Genetic and Pediatric Diseases

1. Genetic and Pediatric Diseases Jan Laco, M.D., Ph.D.

2. Genetic diseases 20% pediatric patients hereditary = derived from one´s parent familial = transmitted through generations congenital = present at birth

3. Genetic diseases 1. Mendelian disorders defect of single-gene with large effect 2. Disorders with multifactorial inheritance polygenic > 2 genes with small effect + environment 3. Cytogenetic disorders chromosomal aberation of number and/or structure

4. Mendelian disorders > 5,000 disorders autosomal dominant autosomal recessive X-linked (recessive) pleiotropy – various phenotype

5. Autosomal dominant disorders one parent is affected (heterozygot) child – heterozygot (50% chance) males and females 50% reduction in gene product ? clinical symptoms

6. Autosomal dominant disordes Nervous Huntington disease, neurofibromatosis Urinary polycystic kidney disease (adult type) GIT familial polyposis coli Skeletal Marfan syndrom, Ehlers-Danlos syndromes Metabolic familial hypercholesterolemia

7. Marfan syndrome abnormality of fibrillin 1 (elastic fibres) FBN1 gene (15q21), > 100 mutations prevalence 1 in 20,000 75% cases familial skeleton + eye + CVS

8. Marfan syndrome Skeleton elongated habitus + arachnodactyly high-arched palate joints hyperextensibility chest deformity (pectus excavatum) Eye bilateral dislocation of lenses

9. Marfan syndrome CVS - most serious aortic aneurysma aortic dissection aortic incompetence myxoid degeneration of mitral valve ? floopy valve syndrome

10. Ehlers-Danlos syndromes defects of collagen synthesis or structure ? 18 collagen types 10 variants of E-D syndromes skin and joints hyperextensibility

11. Familial hypercholesterolemia common mendelian disorder prevalence 1 in 500 mutation of LDL receptor accumulation of LDL in blood cholesterol traffic into macrophages and vessel wall heterozygotes: 2-3fold elevation homozygotes: 5fold elevation

12. Familial hypercholesterolemia clinical features xantomas on eyelids + upon extensors xantoma = accumulation of macrophages !!! increased risk of atherosclerosis + complications !!!

13. Autosomal recessive disorders largest group both of alleles are mutants (homozygot) parents not affected (heterozygotes) child homozygot (1 to 25 chance) metabolic disorders (enzymopathies) hematopoietic disorders

14. Autosomal recessive disorders cystic fibrosis phenylketonuria galactosemia lysosomal storage diseases Wilson disease hemochromatosis glycogen storage diseases

15. Cystic fibrosis most common AR disorder in whites carrier frequency 1 in 30 prevalence 1 in 2,000 defect of secretory process of all exocrine glands

16. Cystic fibrosis defective CFTRs ? defect of chloride ions transport across epithelium ? epithelium impermeable to chloride ions ? dehydrated viscid mucus with increased content of NaCl CFTR gene (7q31-32), 300 mutations 70% patients: dF508

17. Cystic fibrosis GIT - pancreas (80% patients) viscid mucus in dilated ducts atrophy (Langerhans islets spared) fibrocystic disease malabsorption of fat + vitamins A, D, E, K

18. Cystic fibrosis GIT - small GIT glands newborn: viscid mekonium ? obstruction of small bowel ? rupture ? peritonitis GIT - bile ducts secondary biliary cirrhosis male reproductive tract – vas deferens infertility (95% males)

19. Cystic fibrosis Lungs - dilation of bronchioles and bronchi ? secondary infection ? bronchiectasis + abscesses S. aureus + P. aeruginosa + Burkholderia cepacea ? pulmonary hypertension ? cor pulmonale

20. Cystic fibrosis diagnosis - sweat chloride test treatment – symptomatic life expectancy - 30 years

21. Phenylketonuria = lack of Phe hydroxylase (Phe ? Tyr) ? hyperPhemia and PKU normal at birth ? 1st year ? symptoms mental retardation + no walking, talking seizures, albinismus Phe intermediates in urine + mousy odor of sweat Guthrie test ? Phe free diet

22. Galactosemia = disorder of galactose metabolism lack of galacto-1-phosphate-uridyltranferase lactose (milk) ? glucose + galactose ? glucose ? accumulation of galactose-1-phosphate liver + eyes + brain fatty change ? cirrhosis + cataracts + mental retardation after milk ingestion vomiting + diarrhea jaundice + hepatomegaly

23. Hemochromatosis = increased uptake of iron in intestine ? depositions of hemosiderin liver + pancreas + skin + heart chocolate brown cirrhosis fibrosis ? diabetes mellitus skin pigmentations

