Genetics

- Learning objectives:
• Demonstrate understanding of chromosome abnormalities
• Solve problems concerning hereditary diseases in pediatrics.

Human chromosomes:

 Chromosomes carry all the genetic features of the individual.

 Each chromosome is formed of two chromatids (DNA and proteins)
connected together at a point by the centromere.
 There are two types of chromosomes: autosomes and sex
chromosomes (X and Y chromosomes).
 Each somatic cell contains 46 chromosomes (diploid number)
arranged in pairs: 22 pairs of autosomes and two sex chromosomes
(XX in females and XY in males).
 Each germ cell (ova or sperm) contains 23 chromosomes (haploid
number), 22 autosomes and one sex chromosome (either X in the
ova or Y in the sperm).
 Karyotyping is a laboratory way to detect the count and structure of
the individual’s somatic cell (leukocytes or fibroblasts are usually
used).

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- The Gene:
This is the DNA part that codes for the synthesis of a single
polypeptide chain. Each trait is controlled by a pair of genes located
on a pair of chromosomes. Each gene of this pair is inherited from a
parent. If these two genes are identical, the individual is homozygous
for this trait. And if these inherited pair of genes are not similar, the
individual is heterozygous for this trait.
. Types of genes:
o Dominant gene
Express itself whether homozygous or heterozygous, the trait is
determined by only one of the two genes.
o Recessive gene
Express itself, only when homozygous, the trait is determined by the
presence of both genes
o Codominant genes
Both genes are expressed in the heterozygous

Genetic disorders
Ι-Chromosomal abnormalities:
1. Numerical abnormalities:
 Autosomal abnormality:
- Trisomy: cells contain extra chromosome e.g. trisomy
21(Down syndrome), trisomy 13 and 18.
- Monosomy: one chromosome is missing e.g. monosomy 22.
 Sex chromosomes abnormality: Turner syndrome (45, X)
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 female and Klinfelter syndrome (47, XXY male).

2. Structural abnormalities:
- Translocation: transfer of material from one chromosome to
another.
- Deletion: loss of a portion of the chromosome.
- Ring chromosome: a special type of deletion in which the
broken ends re-unit to form a ring.
- Inversion: fragmentation of a chromosome followed by
reconstruction.
- Duplication: presence of an extra piece of a chromosome.

- Isochromosomes: it is the division of chromosomes transversely

instead of longitudinally.
- Non-disjunction

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П- Single gene disorders:
 Autosomal dominant inheritance: it appears with only one single
copy of the abnormal gene.
 Autosomal recessive inheritance: it appears if the two copies of the
abnormal gene is present.
 X-Linked inheritance: the abnormal gene is on the X chromosome
(X-linked dominant or recessive).

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 Ш- Multifactorial (polygenic) inheritance
It results from interaction between genetic predisposition and adverse
environmental factors e.g. rheumatic fever and congenital heart
diseases.
IV-Mitochondrial gene inheritance
 It is inheritance through mitochondrial DNA (mitochondria contain small
amount of DNA
 It is exclusively transmitted by the mother [Sperm does not contain
mitochondria]
 Example: mitochondrial encephalopathy and cardiomyopathy.

Down Syndrome (Trisomy 21 or Mongolism)

This is the commonest autosomal trisomy that affects 1:800 newborns.

Etiology:
In this syndrome, every somatic cell carries 47 chromosomes due to
the presence of three 21 chromosomes. This condition occurs due to one
of the following abnormality:
1- Non-disjunction: In 95% of cases, with higher incidence with
advanced maternal age. Karyotyping will show that the cells carry 47
chromosomes.
2- Robertsonian Translocation: In this type (4% of cases), karyotyping
reveals that cells carry 46 chromosomes, and one of the 21
chromosome is structurally abnormal.
3- Mosaic type: Some cells of the affected individual are normal (46

