GENETIC DISORDER AND

PEDIATRIC DISEASES
OUTLINE
• Overview of the Anatomy of the Lungs
• Congenital Lung Diseases
• Lung Collape (Atelectasis)
• Obstructive Lung Diseases
• Restrictive Lung Diseases
SOME KEY TERMINOLOGIES
• Genes vrs DNA vrs Chromosomes

• Mutations

• Germ cells

• Somatic Cells
• Hereditary diseases – an inherited medical condition resulting from a DNA abnormality

• Familial diseases

• Congenital diseases - a condition that is present from birth

• Penetrance - the percentage of a population of a specific genotype who express the

phenotype associated with that underlying genotype

• Expressivity - the degree that a particular genotype is expressed as a phenotype within an

individual
GENETIC BASIS OF DISEASES
• Genes as the basic unit of inheritance

• Human genome contain 22,000-25,000 protein-

coding genes

• Several pediatric disorders are of genetic origin

• Not all genetic disorders manifest in infancy and

childhood, and conversely, many pediatric
diseases are not of genetic origin
NATURE OF GENETIC ABNORMALITIES
CONTRIBUTING TO HUMAN DISEASES
• Mutations in protein-coding genes
• Point Mutations - result from the substitution of a single nucleotide base by a different base, resulting
in the replacement of one amino acid by another in the protein product eg. SCD (missense mutation)

“Nonsense” mutation – PM may change an amino acid codon to a chain termination codon, or stop
codon. This interrupts translation, and in most cases RNAs are rapidly degraded, a phenomenon called
nonsense mediated decay, such that little or no protein is formed

• Frameshift Mutations - occur when the insertion or deletion of one or two base pairs alters the
reading frame of the DNA strand.

• Trinucleotide Repeat Mutations - characterized by amplification of a sequence of three nucleotides

(predominantly CG). Eg. Fragile X syndrome CG is repeated 250-4000 x and prevents the expression of
FMR-1 gene, leading to mental redardation
NATURE OF GENETIC ABNORMALITIES
CONTRIBUTING TO HUMAN DISEASES
• Alterations in Protein-Coding Genes Other Than Mutations
• Sequence and copy number variations
• SNPs represent variation at single isolated nucleotide positions and are almost always biallelic
• CNV consists of different numbers of large contiguous stretches of DNA from 1000 base pairs to
millions of base pairs

• Epigenetic changes - are those involving modulation of gene or protein expression in the
absence of alterations in DNA sequence (i.e., mutation) or structure of the encoding
gene.

• Alterations in Non-Coding RNAs - do not encode proteins. Instead, the non- encoded
products of these genes—so-called “non-coding RNAs (ncRNAs)”—play important
regulatory functions eg. miRNA, lncRNA
 SINGLE GENE
DISORDERS

MENDALIAN DISORDERS NON-MENDALIAN DISORDERS

• AD • TRM
• AR • Mitochondrial IInheritance
• XLD • Genomic Imprinting
• XLR
 MENDELIAN DISORDERS
• Virtually all MDs result from mutations of Single Genes and they follow
the Mendelian pattern of inheritance
• Autosomal Dominant
• Autosomal Recessive
• X-linked
• Single gene mutation may lead to many phenotypic effects (pleiotropy)
Eg. Marfan Syndrome
• Mutations at several genetic loci may produce the same trait (Genetic
heterogeneity). Eg. Retinitis pigmentosa
FAMILIAL HYPERCHOLESTROLEMIA
• Familial hypercholesterolemia is an autosomal dominant disorder
caused by mutations in the gene encoding the LDL receptor.
• Patients develop hypercholesterolemia as a consequence of impaired
transport of LDL into the cells.
• In heterozygotes, elevated serum cholesterol greatly increases the risk
of atherosclerosis and resultant coronary artery disease; homozygotes
have an even greater increase in serum cholesterol and a higher
frequency of ischemic heart disease. Cholesterol also deposits along
tendon sheaths to produce xanthomas
MARFAN SYNDROME
• Marfan syndrome is caused by a mutation in the FBN1 gene encoding
fibrillin, which is required for structural integrity of connective tissues.
• The major tissues affected are the skeleton, eyes, and cardiovascular
system.
• Clinical features may include tall stature, long fingers, bilat- eral
subluxation of lens, mitral valve prolapse, aortic aneurysm, and aortic
dissection.
• Clinical trials with drugs that inhibit TGF-β signaling such as
angiotensin receptor blockers are ongoing, as these have been shown
to improve aortic and cardiac function in mouse models.
SICKLE CELL DISORDER
• Autosomal Recessive Inheritance
• PM on codon 6 of chromosome 11
• Glutamic acid (or Glutamate) is replaced by Valine
• This causes a defect in the beta-globulin chain when RBC is
deoxygenated
 CYSTIC FIBROSIS
• CF is an autosomal recessive disease caused by mutations in the CFTR gene encoding the CF
transmembrane regulator.

