The lecture by Dr. Bethelhem Damtie covers common genetic disorders in children, focusing on the fundamental principles of genetics, various inheritance patterns, and specific disorders such as Down syndrome, Edward syndrome, and Patau syndrome. It discusses the prevalence and classification of genetic disorders, and details significant features and risks associated with various conditions, emphasizing the importance of genetic transmission and chromosomal abnormalities. Key topics include Mendelian inheritance, chromosomal disorders, and genetic screening methods, particularly in relation to maternal age and congenital anomalies.

1. Common genetic disorders
By: Dr.Bethelhem Damtie
Assistant professor of pediatrics and child health

2. Objectives
• At the end of this lecture, the student should be able to
understand
 Basic principles of genetics
 Clinical manifestations and diagnosis of common genetic
disorders in children

3. Outline
• Introduction to genetic disorders
• Fundamentals of genetics
• Patterns of genetic transmission
• AD disorders
• AR disorders
• X-linked disorders
• Chromosomal disorders

4. Introduction
• Genetic disorders are diseases that are caused by
abnormalities in an individual’s DNA.
• Abnormalities can range from a small mutation in a single
gene to the addition or subtraction of an entire chromosome
or set of chromosomes.
• The prevalence of congenital malformations is much greater
in inpatient pediatric populations; 30-50% of hospitalized
children have congenital anomalies or genetic disorders.

5.  In children with congenital malformations, the condition's
etiology may be classified into one of five different categories:
1. Single-gene mutations, occurring in 6% of children with
congenital anomalies
2. Chromosomal disorders, accounting for approximately 7.5%
3. Multifactorially inherited conditions, accounting for 20%
4. Disorders that show an unusual pattern of inheritance,
accounting for 2-3%
5. Conditions caused by exposure to teratogens, accounting for
6%

6. Fundamentals of genetics
• DNA is composed of 4 nucleotide building blocks: adenine,
guanine, cytosine, and thymine.
• The purine nucleotides, adenine and guanine, cross link by
hydrogen bonds to the pyrimidines, thymine and cytosine.
• Separating the two strands permits complementary
nucleotides to bind to each DNA strand; this copies the DNA
and replicates the sequence.

8. • DNA exists as multiple fragments that, together with a protein
skeleton (chromatin), form chromosomes.
• Human cells have 23 pairs of chromosomes, with one copy of
each chromosome inherited from each parent.
• 22 pairs of chromosomes are autosomes; the remaining pair
consists of sex chromosomes. Females have two X
chromosomes; males have one X and one Y.
• Spread along the chromosomes like beads on a string, DNA
sequences form genes, the basic units of heredity.

10. • Most of the genetic material is contained in the cell's nucleus.
• The mitochondria (the cell's energy-producing organelles)
contain their own unique genome.
• The mitochondrial chromosome consists of a double-stranded
circular piece of DNA.
• Sperm do not usually contribute mitochondria to the
developing embryo, so all mitochondria are maternally
derived.

11. Patterns of genetic transmission
• Mendelian inheritance
 Autosomal dominant
 Autosomal recessive
 X-linked
• Non traditional inheritance
• Multifactorial/polygenic inheritance

12. Pedigree Drawing
• Pedigrees are pictorial representations of patterns of
inheritance in families.
• Males are represented by squares and females by circles.
Matings are connected with a solid line.
• Children from a couple are represented below their parents
and are the next generation.
• The proband is indicated with an arrow.
• Affected individuals are indicated by shading or some other
technique, which should be explained in a key.
• Carriers are indicated by a dot in the center of their symbol.

16. What kind of inheritance does this pedigree shows?

17. Autosomal dominant disorders
• If a single copy of a gene bearing a mutation is sufficient to
cause disease and that gene is not on one of the sex
chromosomes, that condition is inherited in an AD fashion.
• In AD disorders, each child of an affected parent has a 50%
chance of inheriting the mutated gene.
• Possessing one working gene and one nonworking gene is
termed heterozygous. If both copies are the same, they are
referred to as homozygous.