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 chromosome) while others carry 47 chromosomes. The clinical
manifestation and the mental retardation are usually mild.
Clinical manifestations:
Characteristic features:
 Head: small head circumference, flat occiput, upward slanting
palpebral fissure, depressed nasal bridge, malformed ears, silky hair
and protruded tongue.
 Hands: broad with simian crease.
 Feet: wide space between first and second toe.
 Delayed physical, mental and motor development:
 Short stature and underweight for age.
 Hearing loss (sensorineural, conductive, and mixed)
 Delayed, abnormal speech with delay in all developmental aspects.
 Body systems:
 Cardiovascular system: structural defects, the commonest are
endocardial cushion defect (AVSD), ventricular septal defects,
patent ductus arteriosus, and maybe Fallot tetralogy.
 Nervous system: generalized hypotonia.
 Associated anomalies:
- Heart: cardiac anomalies (40 % of cases): endocardial
cushion defect: VSD, ASD, common atrioventricular canal,
PDA and Fallot tetralogy.
- GIT: duodenal atresia
- Joints: congenital hip dislocation.
 Possible complications:
1. Higher susceptibility to recurrent respiratory tract infections.
2. Heart failure in cases with congenital heart disease.
3. Higher incidence of leukemia:
4. Accidents are one of the most important causes of death in Down syndrome

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Investigations:
1- Karyotyping
2- Investigations for associated problems e.g. heart defects.
3- Antenatal Diagnosis of Down syndrome:
Indications:
 Old maternal age > 35 years
 Previous baby with Down syndrome
 Family history of translocation
Methods:
a- Triple test: maternal serum at 15-16 weeks of gestation (second trimester)
b- Fetal karyotyping:
• Amniocentesis: 14-16 weeks of gestation
• Chorionic villus sample: 9-12 weeks of gestation
c- Fetal US
• Nuchal Translucency thickening: thickening of the nuchal fold at the back of
the neck due to delayed drainage of fluid from the upper part of the body
• Short femur-------- short stature
• Cystic hygroma of the neck, duodenal stenosis
Treatment:
Rehabilitation, management of associated problems and complications.

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 Trisomy 18 (Edwards Syndrome)
Edwards syndrome is the second most common pattern of human
malformation.
• Genetics-older maternal age; nondisjunction
• Many spontaneous abortions
• Feeble from birth
• Most do not survive first year
Findings
• Growth deficiency
• Mental retardation
• Low-set, malformed ears; microcephaly, micrognathia;
• Clenched hand—index over third; fifth over fourth
• Short sternum
• VSD, ASD, PDA, cyanotic lesions
• Rocker-bottom feet, hammer toe
• Omphalocele

Trisomy 13 (Patau Syndrome)

Patau syndrome is a defect of midface, eye, and forebrain development.
It involves older maternal age.
Single defect in first 3 weeks’ development of prechordal mesoderm

Findings
• Holoprosencephaly and other CNS defects
• Severe mental retardation
• Microcephaly; microphthalmia
• Severe cleft lip, palate, or both
• Scalp defects in parietal-occipital area (cutis aplasia)
• Postaxial polydactyly
• VSD, PDA, ASD, cyanotic lesions
• Single umbilical artery

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 Fragile X Syndrome

 Genetics
- Fragile site on long arm of X in affected males and some carrier -
females Molecular diagnosis-variable number of repeat CGG
(preferred diagnosis = DNA-based
molecular analysis)
- X-linked dominant-males (most
common cause of inherited
intellectual disability);
- There are generally fewer
abnormalities seen in girls but
they may present with decreased
IQ
 Findings
- Mild to profound intellectual disability; learning problems; anxiety,
depression, and autistic-like behaviors
- Large ears, dysmorphic facial features, large jaw, long face
- Large testes—mostly in puberty (macroorchidism)(fertile)
 Natural history—normal lifespan

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 Achondroplasia/Hypochondroplasia
 Genetics: autosomal dominant; most common short-limb dwarfism; 90%
from new gene mutation; older paternal age; mutations in gene for
fibroblast growth factor receptor 3 at 4p16.3 (FGFR3)

 Findings:
- Short stature (increased upper-to-lower segment ratio; short limbed
dwarfism)
- Proximal femur shortening
- Megalocephaly, small foramen magnum (may have hydrocephalus),
small cranial base, prominent forehead
- Lumbar lordosis
 Natural history
- Normal intelligence
- Spinal cord compression is rare (cervicomedullary
junction); usually occurs in first year of life
- Tendency of late childhood obesity
- Small Eustachian tube—otitis media and hearing
loss
- Early cervical compression, respiratory problems,
obstructive and central apnea,

