provoked laughter Genetic Pathogenesis 1) del(15)(q11q13) - interstitial deletions of 15q11-q13 (SNRPN , UBE3A ) 2) uniparental disomy (UPD) father (PWS) mother (AS) 3) others : Imprinting defects

  22. DiGeorge Syndrome (DGS) 22q11 Deletion Syndrome Velocardiofacial Syndrome (VCFS) • Disease characteristics: • Congenital heart disease (74%) • Palatal abnormalities (69%) • Characteristic facial features • Learning difficulties (70 - 90%) • Diagnosis: 22q11 submicroscopic deletion

  23. Clinical Application of FISH • Microdeletion syndromes (=contiguous gene syndrome) • Prader-Willi syndrome (del 15q11.2-q13) • Angelman syndrome (del 15q11-q13) • DiGeorge/CATCH 22 syndrome (del 22q11) • Williams syndrome (del7q11.23) • WAGR syndrome (Wilm's tumor, aniridia, genitourinary malformation and mental retardation) (del 11p13) • Langer-Giedion syndrome (del 8q24) • Miller Dieker syndrome (del 17p13.3) • Smith-Magenis syndrome (del 17p11.2) • Retinoblastoma (del 13q13) • Marker chromosome (mar) • = Very small unidentified chromosome • Supernumerary chromosome • Extra structurally abnormal chromosome • Hematologic malignancies • BMT follow-up using X/Y

  24. Double Y Females (Jacob Syndrome) • Karytype : 47,XYY • Incidence : 1 in 1000 male births • Clinical features : Phenotypically normal, Most over 6 feet tall, Increased aggressive behavior(?) Multiple X Females • Karytype : 47,XXX 48,XXXX • Incidence : 1 in 1200 female births • Clinical features : Mental retardation, Menstrual irregularities, Many normal and fertile True Hermaphroditism • Karytype : 46,XX(most cases) 47,XXY/46,XX 46,XX/46,XY(rare) • Incidence : rare • Clinical features : Testicular and ovarian tissue • Varying genital abnormalities

  25. Klinefelter Syndrome • Incidence 1 in 850 male births • Karyotyoe47,XXY (classic) 46,XY/47,XXY • Clinical feature : Testicular atrophy, Azospermia, Eunuchoidism Gynecomastia, Female hair distribution, mental retardation Turner Syndrome (Gonadal Dysgenesis) • Incidence : 1 in 3000 female births • Karyotype : 45,X (classic type) 46,X,i(Xq) 45,X/46,XX • 46,XXp- 46,XXq- 46,X,r(X) • Clinical features Short stature, Primary amenorrhea, Infertility, Webbing of neck, Cubitus valgus, Peripheral lymphedema, Broad chest & wide-spread nipples

  26. Fragile X Syndrome • Incidence : about 1 in 1500 males. Affected female carriers are typically normal. • Most of the affected males have mental retardation, and their testes are larger than normal.

  27. Hermes Aphrodite Hermaphroditus The Nymph Salmacis and Hermaphroditus by François-Joseph Navez (1829)

  28. 168cm, 48kg, 35-24-35 여자보다 더 아름다운 그녀 하리수 (1975생·본명 이경엽) TRANSGENDER SEX REVERSAL

  29. Pseudohermaphroditism(假性半陰陽症) • 여성 가성반음양증 (female pseudohermaphroditism) • 여성거짓남여중간몸증 빈도 : 5,000-15,000 출생아당 1명 자궁, 질강, 난소는 정상 외성기는 애매모호하거나 남성화 선천성부신과형성증 (congenital adrenal hyperplasia, CAH)이 주원인 21-hydroxylase deficiency 17-hydroxyprogesterone증가 염색체검사: 46,XX • 남성 가성반음양증 (male pseudohermaphroditism) • Androgen insensitivity syndrome (testicular feminization) • - due to deletion of X-linked androgen receptor gene

  30. Cystourethrogram (방광요도조영술) Hypospadias (尿道下裂) Cryptorchism (潛伏睾丸) Ambiguous or masculinized external genitalia (외성기의 남성화)