• The principal defect is of chloride ion transport, resulting in high salt concentrations in sweat
and in viscous luminal secretions in respiratory and gastrointestinal tracts.

• CFTR mutations can be severe (ΔF508), resulting in multisystem disease, or mild, with limited
disease extent and severity.

• Cardiopulmonary complications constitute the most common cause of death; pulmonary

infections, especially with resistant pseudomonads, are frequent. Bronchiectasis and right-sided
heart failure are long-term sequelae.

• Pancreatic insufficiency is extremely common; infertility caused by congenital bilateral absence

of vas deferens is a characteristic finding in adult patients with CF.
HEMOPHILIA A
• X-linked recessive inheritance
• Leads to deficiency in blood clotting ability
• Bleeding disorder due to lack of blood clotting factor VIII
• Can be spontaneous
• More prevalent in males than females
 SINGLE GENE DISORDERS
WITH ATYPICAL PATTERNS OF
INHERITANCE
 COMPLEX MULTIGENETIC
OR
MULTIFACTORIAL DISORDERS
CYTOGENETIC DISORDERS
 CONGENITAL ANOMALIES
AND PRENATAL INFECTIONS
CONGENITAL ANOMALIES
• Pediatric diseases and disorders are comparatively unique to that of
adults
• More important due to high morbidity and mortality
• Each stage of development of the infant and child is prey to a somewhat
different group of disorders (from neonates, infants, under 5, early
adolescence)

• Congenital anomalies are morphologic defects that are present at

birth
• Term does not imply or exclude genetic defects
TERMINOLOGIES
• Malformations - primary errors of morphogenesis.
• Intrinsically abnormal developmental process
• Often multifactorial and not singe gene d/o or chromosomal defect
• Occurs in many forms such as congenital heart defects or anencephaly
• Involving one organ or multiple organs

• Disruptions – result from secondary destruction of an organ or body region that

was previously normal in development
• Extrinsic disturbances in morphogenesis
• Not heritable
• Not associated with risk of recurrence in subsequent pregnancies
• Eg. Amniotic bands, vascular accidents leading to intestinal atresia
TERMINOLOGIES (CONT’D)
• Deformations – common problems, affecting approximately 2% of newborn
infants to varying degree
• Extrinsic disturbances in morphogenesis
• Fundamental to the pathogenesis of deformations is localized or generalized
compression of the growing fetus by abnormal biomechanical forces, leading
eventually to a variety of structural abnormalities
• Most common underlying factor is uterine constraint which happens during the 35th-
38th week of gestation due to oligohydramnous and rapid increase in size of fetus
• Others include maternal factors such as first pregnancy, small uterus, malformed
(bicornuate) uterus, and leiomyomas. Fetal or placental factors include
oligohydramnios, multiple fetuses, and abnormal fetal presentation
• Eg. Clubfeet
TERMINOLOGIES (CONT’D)
• Sequence – A cascade of anomalies triggered by one initiating
aberration
• Often presents as a castellation of anomalies defined by a single localized
aberration (malformation, disruptions, deformations)
CAUSES OF CONGENITAL ANOMALIES
PATHOGENESIS OF CAs
• Complex and still poorly understood, but two general principles of
developmental pathology are relevant regardless of the etiologic
agent
• The timing of the prenatal teratogenic insult
• The complex interplay between environmental teratogens and intrinsic
genetic defects is underscored by the fact that features of dysmorphogenesis
caused by environmental insults can often be recapitulated by genetic defects
in the pathways targeted by these teratogens
• Cyclopamine
TIMING……
• Embryonic period (first 9 wks)
• an injurious agent damages either enough cells to cause death and abortion or only
a few cells, presumably allowing the embryo to recover without developing defects.
• Between the third and the ninth weeks, the embryo is extremely susceptible to
teratogenesis, and the peak sensitivity during this period occurs between the fourth
and the fifth weeks. During this period organs are being crafted out of the germ cell
layers

• Fetal period (>9 wks)

