CHROMOSOMES

Choromosomes are condensation of DNA material in the nucleus of a cell.

Each human cell contains 23 pairs of chromosomes(except in the gonads).
There are two types of chromosomes:
Autosomes- Chromosome 1-22
Sex chromosome- X chromosome and Y chromosome

STRUCTURE OF A CHROMOSOME:

NORMAL HUMAN KARYOTYPE:

CHROMOSOMAL ABNORMALITIES
Numerical Abnormalities:
Monosomy
e.g. Turner’s syndrome
Trisomy
e.g. Down’s syndrome, Edward’s syndrome, Patau’s syndrome

Structural Abnormalities
Deletion
Duplication
TURNER SYNDROME
(45 X0 GONADAL DYSGENESIS)
KARYOTYPE: 45 X0
INCIDENCE: 1:3000 newborns
INHERITANCE: Sporadic, meiotic or mitotic nondisjunction
GENITALIA: Female

CLINICAL FEATURES:
 The disorders maybe recognizable at birth - *lymphedema of the dorsum of
hands&feet, loose skin folds at the nape of neck.
 Short stature, short neck with webbing, low posterior hairline
 Facies - Anomalous ears, prominent narrow & high arched palate, small mandible
&epicanthal fold
 Broad shield-like chest & widely spaced nipples
 Increased carrying angle at elbow
 Knee anomalies e.g medial tibialexostosis
 Short 4th metacarpals & metatarsals
 At puberty, sexual maturation fails to occur
 Adult stature <145 cm
 Pigmented naevi, keloid, abnormal nails, puffiness of dorsum of fingers
 Mentally normal unless ring chromosome is present
 Associated congenital defects are common
Kidney – horse-shoe kidney, double or cleft renal pelvis
Heart – coarctation of aorta
Ears – perceptive hearing defect
Congenital lymphedema – usually recedes in early infancy*
HORMONE PROFILE
 Low plasma estradiol
 High plasma LH & FSH concentration

DIAGNOSIS
 Hormone profile
 Karyotype/Barr body (absent)
MANAGEMENT
 Height monitoring, cardiac evaluation, BP measurement , ECHO at baseline & every
year is recommended.
 Growth hormone therapy:
0.375mg/kg/week daily SC
Oxandrolone 0.06mg/kg/day early in childhood if diagnosed
 Ovarian hormone replacement – to elicit increase in height and development of
secondary sex characteristics.
100µg/kg/day ETHINYL ESTRADIOL at 12-13 yrs of age.
Dose is gradually increased over 2-3 yrs& subsequently cyclical therapy
estrogen-progesterone combination is started
 Prophylactic GONADECTOMY in Turner syndrome with Y chromosome is
recommended – due to chances of developing gonadoblastoma
KLINFELTER’S SYNDROME
Klinefelter syndrome is a chromosomal condition that affects male physical and
cognitive development.
Incidence 1:500-1000 newborn
Genotype: 47, XXY

CLINICAL FEATURES
Delayed/ incomplete puberty
Gynaecomastia
Reduced facial and body hair
Infertility
Crytorchidism
Hypospadias
Micropenis
Taller than counterparts
High risk of breast cancer and SLE
Learning disabilities and delayed speech and language development
TREATMENT
Early identification and anticipatory guidance are extremely helpful, although Klinefelter
syndrome is rarely diagnosed in prepubertal males. Treatment should address 3 major
facets of the disease: hypogonadism, gynecomastia, and psychosocial problems.

Androgen therapy

Testosterone replacement should begin at puberty, around age 12 years, and the
dose should increase until it is sufficient to maintain age-appropriate serum
concentrations of testosterone, estradiol, follicle-stimulating hormone (FSH), and
luteinizing hormone (LH).

Androgen therapy is used to correct androgen deficiency, to provide appropriate

virilization, and to improve psychosocial status. Regular testosterone injections can
promote strength and facial hair growth; build a more muscular body type; increase
sexual desire; enlarge the testes; improve mood, self-image, and behavior; and protect
against precocious osteoporosis.

Speech and behavioral therapy

A multidisciplinary team approach can assist in improving speech impairments,

academic difficulties, and other psychosocial and behavioral problems.

In children, early speech and language therapy is particularly helpful in developing

skills in the understanding and production of more complex language.

Males with Klinefelter syndrome should receive a comprehensive

psychoeducational evaluation to assess their areas of strengths and weaknesses. The
information obtained from these evaluations may be helpful in planning appropriate
resources and classroom placement.

