Genetic and Pediatric Diseases

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Genetic and Pediatric Diseases

• Jan Laco, M.D., Ph.D.

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Genetic diseases

• 20 pediatric patients
• hereditary derived from ones parent
• familial transmitted through generations
• congenital present at birth

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Genetic diseases

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

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Mendelian disorders

• gt 5,000 disorders
• autosomal dominant
• autosomal recessive
• X-linked (recessive)
• pleiotropy various phenotype

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Autosomal dominant disorders

• one parent is affected (heterozygot)
• child heterozygot (50 chance)
• males and females
• 50 reduction in gene product ? clinical symptoms

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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

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Marfan syndrome

• abnormality of fibrillin 1 (elastic fibres)
• FBN1 gene (15q21), gt 100 mutations
• prevalence 1 in 20,000
• 75 cases familial
• skeleton eye CVS

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Marfan syndrome

• Skeleton
• elongated habitus arachnodactyly
• high-arched palate
• joints hyperextensibility
• chest deformity (pectus excavatum)
• Eye
• bilateral dislocation of lenses

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Marfan syndrome

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

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Ehlers-Danlos syndromes

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

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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

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Familial hypercholesterolemia

• clinical features
• xantomas on eyelids upon extensors
• xantoma accumulation of macrophages
• !!! increased risk of atherosclerosis
• complications !!!

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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

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Autosomal recessive disorders

• cystic fibrosis
• phenylketonuria
• galactosemia
• lysosomal storage diseases
• Wilson disease
• hemochromatosis
• glycogen storage diseases

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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

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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

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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

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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)

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Cystic fibrosis

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

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Cystic fibrosis

• diagnosis - sweat chloride test
• treatment symptomatic
• life expectancy - 30 years

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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

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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

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Hemochromatosis

• increased uptake of iron in intestine
• ? depositions of hemosiderin
• liver pancreas skin heart
• chocolate brown cirrhosis
• fibrosis ? diabetes mellitus
• skin pigmentations

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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

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Glycogen storage diseases (glycogenoses)

• defects of glycogen synthesis or degradation
• 12 forms
• glycogen accumulation in cells ? pale cytoplasm,
  PAS

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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

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Lysosomal storage diseases

• lysosomes hydrolytic enzymes
• incomplete catabolism of sphingolipids and
  mucopolysaccharides
• accumulation in lysosomes in macrophages
• 35 diseases

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Sphingolipidoses

• Tay-Sachs disease (GM2 gangliosidosis)
• hexosaminidase A
• Jews
• brain (neuron glial cells) retina (cherry
  spot)
• mental retardation blindness
• death in 2-3 years

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Sphingolipidoses

• Niemann-Pick disease
• acid sphingomyelinase
• macrophages brain
• spleen liver bone marrow
• death in 3 years

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Sphingolipidoses

• Gaucher disease
• glucocerebrosidase
• macrophages (Gaucher cells) wrinkled tissue
  paper
• type I hepatosplenomegaly long life
• type II lethal
• type III intermediate

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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)

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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

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Hemophilias A and B

• hemophilia A factor VIII
• hemophilia B factor IX (Christmas d.)
• lt 1 of activity ? symptoms
• easy bruising
• massive hemorrhage after trauma
• spontaneous bleeding in joints ? deformities

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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

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Disorders with multifactorial inheritance

• Diabetes mellitus type II
• Essential systemic hypertesion
• Gout
• Schizophrenia, bipolar disorder
• Congenital heart defects
• Skeletal abnormalities

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Cytogenetic disorders

• 1 in 200 of newborn infants
• 50 first trimester abortion
• normal karyotype 2n (46) diploid
• euploid 3n, 4n,
• aneuploid 3n y,
• trisomy 2n1
• monosomy 2n-1
• autosomal x gonosomal

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Down syndrome

• trisomy 21 (47)
• ? maternal age
• lt 20 years 1 in 1500
• gt 45 years 1 in 25 !!!
• most common

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Down syndrome

• increased risk
• acute leukemia
• Alzheimer disease

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Other trisomies

• Edwards syndrome
• trisomy 18
• Patau syndrome
• trisomy 13

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Klinefelter syndrome

• 47 XXY
• male hypogonadism
• elongated body eunuchoid habitus
• reduced body hair
• gynecomastia
• testis atrophy ? azoospermia ? sterility

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Turner syndrome

• 45 X0
• female hypogonadism
• growth retardation
• swelling of nape of neck
• ovarian atrophy ? primary amenorrhea
• infantile breast outer genitalia

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Pediatric Diseases

• childhood birth 15 years
• perinatal period 1st week - ? mortality
• neonatal period 1st month
• mortality
• 700 in 100,000 lt 1st year
• 40 in 100,000 lt 5th year
• 20 in 100,000 lt 15th year

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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

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Causes of death 1 to 15 year

• Injuries
• Congenital anomalies
• Malignant neoplasms
• Homicide
• Heart diseases

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Congenital anomalies

• Malformations primary morphogenesis errors
• multifactorial
• Disruptions destruction of normally developted
  organ
• amniotic bands
• Deformations compression of fetus
• malformed uterus, leiomyoma, multiple fetuses

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Congenital anomalies

• Agenesis
• complete absence of organ
• Hypoplasia
• incomplete development of organ
• Atresia
• absence of opening, e.g. GIT, bile ducts

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Etiology of congenital malformations

• Genetic (see previous lecture)
• Environmental
• infections rubella, toxoplasmosis, syphilis,
  CMV
• maternal diseases - diabetes mellitus
• drugs thalidomide, warfarin
• alcohol, smoking
• irradiation

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Perinatal infections

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

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Prematurity and IU growth retardation

• prematurity gestational age lt 37 weeks
• premature rupture of membranes
• chorioamnionitis, placental anomalies,
• twin pregnancy
• RDS, necrotising enterocolitis, CNS bleeding

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Prematurity and IU growth retardation

• small for gestational age born in term but
  weight lt 2,500 g
• Fetal
• chromosomal disorders, congenital malformations,
  
• Placental
• placenta previa, placental abruption, placental
  infarction,
• Maternal
• preeclampsia, chronic hypertension, drugs,
  smoking,

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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

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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

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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

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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

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Sudden Infant Death Syndrome

• sudden death of infant lt 1 year complete
  autopsy does not reveal other cause of death
• age 2 - 4 months
• crib death
• autopsy big thymus petechiae (mark of
  breathlessness)

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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)

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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

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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

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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

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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

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Benign tumors

• Sacrococcygeal teratoma
• 10 cases congenital anomalies of cloacal
  region, midline defects (spina bifida)
• 75 benign (mature)
• 12 malignant (immature) ? lethal

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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

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Malignant tumors

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

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Malignant tumors

• Eye retinoblastoma
• Soft tissues rhabdomyosarcoma
• Bones osteosarcoma Ewing/PNETs
• Thyroid papillary carcinoma