18. • Some people who are obligate carriers of a mutation known
to cause an AD disorder do not show clinical signs of the
condition, while other such individuals manifest symptoms.
This phenomenon is referred to as penetrance.
• If all individuals who carry a mutation for an AD disorder show
signs of that disorder, the gene is said to have complete
penetrance.
• Often, AD disorders show variability in symptoms expressed in
different individuals carrying the same mutated gene. This
phenomenon is referred to as variable expressivity.
• AD disorders sometimes appear in a child of unaffected
parents because of a spontaneous mutation.

19. Autosomal Recessive Disorders
• Disorders that are inherited in an AR manner manifest only
when both copies of a gene pair located on a non-sex
chromosome have a mutation.
• Children affected with AR disorders are usually born to
unaffected parents, each of whom carries one copy of the
mutation.
• If both members of a couple are carriers (or heterozygotes)
for this mutation, each of their offspring has a 25% chance of
being affected.

20. X-Linked Disorders
• Approximately 2,000 genes have been identified on the X
chromosome, whereas only 200 are believed to be present on
the Y chromosome.
• Females, whose cells have two copies of an X chromosome,
possess two copies of each of these genes, whereas males,
who have one X chromosome and one Y chromosome, have
only one copy.
• Early in female development, one X chromosome is randomly
inactivated in each cell.

21.  All daughters of affected males with X-linked dominant trait
will be affected.
 Affected mothers will transmit to 50 percent of offspring,
regardless of sex, resulting in 50 percent of their children
being affected.
 100% of daughters of affected males with an X-linked
recessive condition will be obligate carriers.
 Maternal carriers will pass the mutation to 50 percent of
offspring. Therefore, 50 percent of sons will be affected and
50 percent of daughters will be carriers.

22. • Examples of X-linked disorders
 Red-green color blindness
 Duchenne muscular dystrophy
 Hemophilia
• There are some X-linked disorders, called X-linked dominant,
in which female carriers typically manifest abnormal findings.
Example; Vitamin D resistant Rickets

23. Chromosomal disorders
• occur in approximately 1% of live births.
• Chromosome anomalies include abnormalities of number and
structure and are the result of errors during cell division.
• Two common errors of cell division may occur during meiosis
or mitosis, and either can result in an abnormal number of
chromosomes.

24. • The 1st error is nondisjunction , in which 2 chromosomes fail
to separate during meiosis and thus migrate together into one
of the new cells, producing 1 cell with 2 copies of the
chromosome and another with no copy.
• The 2nd error is anaphase lag , in which a chromatid or
chromosome is lost during mitosis because it fails to move
quickly enough during anaphase to become incorporated into
1 of the new daughter cells.

25. Abnormalities of chromosomal
number
 Aneuploidy and Polyploidy
• Human cells contain a multiple of 23 chromosomes (n = 23). A
haploid cell (n) has 23 chromosomes (typically in the ovum or
sperm).
• If a cell's chromosomes are an exact multiple of 23 (46, 69, 92
in humans), those cells are referred to as euploid .
• Polyploid cells are euploid cells with more than the normal
diploid number of 46 (2n) chromosomes: 3n, 4n. Polyploid
conceptions are usually not viable, but the presence of
mosaicism with a karyotypically normal cell line can allow
survival.

26. • Mosaicism is an abnormality defined as the presence of 2 or
more cell lines in a single individual.
• Polyploidy is a common abnormality seen in 1st-trimester
pregnancy losses.
• Triploid cells are those with 3 haploid sets of chromosomes
(3n) and are only viable in a mosaic form.

27. • Aneuploidy is the most common and clinically significant type
of human chromosome abnormality, occurring in at least 3–
4% of all clinically recognized pregnancies.
• The most common cause of aneuploidy is nondisjunction, the
failure of chromosomes to disjoin normally during meiosis.
• Monosomies occur when only 1, instead of the normal 2, of a
given chromosome is present in an otherwise diploid cell.

28. • In humans, most autosomal monosomies appear to be lethal
early in development, and survival is possible in mosaic forms
or by means of chromosome rescue.
• An exception to this rule is monosomy for the X chromosome
(45,X), seen in Turner syndrome; the majority of 45,X
conceptuses are believed to be lost early in pregnancy.

