Approach to patients with chromosomal anomalies

1. APPROACH TO PATIENTS
WITH CHROMOSOMAL
ANOMALIES

2. Definition and prevalence
 Chromosomal anomalies refers to missing, extra or irregular portion of
chromosomal DNA.
 Most foetus with chromosomal anomalies do not survive.
 Affects 1 out of 200 of new borns

3. Genetics and Disease
 Most diseases have probable genetic and environmental basis.The
genetic conponent may be the major or the only factor leading to
manifestation of the disease,or it may merely predispose the individual to
get a disease in response to environmental stresses.Based on genetic
mechanism,disease may be of 5 types
1. Chromosomal disorders
2. Single gene disorders
3. Polygenic disorders
4. Mitochondrial disorders
5. Somatic cell disorders

4. Chromosomal disorders
MECHANISM OF CHROMOSOMAL ANOMALIES
 Loss or gain of a whole chromosomes due to abnormalities in a cell division
may cause profound disturbances in the genetic constitution of the fetus
and affect its survival.
 Depending upon the type of abnormality,the chromosome involved and
the type of imbalance ,there may be an early abortion ,still birth,neonatal
death,malformations or intellectual disability.
 There are 2 types of chromosomal abnormalities.
1. Numerical
2. Structural

5. Numerical chromosome anomalies
 Aneuploidies result from failure of chromosomes to separate normally
during cell division.This phenomenon is known as nondisjunction
 Nondisjunction during meiosis 1 leads to formation of disomic or nullisomic
gametes, resulting in trisomic and monosomic zygotes respectively
 Nondisjunction during meiosis 2 results in monosomic,disomic and
nullisomic gametes,leading to disomic ,trisomic and monosomic zygotes.
 Common aneuploides in live born babies include Downs syndrome(trisomy
21),Edward syndrome(trisomy 18),Patau syndrome (trisomy 13) and Turners
syndrome(monosomy X)

6.  STRUCTURAL CHROMOSOME ABNORMALITIES
 Chief types of structural chromosome abnormalities are ;
1. Translocation
2. Inversion
3. Deletion
4. Duplication
5. Ring chromosome
6. Isochromosomes

7.  TRANSLOCATION

8.  DELETION

9.  INVERSION

10.  DUPLICATION

11.  RING CHROMOSOME

12.  ISOCHROMOSOMES

13. Testing for Chromosomal Disorders
 Laboratory testing for chromosomal disorders includes conventional
karyotyping,fluorescent in situ hybridization (FISH),quantitative PCR(qPCR),multiplex
ligation probe amplification(MLPA) and chromosomal microarray (CMA).
 The process of making chromosome preparations by in vitro culture,staining,identification
and classification of chromosomes is called karyotyping.Karyotyping can be performed
on peripheral blood lymphocytes,bone marrow aspirate and tissue biopsy material.
 The process is labor intensive and involves culture,followed by harvesting chromosomes
after the cells are arrested in mitosis
 After preparation of slides,staining (usually Giemsa stain)is done to produce a banding
pattern unique for each chromosome.This enables detection of numerical and structural
abnormalities through the genome at a resolution of approximately 5 Mb
 Molecular cytogenic techniques includes FISH,quantitative polymerase chain reaction
and MLPA.

14. DOWNS SYNDROME
 It is the most common chromosomal disorder,occuring with a
frequency of 1:800 to 1:1000 newborns.
 Chromosome number 21 is present in triplicate usually because of
meiotic non disjunction in either maternal or parental gamete.
Clinical features and Diagnosis
 Poor intellectual ability
 Physical retardation
 Falt facial profile
 Upward slant of eyes
 Epicanthic folds
 Nose is small with flat nasal bridge
 Mouth shows a narrow short palate with small teeth and furrowed
proteuding tongue
 Significant hypotonia

15.  The skull appears small and brachycephalic with
flat occiput.
 Ears are small and dysplastic.
 Characteristic facial grimace on crying
 Hands are short and broad
 Clinodactyly(hypoplasia of middle phalanx of 5th
finger)and simian crease are usual
 There is a wide gap between the first and the
second toe(sandle gap)

16.  Associated abnormalities
 Congenital heart disease
 Gastrointestinal malformations
 Opthalmic problems
 Thyroid dysfunction
 Atlanto occipital subluxation
 Physical growth
 Malignancies

17. Managment and prognosis

18. TURNER SYNDROME
Clinical features
 Lymphedema of the dorsum of hands and feet.
 Loose skin folds at the nape of neck
 Short stature
 Short neck with webbing and low posterior hair line.
 Anomalous ears
 Prominent narrow and high arched palate,small
mandible and epicanthic folds may be noted.
 Chest is broad shield like with widely spaced
hypoplastic nipples