Physical and occupational therapy

Physical therapy should be recommended in boys with hypotonia or delayed gross

motor skills that may affect muscle tone, balance, and coordination.

Occupational therapy is advised in boys with motor dyspraxia.

Treatment for infertility

Men with Klinefelter syndrome were considered infertile until 1996. Over the last
decade, developments in microsurgical techniques and advances in artificial
reproductive technologies (ART) allowed more than 50% of patients with Klinefelter
syndrome to have their own children through the combination of microsurgical
testicular sperm extraction (TESE) and the use of freshly retrieved sperm for in-vitro
fertilization (IVF). The fact that sperm can be found in the testes of men with Klinefelter
syndrome has challenged the previous assumption that men with Klinefelter syndrome
are always sterile. Viable spermatozoa can now be extracted from the testes via surgical
biopsy, and a spermatozoon can be directly injected into an ovum.

More than 60 children have been born worldwide after successful

intracytoplasmicsperm injection (ICSI) in couples in which the male partner has
Klinefelter syndrome.

A minority of men with Klinefelter syndrome have viable sperm in their ejaculate and
are able to provide sperm for cryopreservation for future pregnancies.

Microdissection testicular sperm extraction is an effective sperm retrieval technique in

men with Klinefeltersyndrome.Men with hypogonadism who respond to medical
therapy may have a better chance of sperm retrieval.

Genetic counseling

The recurrence risk is not increased above that in the general population.

Physicians should provide parents with information from unbiased follow-up

studies of children with Klinefelter syndrome.

The best time to reveal the condition to an affected male is probably mid-to-late
adolescence, when he is old enough to understand his condition.

Reproductive genetic counseling

Sperm from patients with the nonmosaic 47,XXY karyotype has been used
successfully in assisted reproduction.

Origin of the meiotic products of patients with the nonmosaic 47,XXY karyotype
remains unclear. First, mosaicism cannot be excluded in the nonmosaic 47,XXY
karyotype. Indeed, the presence of a normal XY germ cell line in the testis could explain
the production of normal haploid sperm in these apparently nonmosaic patients.
Nevertheless, lymphocyte karyotyping neither predicts the chromosomal constitution of
the testis cells nor the presence or absence of spermatogenesis.

ICSI per se is also associated with an increased risk of producing a chromosome

anomaly in offspring. IVF is also associated with an increased risk for de-novo
chromosomal aberrations, especially those involving the sex chromosomes.

Reproductive genetic counseling of patients with the 47,XXY karyotype remains

difficult. Some authors have recommended preimplantation or prenatal diagnosis after
ICSI using sperm cells from patients with the 47,XXY karyotype. Arguments from authors
who propose a preimplantation genetic diagnosis (PGD) include the increased risk of
producing sex chromosomal-abnormal offspring (the unbalanced offsprings are 47,XXX
or 47,XXY karyotypes).

DOWN SYNDROME
 The most common chromosomal disorder (1:800 to 1:1000 newborns).
 The chromosome number 21 is present in triplicate.
 The origin of the extra chromosome maybe maternal or paternal.
 The risk in the newborns:

Age of mother Risk in newborns

15-29 1:1550

30-34 1:800

35-39 1:270

40-44 1:100

>45 1:50

BASIC DEFECTS:-
a) Non-dysjunction – 95%
Meiotic division does not occur for no. 21 chromosome. One
of
the gamete carries an extrachromosomes.
b) Translocation – 4%
Translocation of the third no. 21 chromosome to another
chromosome.
c) Mosaicism – 1%
 Results from a mitotic division error that occurred during earlu
embryonic development.

CLINICAL FEATURES :-
A) Dysmorphic features
1) Dysmorphic facial features
Flat facial profile
Short, upslanting palpebral fissures
Brushfield spots on iris
Flat nasal bridge with epicanthal folds
Small mouth with protruding tongue
Small retroplaced chin
Short ears with abnormal ear lobes that are usually downfolded
Cataract and squint are common
High arched palate with small teeth
‘scrotal’ (furrowed) tongue
2) Other dysmorphic features
Small head (microcephaly), brachycephaly (flat occiput)
Skin- excess posterior neck skin
Short stature
Short sternum
Small genitalia
Short, broad hands and fingers marked by incurved fifth finger
(clinodactyly) with hypoplastic middle phalanx
Single palmar crease (Simian crease)
 Wide gap between first and second toes (sandle gap)