29. • The most common cause of aneuploidy is nondisjunction , the
failure of chromosomes to disjoin normally during meiosis.
• Nondisjunction can occur during meiosis I or II or during
mitosis, although maternal meiosis I is the most common
nondisjunction in aneuploidies.
• Trisomy is characterized by the presence of 3 chromosomes,
instead of the normal 2, of any particular chromosome.

30. • The most common numerical abnormalities in live born
children include:
- Trisomy 21
- Trisomy 18
- Trisomy 13
 Sex chromosomal aneuploidies:
- Turner syndrome
- Klinefelter syndrome

31. Down syndrome(Trisomy 21)
• Down syndrome (DS) is the most common chromosome
abnormality among live born infants.
• The incidence of Down syndrome in live births is
approximately 1 in 733 live births.
• It is the most frequent form of intellectual disability (mental
retardation) caused by a microscopically demonstrable
chromosomal aberration.
• The occurrence increases with advanced maternal age (≥35
year).
• Cytogenetics
 Non-disjunction(47xx/xy)-(95%)
 Translocation- (4%)
 Mosaic Down syndrome (1%)

33.  Clinical features
 Characteristic dysmorphic features of DS affecting the head
and neck include:
• Upslanting palpebral fissures
• Epicanthic folds
• Flat facial profile/flat nasal bridge
• Folded or dysplastic ears and low-set small ears
• Brachycephaly
• Brushfield spots
• Open mouth and protruding tongue
• Short neck
• Excessive skin at nape of the neck
• Narrow palate
• Abnormal teeth

34.  Characteristic dysmorphic features of DS affecting the
extremities include:
• Short broad hands
• Incurved fifth finger with hypoplastic mid phalanx
• Transverse palmar crease
• Space between the first and second toes (sandal gap)
• Hyperflexibility of joints

37. • Affected individuals are more prone to CHD (50%) such as
AVSD, VSD, isolated secundum ASD, PDA, and TOF.
• Pulmonary complications include recurrent respiratory
infections, sleep-disordered breathing, laryngo- and
tracheobronchochomalacia, tracheal bronchus, pulmonary
hypertension, and asthma.
• Affected Children are at increased risk for GI anomalies,
including duodenal atresia or stenosis, imperforate anus, and
EA with TEF. They are also at increased risk for celiac disease
and HSD.

38. • Ophthalmologic disorders are common in patients with DS
and increase in frequency with age. These disorders include
refractive errors, strabismus, nystagmus, cataracts, and
keratoconus.
• Hearing loss is also common, and otitis media is a frequent
problem.
• Endocrine abnormalities in DS include thyroid dysfunction and
type 1 diabetes.

39. • Hematologic abnormalities are common in DS and include
polycythemia, macrocytosis, leukopenia, thrombocytosis, and
leukemia (transient, acute megakaryoblastic, and acute
lymphoblastic).
• Alzheimer disease like dementia is a known complication that
occurs as early as the 4th decade and has an incidence 2-3
times higher than sporadic Alzheimer disease.
• Most males with Down syndrome are sterile, but some
females have been able to reproduce, with a 50% chance of
having trisomy 21 pregnancies.

40. • Developmental delay is universal. Cognitive impairment does
not uniformly affect all areas of development.
• Social development is often relatively spared, but autism
spectrum disorder can occur.
• Up to 15% of children with Down syndrome have
misalignment of the 1st cervical vertebra (C1), which places
them at risk for spinal cord injury with neck hyperextension or
extreme flexion.
• The life expectancy for children with Down syndrome is
reduced and is approximately 50-55 yr.

41. • All women should be offered screening for Down syndrome in
their 2nd trimester by means of 4 maternal serum tests (free
β-hCG, unconjugated estriol, inhibin, and α-fetoprotein).
• This is known as the quad screen; it can detect up to 80% of
Down syndrome pregnancies.
• During the 1st trimester, fetal nuchal translucency (NT)
thickness can be done alone or in conjunction with maternal
serum β-hCG and pregnancy-associated plasma protein-A
(PAPP-A).

42. • If both 1st- and 2nd-trimester screens are combined using NT
and biochemical profiles (integrated screen), the detection
rate increases to 95%.
• Detection of cell-free fetal DNA in maternal plasma is also
diagnostic and replacing conventional 1st- and 2nd-trimester
screens.
• Chromosome analysis is indicated in every person suspected
of having Down syndrome.