19.  At puberty, sexual maturation fails to occur.It has been recommended
that the diagnosis of Turners syndrome should be considered in all girls with
short stature.
 Ultrasound may show streak ovaries and hypoplastic uterus.
 Levels of FSH and LH are increased

20. Management
 Height monitoring should be done using growth charts for Turner syndrome
 Cardiac evaluation and measurement of BP is recommended at baseline
and every year
 Treatment with growth hormone is recommended. While therapy may
increase the final height by 8-10 cm,the cost is prohibitive
 Thyroid testing should be done in infancy or early childhood.if child is lagging
in growth.Routine evaluation is required after 10 years of age.
 Counselling regarding behavioral problems due to short stature,amenorrhea
and sterility is an integral part of management
 Ovarian hormone replacement is advised around 14 years

21.  Conjugated estrogen(0.3 mg/day) or ethinyl estradiol
are given for 3-6 months.After 6-12 months ,cyclical
therapy with estrogen and progesterone is stated
 Regular audiometry is advised in adulthood or earlier, if
indicated.
 Evaluation for renal malformation by USG should be
done at first contact

23. Single Gene Disorders
 Single gene disorders are inherited as autosomal dominant,autosomal recessive or X
linked disorders due to mutation in the disease Specific genes.
Drawing and interpreting a pedigree is an integral part of diagnosis of single gene
disorders
Mutations refers to the heritable change in the DNA resulting in the perturbed protein
structure and function.
There are 3 types of mutations;
 Substitution or point mutation
 Deletion mutation
 Insertion

24. AUTOSOMAL DOMINANT INHERITANCE
 Generally it impairs the synthesis of
structural or non enzyme proteins
e.g:Huntington chorea and
connective tissue disorders.
 These disorders manifest even if only
one of the alleles of the abnormal
gene is affected.
 Physical examination of other siblings
and parents should be done to
uncover milder forms of the disorder.

25.  AUTOSOMAL RECESSIVE INHERITANCE
 They manifest only in homozygous state,i.e.both the
alleles are mutant genes.
 Generally they affect synthesis of enzyme ,leading
to inborn errors of metabolism.
 The parents of the affected individuals are
apparently normal but carry the mutant genes
 E.g: Beta thalassemia, sickle cell disease,spinal
muscular atrophy,phenylketonuria and
galactosemia

26. X LINKED RECESSIVE INHERITANCE
 Since in males,there is no corresponding locus for
a mutant alllele of the X chromosome on the
shorter Y chromosome, the mutant X linked
recessive gene expresses as a clinical disorder in
the male child because it is not suppressed by
ajormal alllele
 In the female, the disorder does not manifest
clinically since the mutant gene is compensted for
by the normal allele in the other X chromosome
 E.g:color blindness

27.  X LINKED DOMINANT INHERITANCE
 These are rare.Both heterozygous female
and hemizygous males are affected.
 All the sons of the affected males are
normal and all daughters are
affected.The affected females transmitt
the disease to half of the sons and half of
the daughters.
 E.g:hypophosphatemic type of vitamin D
resistant rickets

28.  MITOCHONDRIAL INHERITANCE
 Mutation within a mitochondrial gene can lead to phenotypic
defects and show a pattern of maternal genetic transmission .
 Since mitochondria are only present in ovum and not
sperms,the inheritance is maternal
 All affected daughters transmitt the disease.Sons are affected
but do not transmit the disease
 E.g:Leigh disease,mitochondrial encephalopathy,lactic
acidosis,stroke like syndrome.

29.  SOMATIC CELL GENETIC DISORDERS
 In somatic cell disorders,the defects are restricted to specific
somatic cells,in contrast to previous 4 types of gamete disease in
which abnormality is present in all the cells,including germ line cells.
 These include cancers which can arise due to genetic changes in
somatic cells alone.

30. THERAPY OF GENETIC DISORDERS
While genetic disorders cannot be cured completly,symptoms may be
ameliorated and irreversible damage or handicap prevented or reduced
through several therapeutic approaches
 Specific diets
 Providing deficient proteins
 Promoting excretion of toxic substances
 Avoid precipitating factors and drugs
 Supportive care

31. PREVENTION OF GENETIC DISORDERS
 Carrier screening: HbA2 levels are highly useful in identifying carriers of thalassemia trait pre pregnancy
or early in pregnancy.
 Newborn screening:This is an example of secondary prevention by early diagnosis and treatment.
Newborn infants are screened routinely for some endocrine disorders and inborn errors of metabolism.
 Prevention of Neural Tube Defects:Folic acid supplementation is recommended at a dose of 0.4 mg
daily from 1 month before to 3months after conception to prevent neural tube defects.
 Maternal serum screening:Estimation of pregnancy associated plasma protein A(PAPP-A) and free
hCG int 1st trimester and serum alpha fetoprotein unconjugated estriol and inhibin A in the 2nd trimester
are useful biochemical markers to detect aneuploidies

32. THANKYOU