Chromosome abnormality

1. CHROMOSOMAL
ABNORMALITIES

2. INTRODUCTION
• A chromosome is a thread-like structure composed of DNA and
associated proteins found in the nucleus of eukaryotic cells.
• Errors that occur in meiosis during the production of gametes can
lead to abnormalities of chromosome structure or number.
• Chromosome abnormalities are very common and occur in
approximately 1–2% of live births, 5% of stillbirths, and 50% of early
fetal losses in the 1st trimester of pregnancy.

3. cont’n
In newborns and older children, features that suggest the presence of a
chromosome anomaly include,
• low birthweight (small for gestational age)
• failure to thrive
• developmental disability
• presence of three or more congenital malformations.
Chromosome abnormalities are more common among individuals with
intellectual disability and play a significant role in the development of some
neoplasias.

4. TYPES OF CHROMOSOMAL ABNORMALITIES
• Chromosomal abnormalities include;
• Abnormalities of chromosome structure
• Abnormalities of chromosome number

5. ABNORMALITIES IN NUMBER
• Changes in the number of chromosomes
o Aneuploidy
Abnormal cells that do not contain a multiple of haploid number of chromosomes.
o Polyploidy
Cells with more than the normal diploidnumberof 46 (2n) chromosomes,3n,4n.
o Aneuploidy is the most common and clinically significant type of human chromosome abnormality,
occurring in at least 3–4% of all clinically recognized pregnancies.
o Monosomies occur when only 1, instead of the normal 2, of a given chromosome is present in an
otherwise diploid cell.

6. Cont’n
• The most common cause of aneuploidy is nondisjunction , the failure of
chromosomes to disjoin normally during meiosis.
• After meiotic nondisjunction, the resulting gamete either lacks a chromosome or
has 2 copies instead of 1 normal copy, resulting in a monosomic or trisomic zygote,
respectively.
• Trisomy is characterized by the presence of 3 chromosomes, instead of the normal
2, of any particular chromosome.
• Trisomy is the most common form of aneuploidy.

7. Cont’n
oThe most common numerical abnormalities in liveborn children include
1. trisomy 21 (Down syndrome)
2. trisomy 18 (Edwards syndrome)
3. trisomy 13 (Patau syndrome)
o sex chromosomal aneuploidies:
1. Turner syndrome (usually 45,X)
2. Klinefelter syndrome (47,XXY), 47,XXX, and 47,XYY.
oBy far the most common type of trisomy in liveborn infants is trisomy 21 (47,XX,+21 or
47,XY,+21)

8. Trisomies
1:TRISOMY 21(DOWN SYNDROME)
• DS is the most common abnormality of chromosomal number in
liveborn infants. It occurs in approximately 1 of every 700 births.
• Most cases (95%) are due to nondisjunction.
• As a result of nondisjunction, the fertilized egg contains three copies
of chromosome 21 (trisomy 21). Using standard cytogenetic
nomenclature, trisomy 21 is designated 47,XX,+21 or 47,XY,+21.

9. Clinical features
• Children with DS are usually diagnosed in the newborn period.
• They tend to have normal birthweight and length, but they are hypotonic.
The characteristic facial appearance, with brachycephaly
flattened occiput
hypoplastic midface
flattened nasal bridge
upslanting palpebral fissures
epicanthal folds
large protruding tongue, is often apparent at birth.
Infants also have short broad hands, often with a single transverse palmar crease,
wide gap between the first and second toes.
• Hypotonia may cause feeding problems and decreased activity. Intellectual disability is noted in almost all
patients with DS.

10. Cont’n
• Almost half of all children with DS have congenital heart disease, including ventriculoseptal or
atrioseptal defects, and valvular disease.
• Between 5% and 10% of newborns with DS have gastrointestinal tract anomalies; the three most
common defects are

duodenal atresia

annular pancreas
imperforate anus
• Congenital hypothyroidism occurs in 4–18% of infants with DS. Acquired hypothyroidism is a more
common problem. Thyroid function should be checked at birth, 6 months of age, and then annually.
• Polycythemia with markedly elevated white blood cell counts.

11. cont’n
• Children with DS are more susceptible to infection, more likely to
develop cataracts.
• between 10% and 30% have atlantoaxial instability, an increased
distance between the first and second cervical vertebrae that may
predispose to spinal cord injury.
• Many individuals older than 35 years of age develop Alzheimer-like
features.