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 Marfan Syndrome

Genetics: autosomal dominant with wide variability; mutation

in fibrillin gene (FBN1)—15q21.1
 Findings
- Early rapid growth of the appendicular skeleton and anterior ribs
- Major findings are skeletal, cardiovascular, and ocular
- Tall stature with long, slim limbs and little fat
- Arm span > height
- Arachnodactyly
- Decreased U: L segment ratio (as with XXY)
- Joint laxity with kyphoscoliosis
- Pectus excavatum or carinatum
- Lens subluxation (upward; defect in suspensory ligament); secondary
glaucoma, myopia, retinal detachment
- Ascending aortic dilatation with or without dissecting aneurysm
(uncommon in children and adolescents unless case is severe) with
secondary aortic regurgitation.
- Mitral valve disease (MVP and regurgitation) is the most common in
children.
 Natural history
- Prevent scoliosis
- Vascular complications chief cause of death

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 Sex chromosomes abnormalities:

Turner Syndrome (45, XO female):

 This is a rather common disorder occurring in 1/3000 newborns
(1/500 females).
 The basic defect is loss of one X chromosome (monosomy).
 Clinically, there is short stature, webbing of the neck, cubitus vulgus
(increased carrying angle) and gonadal dysgenesis.
 Horseshoe kidney

 Associated cardiac (Co-arcitation of the aorta) and renal anomalies

may occur.

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 Klinefelter Syndrome (47, XXY male)
 Occurs in 1/1000 males due to the
presence of an extra X chromosome.
 Clinical features are gynecomastia, small
atrophic testes and azoospermia.
 It is usually not diagnosed except after
puberty.

Single Gene Disorders

These disorders are due to an abnormal gene inherited on one of the
chromosomes. This inheritance can be:
I- Autosomal dominant inheritance:
A single mutant gene, located on an autosome, expresses itself
whether the individual is homo or heterozygous for this gene.
Characteristic features:
 Affected individual can be homozygous or heterozygous, and has at
least one affected parent. If the individual is heterozygous, 50% of
his children will be affected. The trait appears in every generation
with no skipping. Usually associated with structural defects.
 Unaffected individuals are normal (no carrier state).
 Examples: skeletal diseases as achondroplasia, renal diseases as
polycystic kidney.

II- Autosomal recessive inheritance:

 A single mutant gene, located on an autosome, expresses itself
only in homozygous individual.
Characteristic features:
- Affected individual should be homozygous, and both his
parents have the affected gene.
- Unaffected individual may be normal or heterozygous for the
affected gene (carrier).
- Recurrence risk: when parents have one affected child, the risk
of having another affected offspring is 1 in 4.
- Strong correlation to consanguinity.

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 - Examples: metabolic disorders as galactosemia,
hematological disorders as thalassemia and sickle
cell anemia.

III- Sex-linked inheritance:

In these disorders, the abnormal genes are located
on the X orY chromosomes.
a) X-linked recessive inheritance:
 The carrier female transits the abnormal gene to
50% of her daughters (carriers), and 50% of her
sons (affected).
 No male to male transmission
 Females are affected if homozygous for the
affected gene, or she has a Turner syndrome.
 Examples: hemophilia A, glucose-6-phosphate deficiency.

b) X-linked dominant inheritance:

 The affected gene expresses itself in heterozygous female

c) Y- linked inheritance:
Genes on the Y chromosomes show holandric
inheritance i.e. they are passed down
exclusively to males by the affected father.
Example: hairy pinna.

Genetic Counseling
A communication process whereby an individual or family obtains information
about a genetic condition, is helped to understand the implications and significance
of the condition, and is given resources to help with coping and management.

Value:

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 Assess the risk of having another child with a genetic disorder
 Assess the possibility of other family members having a child with an
inherited disease
 Assess the risk of having an inherited disease that affects your health later in
life, such as mitochondrial disorders, Fabry disease and Marfan syndrome
 Make recommendations for genetic testing
 Explain possible scenarios and outcomes

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