Genetic and Pediatric Diseases

Jan Laco, M.D., Ph.D.

 Genetic diseases
20% pediatric patients

hereditary = derived from ones parent

familial = transmitted through generations
congenital = present at birth
 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
 Mendelian disorders
> 5,000 disorders
autosomal dominant
autosomal recessive
X-linked (recessive)

pleiotropy various phenotype

 Autosomal dominant disorders
one parent is affected (heterozygot)
child heterozygot (50% chance)
males and females

50% reduction in gene product clinical

symptoms
 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
 Marfan syndrome
abnormality of fibrillin 1 (elastic fibres)
FBN1 gene (15q21), > 100 mutations
prevalence 1 in 20,000
75% cases familial

skeleton + eye + CVS

 Marfan syndrome
Skeleton
elongated habitus + arachnodactyly
high-arched palate
joints hyperextensibility
chest deformity (pectus excavatum)
Eye
bilateral dislocation of lenses
 Marfan syndrome
CVS - most serious
aortic aneurysma
aortic dissection
aortic incompetence
myxoid degeneration of mitral valve floopy
valve syndrome
 Ehlers-Danlos syndromes
defects of collagen synthesis or structure
> 18 collagen types
10 variants of E-D syndromes

skin and joints hyperextensibility

 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
 Familial hypercholesterolemia
clinical features
xantomas on eyelids + upon extensors
xantoma = accumulation of macrophages

!!! increased risk of atherosclerosis

+ complications !!!
 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
 Autosomal recessive disorders
cystic fibrosis
phenylketonuria
galactosemia
lysosomal storage diseases
Wilson disease
hemochromatosis
glycogen storage diseases
 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
 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: F508
 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
 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)
 Cystic fibrosis
Lungs - dilation of bronchioles and bronchi
secondary infection bronchiectasis +
abscesses
S. aureus + P. aeruginosa + Burkholderia
cepacea

pulmonary hypertension cor pulmonale

 Cystic fibrosis
diagnosis - sweat chloride test

treatment symptomatic

life expectancy - 30 years

 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
 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
 Hemochromatosis
= increased uptake of iron in intestine
depositions of hemosiderin
liver + pancreas + skin + heart

chocolate brown cirrhosis

fibrosis diabetes mellitus
skin pigmentations
 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
 Glycogen storage diseases
(glycogenoses)
= defects of glycogen synthesis or
degradation
12 forms

glycogen accumulation in cells pale

cytoplasm, PAS +
 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
 Lysosomal storage diseases
lysosomes: hydrolytic enzymes
= incomplete catabolism of sphingolipids
and mucopolysaccharides

accumulation in lysosomes in macrophages

35 diseases
 Sphingolipidoses
Tay-Sachs disease (GM2 gangliosidosis)
hexosaminidase A
Jews
brain (neuron + glial cells) + retina (cherry
spot)
mental retardation + blindness
death in 2-3 years
 Sphingolipidoses
Niemann-Pick disease
acid sphingomyelinase
macrophages + brain
spleen + liver + bone marrow
death in 3 years
 Sphingolipidoses
Gaucher disease
glucocerebrosidase
macrophages (Gaucher cells): wrinkled tissue
paper

type I: hepatosplenomegaly + long life

type II: lethal
type III: intermediate
 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)
 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
 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
 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
 Disorders with multifactorial
inheritance
Diabetes mellitus type II
Essential systemic hypertesion
Gout
Schizophrenia, bipolar disorder
Congenital heart defects
Skeletal abnormalities
 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
 Down syndrome
= trisomy 21 (47)
maternal age
< 20 years: 1 in 1500
> 45 years: 1 in 25 !!!
most common
 Down syndrome
increased risk
acute leukemia
Alzheimer disease
 Other trisomies
Edwards syndrome
= trisomy 18

Patau syndrome
= trisomy 13
 Klinefelter syndrome
47 XXY
male hypogonadism
elongated body + eunuchoid habitus
reduced body hair
gynecomastia
testis atrophy azoospermia sterility
 Turner syndrome
45 X0
female hypogonadism
growth retardation
swelling of nape of neck
ovarian atrophy primary amenorrhea
infantile breast + outer genitalia
 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
 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
 Causes of death 1 to 15 year
Injuries
Congenital anomalies
Malignant neoplasms
Homicide
Heart diseases
 Congenital anomalies
Malformations = primary morphogenesis
errors
multifactorial
Disruptions = destruction of normally
developted organ
amniotic bands
Deformations = compression of fetus
malformed uterus, leiomyoma, multiple fetuses
 Congenital anomalies
Agenesis
= complete absence of organ
Hypoplasia
= incomplete development of organ
Atresia
= absence of opening, e.g. GIT, bile ducts
 Etiology of congenital
malformations
Genetic (see previous lecture)

Environmental
infections rubella, toxoplasmosis, syphilis, CMV
maternal diseases - diabetes mellitus
drugs thalidomide, warfarin
alcohol, smoking
irradiation
 Perinatal infections
Transplacentally
viruses, parasites, bacteria
TORCH
encephalitis, chorioretinitis, hepatospenomegaly, ..

Transcervically
during pregnancy (infected amniotic fluid) or delivery
Streptococcus agalactiae, HSV
+ chorioamnionitis + funisitis
 Prematurity and IU growth
retardation
prematurity = gestational age < 37 weeks
premature rupture of membranes
chorioamnionitis, placental anomalies,
twin pregnancy

RDS, necrotising enterocolitis, CNS bleeding

 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,
 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
 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
 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

 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
 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)
 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)
 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
 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
 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
 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
 Benign tumors
Sacrococcygeal teratoma
10% cases + congenital anomalies of cloacal
region, midline defects (spina bifida)
75 % benign (mature)
12% malignant (immature) lethal
 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
 Malignant tumors
Hematopoietic system
leukemias (ALL)
lymphomas Hodgkin x non-Hodgkin (Burkitt,
DLBCL)
CNS medulloblastoma, ependymoma
Liver - hepatoblastoma
Kidney - Wilms tumor
Neural crest - neuroblastoma
 Malignant tumors
Eye retinoblastoma
Soft tissues rhabdomyosarcoma
Bones osteosarcoma + Ewing/PNETs
Thyroid papillary carcinoma