43. • In approximately 95% of the cases of Down syndrome, there
are 3 copies of chr 21. The origin of the supernumerary chr 21
is maternal in 97% of the cases as a result of errors in meiosis.
• If a translocation is identified, parental chromosome studies
must be performed to determine whether one of the parents
is a translocation carrier.
• Translocation (21;21) carriers have a 100% recurrence risk for
a chromosomally abnormal child, and other robertsonian
translocations, such as t(14;21), have a 5–7% recurrence risk
when transmitted by females.

44. Edward syndrome(Trisomy 18)
• The second most common autosomal trisomy observed in live
births.
• The incidence is 1 in 5500 live births.
• There is a 3:1 female to male ratio among affected infants.
• 50 percent of affected infants die within the first two weeks of
life, and only 5 to 10 percent survive the first year.
• Related to advanced maternal age.
• Cytogenetics; 90% percent of cases of trisomy 18 are the
result of meiotic nondisjunction. The remaining; translocation
and mosaicism.

45.  Clinical features
• Low birth weight
• Short sternum
• Microcephaly
• Prominent occiput
• Micrognathia,
• Cardiac and renal malformations
• Closed fists with index finger overlapping the 3rd digit and
the 5th digit overlapping the 4th
• Narrow hips with limited abduction
• Rocker-bottom feet
• Mental retardation

47. • Congenital heart disease occurs in greater than 50 percent of
affected individuals with common valvular involvement. VSD
and PDA are the most common defects.
• The GI system is involved in approximately 75 percent of
cases. Meckel's diverticulum and malrotation are the
predominant abnormalities. Omphalocele is relatively
common prenatally.
• IUGR associated with polyhydramnios, especially in a fetus
with abnormal hand positioning ("clenched hands"), is
suggestive of this disorder.

48. Patau syndome(Trisomy 13)
• Trisomy 13 is the least common but most severe of the viable
autosomal trisomies.
• The incidence is 1.9 per 10,000 total births.
• The sex ratio at birth is slightly skewed toward females,
presumably because of decreased survival among males.
• Median survival age is 2.5 days, with only 5% of children
survive longer than 6 months.
• There is significant association between patau syndrome and
increased maternal age.

49.  Clinical features
• Cleft lip, cleft palate
• Polydactlyly (postaxial)
• Bulbous nose
• Low-set malformed ears
• Small abnormal skull and Scalp defects(cutis aplasia)
• Cerebral malformation, especially holoprosencephaly
• Microphthalmia
• Hypotelorism
• Cardiac defect(80% of cases; PDA, VSD,ASD, Dextrocardia)
• Omphalocele
• Hernia
• NTDs

51. Abnormalities of Chromosome
Structure
 Translocations
• Translocations, which involve the transfer of material from
one chromosome to another, occur with a frequency of 1 in
500 live born human infants.
• They may be inherited from a carrier parent or appear de
novo, with no other affected family member.
• Translocations are usually reciprocal or robertsonian, involving
2 chromosomes.

52.  Reciprocal translocations are the result of breaks in
nonhomologous chromosomes, with reciprocal exchange of
the broken segments.
• Carriers are usually phenotypically normal but are at an
increased risk for miscarriage.
 Robertsonian translocations involve 2 acrocentric
chromosomes (chromosomes 13, 14, 15, 21, and 22) that fuse
near the centromeric region with a subsequent loss of the
short arms.
• The resulting karyotype has only 45 chromosomes.
• Carriers are usually phenotypically normal but at increased
risk for miscarriage and unbalanced translocations in
phenotypically abnormal offspring.

54.  Inversions
• An inversion requires that a single chromosome break at 2
points; the broken piece is then inverted and joined into the
same chromosome.
• Inversions occur in 1 in 100 live births. There are 2 types of
inversions: pericentric and paracentric.
• Carriers are usually phenotypically normal, but they are at
increased risk for miscarriages, typically in paracentric
inversions, and chromosomally abnormal offspring in
pericentric inversions.