12. Face of a child with Down syndrome
Prehensile foot in a 1mnth old child with
Down syndrome.

13. Diagnosis of Down Syndrome
• Prenatal screening:
Combined test done within the 1st
trimester
Maternal serum beta human chorionic gonadotropin (beta-hCG)
Maternal serum pregnancy-associated plasma protein-A (PAPP-A)
Ultrasound measurement of nuchal translucency (NT)
Integrated test
Quadruple test(BHCG,AFP,E3,inhibin A) done within the 2nd
trimester
• Physical examination
• Diagnosis should be confirmed with a genetic test( e.g. a karyotype
preformed on a blood sample)

14. Management
1. Growth
• Pts should be monitored for growth disturbances associated with other disorders i.e
hypothyroidism, excessive weight gain.
• Obesity prevention: Interventions begin at 24mths;
• Attention to diet and promotion of physical activity
• Calorie intake < the age-specific recommendation for unaffected individuals
• Calcium and vitamin D intake to be monitored closely.
2. Cardiac disease
• All newborns should be evaluated for congenital heart disease in consultation with a
pediatric cardiologist.
• Echocardiogram- to detect abnormalities.
• Continued clinical cardiac evaluation because;
• High risk of mitral valve prolapse and aortic regurgitation

15. cont’n
3. Hearing
• Newborns should have a newborn hearing screening with BAER
• Repeat hearing screening every 6 months until 4-5yrs of age and then
yearly.
4. Ophthalmologic disorders
• Ophthalmologic assessment should be performed in the newborn
period or at least before 6months of age;
• To detect strabismus, nystagmus, and cataracts.
• Affected children should have annual assessments of vision.

16. cont’n
5. Thyroid function
• Thyroid function testing should be obtained in the newborn period.
• Repeated screening at 6 and 12 months and then annually.
• Height and weight should be measured yearly.
6. Celiac disease
• Screening should be begin at 1 yr of age.
7. Behavior and psychiatric problems.
• Assessment and tx of behavior and psychiatric problems should be expeditious.
• It should include evaluation of problems at school and at home

17. cont’n
8. Hematology
• CBC and differentials should be obtained at birth to evaluate
myeloproliferative disorders and polycythemia.
• Infants with myeloproliferative disorders should be followed with a
CBC and a differential:
• every 3mths until 3yrs and then every 6mths until 6yrs
9. Sleep Apnea
• Children with Down syndrome have an increased risk of obstructive
sleep Apnea
• Polysomnography or pulse oximetry monitoring during sleep is
recommended in all children by 4 yrs.

19. 2) Trisomy 18(Edward’s syndrome)
• Trisomy 18 (47,XX,+18 or 47,XY,+18) is the second most common autosomal
trisomy, occurring in approximately 1 in 6,000 live births.
• Virtually all cases of trisomy 18 are due to nondisjunction.
• More than 95% of conceptuses with trisomy 18 are lost as spontaneous abortuses
in the first trimester; females are far more likely to survive to term than males; the
ratio of male to female liveborns with trisomy 18 is 1:4
• Infants with trisomy 18 rarely survive; only 12% will reach their first birthday. Most
infants with trisomy 18 are small for gestational age.

20. Clinical features
hypertonia
prominent occiput
micrognathia
 low-set and malformed ears
 short sternum
 rocker-bottom feet
 hypoplastic nails
 characteristic clenching of fists—the second and fifth digits overlap the
third and fourth digits

22. 3) Trisomy 13(Patau syndrome)
• The third of the common trisomies, trisomy 13 (47,XX,+13 or 47,XY,+13).
• Occurs in 1 in 10,000 live births.
• As in trisomy 18, trisomy 13 is usually fatal in the first year of life, with
only 20% of infants surviving beyond their first birthday.
• As in DS, trisomy 13 can be caused by nondisjunction (seen in 75% of
cases)

23. Clinical features
Infants with trisomy 13 have numerous malformations.
• They are small for gestational age and microcephalic.
• Midline facial defects such as cleft lip and palate are common
• Midline central nervous system anomalies, such as alobar holoprosencephaly.
• The forehead is generally sloping.
• Ears are often small and malformed.

24. cont’n
•Microphthalmia or anophthalmia may occur.
•Postaxial polydactyly of the hands is common, as are overlapping fingers
and hyperconvex nails.
•Hypospadias and cryptorchidism are common in boys.
• Girls generally have hypoplasia of the labia minora.
• In addition, most infants with trisomy 13 have congenital heart disease.
•When seen in conjunction with polydactyly and some or all the facial features, this
finding is essentially pathognomonic for the diagnosis of trisomy 13.