24. Wilson disease (hepatolenticular degeneration) = disorder of copper metabolism defect at level of ceruloplasmin ? accumulation: liver + brain + eye cirrhosis basal ganglia (neurologic symptoms) Kayser-Fleischer green brown ring

25. Glycogen storage diseases (glycogenoses) = defects of glycogen synthesis or degradation 12 forms glycogen accumulation in cells ? pale cytoplasm, PAS +

26. Glycogen storage diseases (glycogenoses) Glycogenosis I (von Gierke) glucose-6-phosphatase hepatic (hepatorenal) form hepatomegaly + hypoglycemia Glycogenosis II (Pompe) acid maltase cardiomegaly Glycogenosis V (McArdle) phosphorylase myopathic

27. Lysosomal storage diseases lysosomes: hydrolytic enzymes = incomplete catabolism of sphingolipids and mucopolysaccharides accumulation in lysosomes in macrophages 35 diseases

28. Sphingolipidoses Tay-Sachs disease (GM2 gangliosidosis) hexosaminidase A Jews brain (neuron + glial cells) + retina („cherry spot“) mental retardation + blindness death in 2-3 years

29. Sphingolipidoses Niemann-Pick disease acid sphingomyelinase macrophages + brain spleen + liver + bone marrow death in 3 years

30. Sphingolipidoses Gaucher disease glucocerebrosidase macrophages (Gaucher cells): „wrinkled tissue paper“ type I: hepatosplenomegaly + long life type II: lethal type III: intermediate

31. Mucopolysaccharidoses defective degradation of MPSs dermatan-, heparan-, keratan-, chondroitin- sulfate liver + spleen + hear + blood vessels coarse facial features (gargoylism), clouding of cornea, mental retardation 7 variants MPS I: Hurler MPS II: Hunter (X-linked)

32. X-linked disorders NO Y-linked disorders known X-linked recessive heterozygous female carrier only sons affected daughters carriers X-linked dominant – rare vitamin D - resistant rickets

33. Hemophilias A and B hemophilia A: factor VIII hemophilia B: factor IX (Christmas d.) < 1% of activity ? symptoms easy bruising massive hemorrhage after trauma spontaneous bleeding in joints ? deformities

34. Duchenne muscular atrophy = absence of dystrophin (all muscles types) impaired contractile activity muscle weakness ? lipomatous atrophy calves, legs, shoulders chest muscles ? respiratory insufficience Becker muscular dystrophy abnormal form of dystrophin less severe symptoms

35. Disorders with multifactorial inheritance Diabetes mellitus type II Essential systemic hypertesion Gout Schizophrenia, bipolar disorder Congenital heart defects Skeletal abnormalities

36. Cytogenetic disorders 1 in 200 of newborn infants 50% first trimester abortion normal karyotype: 2n (46) … diploid euploid: 3n, 4n, … aneuploid: 3n + y, … trisomy: 2n+1 monosomy: 2n-1 autosomal x gonosomal

37. Down syndrome = trisomy 21 (47) ? maternal age < 20 years: 1 in 1500 > 45 years: 1 in 25 !!! most common

38. Down syndrome increased risk acute leukemia Alzheimer disease

39. Other trisomies Edwards syndrome = trisomy 18 Patau syndrome = trisomy 13

40. Klinefelter syndrome 47 XXY male hypogonadism elongated body + eunuchoid habitus reduced body hair gynecomastia testis atrophy ? azoospermia ? sterility

41. Turner syndrome 45 X0 female hypogonadism growth retardation swelling of nape of neck ovarian atrophy ? primary amenorrhea infantile breast + outer genitalia

42. Pediatric Diseases childhood: birth – 15 years perinatal period: 1st week - ? mortality neonatal period: 1st month mortality 700 in 100,000 … < 1st year 40 in 100,000 … < 5th year 20 in 100,000 … < 15th year

43. Causes of death – under 1 year IU growth retardation / low birth weight Respiratory distress syndrome (RES) IU hypoxia / birth asphyxia Birth trauma Congenital anomalies Sudden infant death syndrome (SIDS) Pneumonia GIT disorders

44. Causes of death – 1 to 15 year Injuries Congenital anomalies Malignant neoplasms Homicide Heart diseases

45. Congenital anomalies Malformations = primary morphogenesis errors multifactorial Disruptions = destruction of normally developted organ amniotic bands Deformations = compression of fetus malformed uterus, leiomyoma, multiple fetuses

46. Congenital anomalies Agenesis = complete absence of organ Hypoplasia = incomplete development of organ Atresia = absence of opening, e.g. GIT, bile ducts