55.  Deletions and Duplications
• Deletions involve loss of chromosome material and,
depending on their location, can be classified as terminal (at
the end of chromosomes) or interstitial (within the arms of a
chromosome).
• They may be isolated or may occur along with a duplication of
another chromosome segment.
• Deletions are usually associated with intellectual disability
and malformations.

57. Sex Chromosome Aneuploidy
• Sex chromosome abnormalities are the most common
chromosome abnormalities seen in live born infants, children,
and adults.
• About 1 in 400 males and 1 in 650 females have some form of
sex chromosome abnormality.
• Sex chromosome abnormalities can be either structural or
numerical and can be present in all cells or in a mosaic form.

58. Turner syndrome
• Turner syndrome is a condition characterized by complete or
partial monosomy of the X chromosome and defined by a
combination of phenotypic features.
• It occurs in approximately 1 in 5,000 female live births.
• Half the patients with Turner syndrome have a 45,X
chromosome complement. The other half exhibit mosaicism
and varied structural abnormalities of the X or Y chromosome.

59. • Maternal age is not a predisposing factor for children with
45,X.
• In 75% of patients, the lost sex chromosome is of paternal
origin (whether an X or a Y).
• It has been estimated that 95–99% of 45,X conceptions are
miscarried.

60. • Clinical findings in the newborns can include small size for
gestational age, webbing of the neck, protruding ears, and
lymphedema of the hands and feet, although many newborns
are phenotypically normal.
• Older children and adults have short stature and exhibit
variable dysmorphic features.
• Congenital heart defects (40%) and structural renal anomalies
(60%) are common.
• The most common heart defects are bicuspid aortic valves,
coarctation of the aorta, aortic stenosis, and mitral valve
prolapse.

61. • The gonads are generally streaks of fibrous tissue (gonadal
dysgenesis ).
• There is primary amenorrhea and lack of secondary sex
characteristics.
• Most patients tend to be of normal intelligence, but
intellectual disability is seen in up to 6% of affected children.
• They are also at increased risk for behavioral problems and
deficiencies in spatial and motor perception.

63. • Turner syndrome may be diagnosed incidentally during
prenatal testing.
• More commonly, it is suspected based upon characteristic
clinical features, which may include webbed neck and
congenital lymphedema in a neonate, short stature and
reduced growth velocity in a child, and/or failure to develop
breasts.
• The diagnosis is confirmed by karyotype analysis.
• Prompt diagnosis is important to permit effective treatment
of short stature and management of comorbidities.

65. Klinefelter Syndrome
• Klinefelter Syndrome is the most common cause of
hypogonadism and infertility in males and the most common
sex chromosome aneuploidy in humans.
• The prevalence of 47,XXY is approximately 1 in 580 live born
males.
• Errors in paternal nondisjunction in meiosis I account for half
the cases.

66. • Eighty percent of children with Klinefelter syndrome have a
male karyotype with an extra chromosome X-47,XXY.
• The remaining 20% have multiple sex chromosome
aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism
(46,XY/47,XXY), or structurally abnormal X chromosomes.
• The greater the aneuploidy, the more severe the mental
impairment and dysmorphism.

67. • Puberty commences at the normal age, but the testes remain
small.
• Patients develop secondary sex characters late, and 50%
ultimately develop gynecomastia. They have taller stature.
• Many patients with Klinefelter syndrome are phenotypically
normal until puberty, and it is often undiagnosed until they
reach adulthood, when their infertility leads to identification.

68. • Patients with 46,XY/47,XXY have a better prognosis for
testicular function.
• Their intelligence shows variability and ranges from above to
below average.
• They can show behavioral problems, learning disabilities, and
deficits in language.
• Problems with self-esteem often occur in adolescents and
adults.
• Substance abuse, depression, and anxiety have been
reported.
• Those who have higher X chromosome counts show impaired
cognition.

69. • Diagnosis of Klinefelter syndrome usually can be made by
determining the karyotype of the peripheral leukocytes.
• Testosterone deficiency and the resulting hypogonadism, if
present, can be treated with testosterone.
• Hormone replacement is unlikely to improve the other
abnormalities.
• Fertility has been achieved with assisted reproductive
technologies.

70. THANK YOU