25. Klinefelter Syndrome
• Occurring in 1 in 580 newborn males.
• KS is the most common genetic cause of hypogonadism and infertility in men.
• It is caused by the presence of an extra X chromosome (47,XXY).
• The extra chromosome arises from nondisjunction in either the sperm or egg.
• Before puberty, males with KS are phenotypically indistinguishable from the rest of the population.
• The diagnosis is often made in adolescence when the hallmark of the condition, under androgenation
in the presence of testes that remain infantile in volume, should alert the clinician.

26. Clinical features
• Clinical features of this syndrome differ by developmental stage and
severity of the phenotype.
Neonates and prepubertal boys
• Micropenis
• Hypospadias
• Cryptorchidism
Puberty
• Failure to begin or complete pubertal development
• Gynecomastia
• Tall, with legs that grow out of proportion to arm length
Biochemical findings
• Low serum total and free testosterone
• High FSH and LH concentrations

27. Management
• Treatment is based on the;
• age of the patient at diagnosis
• the severity of the phenotype
• Specific clinical endpoint
• Testosterone therapy
• Short course in neonatal and prepubertal boys (monthly for 3 doses)
• Age 13 to 18 , goal is to cause gradual virilization

28. Monosomies
Turner Syndrome
• TS is the only condition in which a monosomic conceptus survives to term;
however, 99% of embryos with 45,X are spontaneously aborted.
• TS is seen in up to 10% of first trimester pregnancy losses.
• Occurring in 1 in 3,200 liveborn females, TS is notable for its relatively mild
phenotype.
• Affected women tend to have typical intelligence and normal life
expectancy.

29. Clinical features
• Females with TS typically have a characteristic facial appearance with; low-set mildly
malformed ears, triangular face, flattened nasal bridge, and epicanthal folds.
• webbing of the neck
• a shieldlike chest with widened internipple distance.
• puffiness of the hands and feet.
Internal malformations may include;
• congenital heart defect (bicuspid aortic valve is most common).

31. Cont’n
• Renal anomalies, including horseshoe kidney.
• Short stature is a cardinalfeature of this condition.
• Acquired hypothyroidism.
• The presence of streak gonads instead of well-developed ovaries
leads to estrogen deficiency, which often results in incomplete
development of secondary sex characteristics and amenorrhea.

32. Diagnosis
• Many females with TS escape detection during the newborn period because
phenotypic features are subtle.
• While most patients with TS are diagnosed in the newborn period
because of the presence of physical features.
• Some are diagnosed in childhood during a work-up for short stature.
• others are diagnosed during adolescence or adulthood when they fail to develop
secondary sexual characteristics or during work-ups
for infertility

33. Cont’n
• Diagnosis confirmed by karyotype analysis.
• Prompt diagnosis is important to permit management of comorbidities.
• Diagnostic tests include;
Standard karyotype analysis
Renal ultrasonography
Echocardiography
Laboratory tests
Serum TSH and tTG (age 4yrs or older)
Fasting Blood Glucose,HbA1C,ALT,AST,serum creatinine, urinalysis(age 10yrs and older)

34. Management
Cardiovascular anomalies:
• At the time of diagnosis, all infants with this syndrome should have a comprehensive
Cardiovascular evaluation.
• It should include;
• Measurement of blood pressure
• ECG
• Cardiac imaging
• Pts with coarctation of the aorta usually require corrective surgery
• For those with prolonged QTC interval, drugs that prolong this interval should be
avoided.
• Antimicrobial prophylaxis is not indicated for those patients with heart valve disease.
• Monitor for aortic dilatation.

35. cont’n
Cognitive function and learning disabilities
• Neuropsychology and allied behavior health services should be integrated into
the care of affected girls and women.
Tympanometry and audiology
• Regular monitoring of hearing, including serial audiology evaluations, is
recommended through out life.
• Every 3 yrs in children and every 5 yrs in adults
Scoliosis and kyphosis;
• Surveillance for scoliosis and kyphosis is important throughout childhood
especially during adolescence.
• It should include a physical examination for scoliosis annually and every 6
mths during growth homorne therapy.