47. Etiology of congenital malformations Genetic (see previous lecture) Environmental infections – rubella, toxoplasmosis, syphilis, CMV maternal diseases - diabetes mellitus drugs – thalidomide, warfarin alcohol, smoking irradiation

48. Perinatal infections Transplacentally viruses, parasites, bacteria TORCH encephalitis, chorioretinitis, hepatospenomegaly, .. Transcervically during pregnancy (infected amniotic fluid) or delivery Streptococcus agalactiae, HSV + chorioamnionitis + funisitis

49. Prematurity and IU growth retardation prematurity = gestational age < 37 weeks premature rupture of membranes chorioamnionitis, placental anomalies, … twin pregnancy RDS, necrotising enterocolitis, CNS bleeding

50. Prematurity and IU growth retardation small for gestational age = born in term but weight < 2,500 g Fetal chromosomal disorders, congenital malformations, … Placental placenta previa, placental abruption, placental infarction, … Maternal preeclampsia, chronic hypertension, drugs, smoking, …

51. Respiratory distress syndrome = RDS, hyaline membrane disease inability of immature lungs to synthesize surfactant 20% children, boys alveoli collapse ? greater inspiration effort to open ? atelectasis ? hypoxia ? damage of epithelium and endothelium ? hyaline membranes

52. Respiratory distress syndrome airless, heavy lungs, mottled color Mi: congestion, atelectasis, hyaline membranes complication – bronchopulmonary dysplasia + ? O2 concentration Mi: hyperplasia/metaplasia of bronchial epithelium + peribronchial/interstitial fibrosis

53. Necrotizing enterocolitis intestinal ischemia + bacterial colonisation + feed formulas terminal ileum, cecum, right colon distended, friable, congested segment perforation ? peritonitis Mi: mucosal or transmural necrosis complication: post-NEC fibrosis

54. CNS - germinal matrix hemorrhage GM: persists until 35th week subependymal location primitive cells + thin-walled vessels hypoxia ? damage of endothelium hemorrhage ? ventricular system death scarring ? obstructive hydrocephalus

55. Sudden Infant Death Syndrome „sudden death of infant < 1 year + complete autopsy does not reveal other cause of death“ age: 2 - 4 months crib death autopsy: big thymus + petechiae (mark of breathlessness)

56. Hydrops fetalis = generalized edema of fetus x partial (pleural, peritoneal effusion) chromosomal abnormalities (trisomies,…) fetal anemia immune – Rh and ABO incompatibility non-immune - thalassemia, parvovirus B19 CVS (heart defects)

57. Immune hydrops = Abs induced hemolytic disease of fetus blood – Rh incompatibility mother x fetus mother Rh0 x fetus Rh+ during delivery fetus RBCs ? mother circulation ? Ab (IgM ? IgG) ? next pregnancy ? cross placenta ? hemolysis of fetus RBCs ? anemia ? hypoxia ? cardiac failure

58. Immune hydrops Gross: pale fetus + placenta hepatosplenomegaly Mi: BM hyperplasia + extraBM hematopoiesis immature erythroblasts in fetus circulation „Erythroblastosis fetalis“ ? bilirubin from RBCs breakdown ? CNS damage (basal ganglia) ? „kernicterus“

59. Tumors of Infancy and Childhood tumor-like lesions hamartoma = focal overgrowth of tissue in organ where it normally occurs hem- and lymphangioma, heart rhabdomyomas choristoma = normal cells in abnormal location pancreatic tissue in stomach wall

60. Benign tumors hemangioma - cavernous + capillary skin of face, scalp red blue mass („port wine stains“) regress lymphangioma – cystic skin + deep tissues (neck, axilla, mediastinum, retroperitoneum) growth ? compression Turner syndrome

61. Benign tumors Sacrococcygeal teratoma 10% cases + congenital anomalies of cloacal region, midline defects (spina bifida) 75 % benign (mature) 12% malignant (immature) ? lethal

62. Malignant tumors hematopoietic system + CNS + soft tissues spontaneous regress x differentiation into mature elements improved survival – chemotherapy/ actinoterapy ? secondary malignancies Mi: primitive appearance „small round blue cell tumors“

63. Malignant tumors Hematopoietic system leukemias (ALL) lymphomas – Hodgkin x non-Hodgkin (Burkitt, DLBCL) CNS – medulloblastoma, ependymoma Liver - hepatoblastoma Kidney - Wilms tumor Neural crest - neuroblastoma

64. Malignant tumors Eye – retinoblastoma Soft tissues – rhabdomyosarcoma Bones – osteosarcoma + Ewing/PNETs Thyroid – papillary carcinoma