B) Functional and structural abnormalities

1) Hypotonia – most noticeable in the newborns.
2) Mental retardation and developmental delay.
3) cardiac defects – a) endocardial cushion defects
b) septal defects
c) A-V communis
d) ventricularseptal defects
e) patentductusarteriosus

4) abdomen – a) duodenal atresia and Hirschsprung disease

b) small penis
c) cryptorchidism

5) dysplastic pelvis.
6) hypothyroidism and leukaemia.
7) a pattern of dementia much like Alzheimer’s disease.
8) Social aspects – behave as good babies, happy children and tend towards
mimicry, are friendly and have a good sense of rhythm and enjoy music.
 C) Common complications
1) Death due to congenital heart disease and lower respiratory tract infection.
2) Chronic rhinitis.
3) Conjunctivitis.
4) Periodontal disease.

 Risk of recurrence
 Non-dysjunction – subsequenct chances are 1% in addition to the risk of high
maternal age.
 Mosaicism – if one child is Down, the subsequent chances is 1%.
 Translocation – subsequent chances are 5% to 100%
MANAGEMENT
A) Principle of genetic counselling
 To be given after confirmation of diagnosis.
 Both the parents should be present.
 Given by a team of physician, geneticist and psychiatrist.
 A number of sittings are required.
B) Counselling
 Explain the parents about the disease, that the child is going to be mentally
retarded, require special schooling.
 Explain about congenital heart diseases, other abnormalities, social
performances is good-smiles, laughs (lovable moron), interested in music and
mimicry.
 Counselling about the recurrence risk.
C) Antenatal diagnosis
1) Initial screening with
 maternal serum markers
PAPP-A and betaHCG ( 1st trimester)
Serum alpha fetoprotein (AFP), HCG, unconjugated estriolandinhibin A
(2nd trimester)
 Fetal ultrasonography
1st trimester – nuchal translucency and nasal bone
2nd trimester - Increased nuchal fold thickness, short femur and humerus
length and duodenal atresia.
2) Prenatal karyotyping
Chorionic villous sampling – can be carried out between 10 to 12 weeks
of pregnancy (transcervical or transabdominal).
Amniocentesis – on 16 to 18 weeks
Cordocentesis – after 18 weeks
The risk of fetal loss after CVS is 3-4%, after cordocentesis is 3% and after
amniocentesis is 0.5-1 %.
 Recommended follow up for patients of Down Syndrome
0-1 month infancy 1-5 year 5- 13
year
Clinical examination + (or 1st visit) + + +
Chromosomal study + (or 1st visit)
Stimulation programme + + +
Growth assessment + + + +
Thyroid screening + 3 yearly
hearing + 3 yearly
vision + 3 yearly
Cervical spine x-ray +
ECG and echocardiography First visit or clinical suspicion / abnormal ECG
Psychosocial development & + + + +
behavioural assessment
EDWARD’S SYNDROME(TRISOMY 18)
First described in 1960 by Edwards et al.
Incidence : 1 in 3000 live births. It is the second most common autosomal trisomy
among live births.
Genetics : Presence of three chromosome 18 instead of the normal two. This is due to
an error in cell division,known as meiotic dysjunction.

CLINICAL FEATURES
 Failure to thrive
 Severe developmental delay
 Hypertonia-extreme rigidity
 Head-Microcephaly, dolichocephaly,prominent occiput, strawberry-shaped head
 Face-Small eyes, upturned nose, small mouth, small jaw( micrognathia) ,low set and
malformed ear
 Hands
-Clenched hands with index finger overlapping middle finger, little finger overlapping
ring finger, due to flexion deformity of fingers
-Underdeveloped nails
-Simple dermal arches on nearly all digits
-Very short fourth digits with a single crease
 Thorax
Shield-like chest, short sternum
 Abdomen- Inguinal or umbilical hernia, part of the intestinal tract is outside the
stomach (omphalocele)
 Small pelvis
 Rocker bottom feet , prominent calcaneum, short dorsiflexed of first toe
 Skin mottling
 Heart
 Congenital Heart Defects
 Ventricular SeptalDefect(90%)
 Patent DuctusArteriosus(70%)
 Atrial SeptalDefect(20%)
 Valvular regurgitation may occur at multiple sites
 Coarctation of aorta
 Eesophageal atresia
 Kidney anomalies
 Undescended testis
 Vertebral abnomalies
 Arthrogryposis (Stiff joint)
 Psychomotor retardation
INVESTIGATION:
 To confirm diagnosis
 Karyotyping
 To diagnose complication
 Complete blood count
 Urine examination
 Chest X-ray
 X-ray of bones, cranium,vertebralcolumn,pelvis
 ECHO and ECG for congenital heart defects
 Ultrasonography of abdomen
TREATMENT
 Resuscitation is often required at birth. Baby is kept in intensive care unit.
-Poor sucking ability so nasogastric tube is needed
 Surgery maybe needed to correct defects or abnormalities, eg. Heart defects,
omphalocele, hernia
 Access to programs and services as required eg.physical therapy, speech therapy,
educational support, social, vocational, and medical services.
 Genetic counseling and joining a support group is recommended.