36. cont’n
Renal anomalies and Urinary tract infections:
• Patients should undergo renal ultrasonography at the time of diagnosis
Ophthalmology
• Ophthalmologic examination is recommended at the time of
diagnosis( starting from the second yr of life)
• Its repeated every 3 years thereafter.
Edema
• Can be controlled with support from stocking, lymphatic drainage
massage therapy and physical therapy.

37. cont’n
Short stature management
• Monitoring growth using growth charts
• Growth hormone therapy
• Should be initiated as soon as the height of the girl falls below the 5th
percentile
Puberty induction
• Pubertal development should be assessed with serial examinations
throughout childhood and adolescence
• Estradiol replacement therapy should be initiated if there is no
evidence of breast development by 11 to 12 yrs of age

38. SYNDROMES INVOLVING CHROMOSOMAL
DELETIONS
Cri du Chat Syndrome
• A deletion in the short arm of chromosome 5 is responsible for cri du
chat syndrome.
• Deletions involve loss of chromosome material and, depending on their
location.
• characteristic catlike cry during infancy, the result of tracheal hypoplasia

39. Clinical features
• clinical features include;
• low birthweight
• postnatal failure to thrive
• hypotonia
• developmental disability
• microcephaly
• epicanthal folds
• downward obliquity of the palpebral fissures
• low-set malformed ears.
• Clefts of the lip and palate, congenital heart disease, and other malformations may be
seen

40. Williams Syndrome
• Caused by a 1.55 megabase deletion in chromosome 7q11.2 that contains at least 28 genes,
Williams syndrome is associated with a unique phenotype.
Clinical features.
congenital heart disease (in 80%), with supravalvar aortic stenosis
growth delay with short stature
median flare of the eyebrow
fullness of the peri-oral and periorbital region
blue irides with a stellate patternof pigment
depressed nasal bridge with anteversion of the nares
moderate intellectual disability (average IQ 57) with strengths in personal social skills and
deficiencies in cognitive areas
hypercalcemia

41. Chromosome 22q11.2 Deletion Syndromes
• Deletions of chromosome 22q11.2 are responsible for a group of findings that have been
called by several names, including velocardiofacial syndrome, conotruncal anomaly face
syndrome, Shprintzen syndrome, and DiGeorge syndrome.
• These conditions represent a continuum of findings, virtually all of which are due to the same
chromosomal deletion.
Common features;
• include clefting of the palate with velopharyngeal insufficiency
• conotruncal cardiac defects (including truncus arteriosus)
• a facial appearance characterized by a prominent nose and broad nasal root.
• Speech and language difficulties are common
• mild intellectual impairment.

42. Cont’n
• About 70% have immu-nodeficiency, largely related to T-cell dysfunction.
• A widespectrum of psychiatric disturbances, including schizophrenia and bipolar
disorder, has been seen in at least one third of affected adults.
• Damage to the third and fourth pharyngeal pouches, embryonic structures leads to
abnormalities in the developing face (clefting of the palate, micrognathia), the
thymus gland, the parathyroid glands, and the conotruncal region of the heart.
• This spectrum of findings, called the DiGeorge malformation sequence, is an
important part of 22q11DS

43. Prada-willi syndrome
• Prader-Willi syndrome (PWS), occurs in 1 in 17,500infants
• It is characterized by ;
1. neonatal hypotonia
2. postnatal growth delay
3. a characteristic appearance including almondshaped eyes
4. small hands and feet
5. developmental disability
6. hypogonadotropic hypogonadism
7. obesity after infancy

44. REFERENCES
1. Robert M. Kliegman, MD, Joseph W. St Geme Iii, MD, Nathan J. Blum,
MD, Robert C. Tasker, MBBS, MD, Samir S. Shah, MD, MSCE, Karen M.
Wilson, MD, MPH.(2020).Nelson Textbook Of Pediatrics. Elsevier
Publishers.
2. Kathryn K Ostermaier,MD,FAAP;Down Syndrome: Clinical features and
diagnosis. In:UptoDate, Connor FR (Ed),Wolters Klumer.(Assessed on Feb
17,2024)
3. Kathryn K Ostermaier,MD,FAAP;Down Syndrome: Management.
In:UptoDate, Connor FR (Ed),Wolters Klumer.(Assessed on Oct 06,2022)
4. Phillippe Backeljauw,MD;Clincal manifestations and diagnosis of Turner
syndrome.In: Uptodate, Connor FR(Ed),Wolters Klumer.(Assessed on Jun
07,2023)