PEDIATRIC GENETICS

DR SAMED ALSALMI

Genetics
The Human Genome Project, culminating in the first publication of the human genome
sequence in 2001, together with the development of genetic databases has resulted in
an explosion of knowledge about the basis of genetic diseases. It is now estimated
that the human genome contains 30 000-35 000 genes, although the function of many
of these genes remains unknownGenetic disorders are: common, with 2% of live-born
babies having a significant congenital malformation and about 5% a genetic disorder
Genetically determined diseases include those resulting from:
chromosomal abnormalities
Mendelian disorders
unusual genetic mechanism
interaction of genetic and environmental factors (multifactorial or polygenic disorde

Genetic testing defined

Diagnostic confirms a clinical diagnosis in a
symptomatic
individual
Presymptomatic (predictive) confirms that an individual
will develop the condition later in life
Susceptibility identifies an individual at increased risk of
developing the condition later in life
Carrier identifies a healthy individual at risk of having
children affected by the condition
Prenatal diagnoses an affected fetus

BASIC GENETICS

Scientists have numbered the chromosomes from the largest

(chromosome number 1) to the smallest (chromosome number 22):
these numbered paired chromosomes are called autosomes.
There are also two chromosomes that have been given the letters
X and Y: these are the sex chromosomes.
The chromosomes are rod like structures and have a constriction
called centromere along its length.

Each chromosome is made up of a long thin thread of DNA that is

coiled up like a ball of string.
If the DNA was stretched out it would look like beads on a string.
Each of these beads of DNA is called a gene that is a piece of
genetic information. Thousands of genes make up each
chromosome.
Each gene has its own specific location on the chromosome. Since
the chromosomes come in pairs, there are two copies of each gene
in each cell.

The information in the genes is in the form of a chemical

(DNA) code, often referred to as the genetic code.
DNA that makes up the genes is often called "coding DNA".
The DNA "string" between the genes is called "non-coding
DNA.

There are four basic building blocks (nucleotide bases) that makes up
DNA: Adenine (A) and Guanine (G), and Thymine (T) and Cytosine (C).
DNA is made up of very long chains of these bases.
A chromosome consists of two of these DNA chains running in opposite
directions; the bases pair up to form the rungs of a ladder twisted into the
now famous double helix.
A can only pair with base T, and vice versa; and base G can only pair
with base C, and vice versa.
Roughly three billion of these base pairs of DNA make up the human
genome.

When the instructions in a gene are to be "read-- the DNA making up

the gene unwinds and the message is "transcribed" into another
chemical called `messenger RNA' (or mRNA).
To the units in the cell where it can be "translated" into a chain of
amino acids.
The long chain of amino acids folds itself up into a distinctive shape
that depends upon its sequence, and is now known as a "protein".
Each gene message can be "read" by the cell in a number of different
ways so that each gene can provide a message to make 2 or 3
different proteins.
While all the different types of cells contain the same genes, each cell
requires particular proteins to function correctly. Therefore, different
genes are active in different cell types, tissues and organs,
producing the

necessary specific proteins.

Changes to the genetic

code cause the message to
be changed - the gene is
broken or faulty.
Changes that make the
genes faulty are called
mutations.
Faulty genes (mutated
genes) may cause a
problem with the
development and
functioning of different body
systems or organs and
result in a genetic condition

So faulty genes build up in the cells of our bodies as we age. These

are called acquired or new mutations.
New faulty genes that build up in our body cells (the somatic cells),
excluding the egg or sperm cells, over our lifetime are called somati
mutations.
They cannot be passed on to our children, as they are not in the egg
or sperm.

It is only when a mutation occurs in a gene in a person's sperm or egg cells

that the faulty gene can be passed onto the next generation (inherited) - germ
cell or germ line mutations.
The germ cell mutation may cause the child to have or develop a genetic
condition.
The faulty gene will now "run in the family".
A person who inherits a faulty gene will have that faulty gene in every cell of
their body

TYPES OF MUTATIONS.