COMPLICATIONS:
 Spontaneous abortion
 Stillbirth
 Apnoea
 Congestive heart failure
 Early infant death
 Failure to thrive
 Mental retardation

PROGNOSIS:
Prognosis is very bad due to life-threatening medical complications. Mortality rate is
high just before and after the baby born.The median survival is about 3 months.
PATAU SYNDROME (TRISOMY 13)

INTRODUCTION
-it is a chromosomal condition associated with severe intellectual disability and physical
abnormalities in many part of body
-result from having 3 copies of chromosomes 13 in each cell in body instead of 2
INCIDENCE
-1 per 5000 births
-although women at any age can have a child with trisomy 13 , the chance of having a
child with this condition increases as a woman gets older

PROGNOSIS
-majority of cases die in the first 6months of life.
-survivors have severe mental defects and seizures and they fail to thrive
CHARACTERISTICS
-severe developmental and physical retardation
-microcephaly with sloping forehead
-holoprosencephaly type of defect with varying degrees of incomplete development of
forebrain, olfactory and optic nerves
-micropthalmia, coloboma of iris, retinal dysplasia, cataract
-malformations of ears
-cleft lip with or without cleft palate
-capillary hemangiomata are characteristic
-abnormalities of fingers and toes like polydactyly,flexion deformities and long and
hyperconvex nails
-congenital heart disease in 80% of patients like ventricular septal defects, patent
ductusarteriosus and arterial septal defect

There is an overlap between clinical features of trisomy 13 and 18.The highest

discriminating values are ECTODERMAL SCALP DEFECTS and HARELIP and CLEFT PALATE
in trisomy 13 , and ELONGATED SKULL and SIMPLE ARCHES on all digits for trisomy 18
CRI DU CHAT SYNDROME
INTRODUCTION
In 1963, Lejeune et al described a syndrome consisting of multiple congenital anomalies,
mental retardation, microcephaly, abnormal face, and a mewing cry in infants with a
deletion of a B group chromosome (Bp-), later identified as 5p-.

DEFINITION
Cri du chat syndrome - also known as 5p- syndrome and cat cry syndrome - is a rare
genetic condition that is caused by the deletion (a missing piece) of genetic material on
the small arm (the p arm) of chromosome 5. The cause of this rare chromosomal
deletion is unknown.

PATHOPHYSIOLOGY
A partial deletion of the short arm of chromosome 5 is responsible for the characteristic
phenotype.

The characteristic cry is perceptually and acoustically similar to the mewing of kittens.
This unusual cry is due to structural abnormalities of the larynx (eg, laryngeal hypoplasia)
and CNS dysfunction. The laryngeal appearance may be normal or may exhibit marked
anatomical abnormalities such as floppy epiglottis, small larynx, and asymmetric vocal
cords. However, the cause of the characteristic cry cannot be entirely ascribed to the
larynx. A developmental field may connect the brain and the affected clivus region of
the cranial base with the laryngeal region from which the characteristic cry derives. This
area of the brain is probably deformed in patients with cri-du-chat syndrome. The
characteristic cry usually disappears over time.

Cri-du-chat syndrome is caused by a partial or total deletionof genetic material on the

short arm of chromosome 5. The size of the deletion could affect from region 5p15.3 to
the complete loss of the short arm. Most of the cases are due to

1. de novo deletion (80%),

2. parental translocation (10%)
3. cytogenetic rare aberrations (10%)
A deletion of 5p15.3 results in the manifestation of a catlike cry and speech
delaywhereas a deletion of 5p15.2 results in the presentation of the other major clinical
features of the syndrome.
SYMPTOMS
The symptoms of cri du chat syndrome vary among individuals. The variability of the
clinical symptoms and developmental delays may be related to the size of the deletion
of the 5p arm.