• Greatly reduced susceptibility to teratogenic agents.
• Instead, the fetus is susceptible to growth retardation or injury to already formed
organs
• possible for a given agent to produce different anomalies
• if exposure occurs at different times of gestation
PATHOGENESIS OF CAs
PERINATAL INFECTIONS
• One of the following 2 means or both
• TRANSVAGINAL (ASCENDING)
• Viral (HSV II) and bacterial infection through the cervicovaginal route
• By inhaling amniotic fluid shortly before birth
• pneumonia, sepsis, and meningitis are the most common sequelae
• By passing through an infected birth canal
• Preterm delivery is the major consequence due to the damage or rupture of amniotic sac
as a direct consequence of the inflammation or to the induction of labor associated with
a release of prostaglandins by the infiltrating neutrophils
PERINATAL INFECTIONS
• TRANSPLACENTAL (HAEMATOLOGICAL)
• Most parasitic, viral, and a few bacterial organisms gain access to the fetal
bloodstream transplacentally via the chorionic villi
• Occurs at anytime during gestation or even during delivery (HIV, HepB)
• Clinical manifestations vary depending on the type of organism and
gestational age of infection
• The TORCH group of infections are grouped together because they may evoke
similar clinical and pathologic manifestations, including fever, encephalitis,
chorioretinitis, hepatosplenomegaly, pneumonitis, myocarditis, hemolytic
anemia, and vesicular or hemorrhagic skin lesions
PERINATAL INFECTIONS
• SEPSIS
• Grouped clinically based on early onset (within the first 7 days of life) versus
late onset (from 7days to 3 months)
• Most cases of early-onset sepsis are acquired at or shortly before birth and
tend to result in clinical signs and symptoms of pneumonia, sepsis, and
occasionally meningitis within 4 or 5 days of life
• Group B streptococcus is the most common organism isolated in early-onset
sepsis and is also the most common cause of bacterial meningitis
• Listeria and Candida infections follow a latent period between the time of
microorganism inoculation and the appearance of clinical symptoms and
present as late-onset sepsis
SUDDEN INFANT DEATH
SYNDROME
DEFINITION
• “The sudden death of an infant under 1 year of age which remains
unexplained after a thorough case investigation, including performance
of a complete autopsy, examination of the death scene, and review of
the clinical history.”

• Thus, SIDS is a disease of unknown cause

• Many cases of sudden death in infancy may have an unexpected

anatomic or biochemical basis discernible at autopsy, and these should
not be labeled as SIDS.
RISK FACTORS
MORPHOLOGY
• In infants who have died of suspected SIDS, a variety of findings have
been reported at postmortem examination.
• They are usually subtle and of uncertain significance and are not present in all
cases.
• Multiple petechiae are the most common finding (80% of cases); these are
usually present on the thymus, visceral and parietal pleura, and epicardium.
• Grossly, the lungs are usually congested, and vascular engorgement with or
without pulmonary edema is demonstrable microscopically in the majority of
cases. These changes possibly represent agonal events, since they are found
with comparable frequencies in explained sudden deaths in infancy.
• Within the upper respiratory system (larynx and trachea), there may be
some histologic evidence of recent infection (correlating with the clinical
symptoms), although the changes are not sufficiently severe to account for
death and should not detract from the diagnosis of SIDS.
MORPHOLOGY (CONT’D)
• The central nervous system demonstrates astrogliosis of the brain stem and cerebellum.

• Nonspecific findings include frequent persistence of hepatic extramedullary hematopoiesis

and periadrenal brown fat; it is tempting to speculate that these latter findings relate to
chronic hypoxemia, retardation of normal development, and chronic stress.

• Thus, autopsy usually fails to provide a clear cause of death, and this may well be related to
the etiologic heterogeneity of SIDS.

• The importance of a postmortem examination rests in identifying other causes of sudden

unexpected death in infancy, such as unsuspected infection, congenital anomaly, or a genetic
disorder, the presence of any of which would exclude a diagnosis of SIDS; and in ruling out the
unfortunate possibility of traumatic child abuse
MOLECULAR DIAGNOSIS OF
GENETIC DISEASES
SOME INDICATIONS
• PRENATAL GERM LINE GENETIC ANALYSIS
• (performed on cells obtained by amniocentesis, on chorionic villus biopsy
material, or on umbilical cord blood)
• A mother of advanced age (>35 years) because of greater risk of trisomies
• A parent who is a carrier of a balanced reciprocal translocation, robertsonian
translocation, or inversion (in these cases the gametes may be unbalanced, and
hence the progeny would be at risk for chromosomal disorders)
• A parent with a previous child with a chromosomal abnormality
• A fetus with ultrasound-detected abnormalities
• A parent who is a carrier of an X-linked genetic disorder (to determine fetal sex)
• Abnormal levels of AFP, βHCG, and estriol performed as the triple test.
SOME INDICATIONS
• POSTNATAL GERM LINE GENETIC ANALYSIS
• (performed on peripheral blood lymphocytes)
• Multiple congenital anomalies
• Unexplained mental retardation and/or developmental delay
• Suspected aneuploidy (e.g., features of Down syndrome)
• Suspected sex chromosomal abnormality (e.g., Turner syndrome)
• Suspected fragile-X syndrome
• Infertility (to rule out sex chromosomal abnormality) Multiple spontaneous
abortions (to rule out the parents as carriers of balanced translocation; both
partners should be evaluated)
DETECTION TECHNIQUES
• PCR (Single Gene D/O)
• Direct
• Indirect

• Polymorphic markers (Multifactoral)

• Southern blotting

• FISH

• Array-Based Comparative Genomic Hybridization