The clinical symptoms of cri du chat syndrome usually include a high-pitched cat-like cry,
mental retardation, delayed development, distinctive facial features, small head size
(microcephaly), widely-spaced eyes (hypertelorism), low birth weight and weak muscle
tone (hypotonia) in infancy. The cat-like cry typically becomes less apparent with time.

Most individuals who have cri du chat syndrome have difficulty with language. Half of
children learn sufficient verbal skills to communicate. Some individuals learn to use
short sentences, while others express themselves with a few basic words, gestures, or
sign language.

Other characteristics may include feeding difficulties, delays in walking, hyperactivity,

scoliosis, and significant retardation. A small number of children are born with serious
organ defects and other life-threatening medical conditions, although most individuals
with cri du chat syndrome have a normal life expectancy.

Both children and adults with this syndrome are usually friendly and happy, and enjoy
social interaction.
DIAGNOSIS
The diagnosis of cri du chat syndrome is generally made in the hospital at birth. A health
care provider may note the clinical symptoms associated with the condition. The cat-like
cry is the most prominent clinical feature in newborn children and is usually diagnostic
for the cri du chat syndrome.

Additionally, analysis of the individual's chromosomes may be performed. The missing

portion (deletion) of the short arm of chromosome 5 may be seen on a chromosome
analysis. If not, a more detailed type of genetic test called FISH analysis may be needed
to reveal the deletion.

TREATMENT
No specific treatment is available for this syndrome. Children born with this genetic
condition will most likely require ongoing support from a team made up of the parents,
therapists, and medical and educational professionals to help the child achieve his or
her maximum potential. With early and consistent educational intervention, as well as
physical and language therapy, children with cri du chat syndrome are capable of
reaching their fullest potential and can lead full and meaningful lives.
CYSTIC FIBROSIS
Cystic fibrosis occur result of mutation at chromosome 7 (7q13). It is an autosomosal
recessive genetic disorder which affects mostly on lungs ,pancrease, liver and intestine.
The defects occur at Delta F508 which denotes a single deletion at 508 position of
protein. This causes mutation in a gene for a protein cystic fibrosis transmembrane
conductance regulator (CFTR). It is required for regulation of sweats, digestive fluid, and
mucus. Mostly the disease appear when two CFTR gene are missing due to disorder
recessive nature.

PATHOLOGY
- CFTR required movements of chorides and sodium ions across the epthelial
membrane. Hence it lead to thick inspissatedsecreation in the epithelial lining of
lungs , sweats glands, pancreases and intestinal mucosa.
- Causes trigger inflammatory reaction leading to fibrosis
- Lead to formation thick mucus plugs result in collapse, stasis, obstruction and
infection in affected organ
CLINICAL FEATURES
1.Gastrointestinal:
- Meconium ileus in neonates
- Malapsorbtion
- Chronic diarrhoea constipation
- Ileoceacal intussusception
- Fibrosingcolonopathy
2.Heapatobiliary
-fatty liver
-jaundice
-potral hypertension
-hepatic failure
-gallstones
3.Pancreatic
-chronic pancreatitis
-Exocrine and endocrine dysfunction
4.Nutritional
-vitamin defficiency mainly fat soluble vitamins
-micronutrient deficiency
DIAGNOSIS
-Diarrhoea during early infancy associated with the respiratory problem(pneumonia)
-Trypsin and duodenal juice and stools reduced
-x-ray show pulmonory involvement
-level of chlorides in sweat above 60 mEq/L

TREATMENT
Supportive treatment includes medicines and home treatment.
1. Nutrition: caloric dense food with enough carbohydrates and protein content.
Rich in polyunsaturated fatty acid and fat soluble vitamins
2. Medical treatment: enzyme supplement: lipase
Infants:2000-4000 units lipase /120ml formula
1-4 years:1000-2000 units lipase/kg/meal
>4 years: 200-2000 units lipase/kg/meal
- use antacids sodium bicarbonate and antihistamine along with enyzme
-taurine and lecithin given to provide substrates for increased hepatic synthesis
of bile acid
- misoprostol given in resistant case to inhibit gastric acid secreation and
stimulate bicorbanatesecreation in upper gut.
- long term antibiotic to prevent pulmonary complication
-aerosol therapy with mucolytics agent such as Dnase and acetylcystein
-ursodeoxycholic acid improves bile flow
-Breathing exercise with chest physiotherapy
-salt(1-2gm/day) to compensates excessive loss of chlorides