Missense or nonsense mutation - cystic fibrosis, haemophilia and Tay-Sachs

disease.
b & c) Too short or too long - haemophilia, Duchenne and Becker types of
muscular dystrophy and neurofibromatosis.
d) Number of repeats within the gene is over a certain critical level - Huntington
disease and Fragile X syndrome

(a

Contigous gene syndromes: variety of rearrangements

Smith Magenis, Prader willi, Rubinstien Taybi, DiGeorge.

Gain of function mutation: autosomal dominant disorders.

charcot marie tooth, peroneal muscular dystrophy,
achondroplasia.
Loss of function mutation: autosomal recessive disorders.
Novel property on the proteins sickle cell disease.
Lastly abnormal expression of gene over time and space.

Type of genetic disease

Single gene (mendelian)

Numerous though individually rare

Clear pattern of inheritance
High risk to relatives
Multifactorial

Common disorders
No clear pattern of inheritance
Low or moderate risk to relatives
Chromosomal

Mostly rare
No clear pattern of inheritance
Usually low risk to relatives
Somatic mutation

Accounts for mosaicism

Cause of neoplasia

Prevalence of genetic disease

Type of genetic disease
population
Single gene
Autosomal dominant
Autosomal recessive
X linked recessive
Chromosomal abnormalities
Common disorders with appreciable
genetic component
Congenital malformations
Total

Estimated prevalence
per 1000

210
2
12
67
710
20
3851

Chromosomal abnormalities

They occur in approximately 10% of spermatozoa

and 25% of mature oocytes and are a very
common cause of early spontaneous miscarriage.
The estimated incidence of chromosomal
abnormalities in live-born infants is about 1 in
150 and these usually, but not always, cause
multiple congenital anomalies and learning
difficulties. Acquired chromosomal changes play
a significant role in carcinogenesis and tumour
progression.

Common reasons for referral to a genetic clinic

Children with congenital abnormalities (birth defect, dysmorphic features
Children with chromosomal disorders or inherited conditions
Adults affected by congenital abnormality or an inherited condition
Adults known to risk of carrying, a balanced chromosomal rearrangement
Couples who have lost a child or stillborn baby with a congenital
abnormality or inherited condition
Couples who have suffered reproductive loss (termination of pregnancy
for fetal abnormality or recurrent miscarriag
Pregnant women and their partners, when fetal abnormalityis detected
Children and adults with a family history of a known genetic disorder
Adults at risk of developing an inherited condition who may request
predictive testing
Couples who may transmit a genetic condition to their children
Individuals with a family history of a common conditio with a strong
genetic component, including familial cancers

Cytogenetic analysis
Chromosomal analysis
Chromosomal analysis is usually performed on white blood cell
cultures.
Other samples analysed on a routine basis include cultures of
fibroblasts from skin biopsy samples, chorionic villiand amniocytes for
prenatal diagnosis, and bone marrow cells.
Karyotypes are reported in a standard format giving the total number
of chromosomes first, followed by the sex chromosome constitution
Additional or missing chromosomes are indicated by or for whole
chromosomes, with an indication of the type of abnormality if there is
a ring or marker chromosome. Structural rearrangements are
described by in dicating the p or q arm and the band position of the
break points.

Common reasons for cytogenetic analysis

Postnatal
Newborn infants with birth defect
Children with learning disability
Children with dysmorphic features
Familial chromosomal rearrangement in relative
Infertility
Recurrent miscarriages
Prenatal
Abnormalities on ultrasound scan
Increased risk of Down syndrome (maternal age or
biochemical screening)
Previous child with a chromosomal abnormality
One parent carries a structural chromosomal abnormality

Reporting of karyotypes
Total number of chromosomes given first
followed by sex chromosome constitution
,46XX Normal female
,47XXY Male with Klinefelter syndrome
,47XXX Female with triple X syndrome
Additional or lost chromosomes indicated
by or
,47XY,21 Male with trisomy 21 (Down syndrome
,46XX,12p Additional unidentified material on short arm of
chromosome 12
All cell lines present are shown for mosaics
,46XX/47,XX,21 Down syndrome mosaic
,46XX/47,XXX/45,X Turner/triple X syndrome mosaic
Structural rearrangements are described, identifying
p and q arms and location of abnormality
,46XY,del 11(p13) Deletion of short arm of chromosome
11 at band 13
,46XX,t(X;7)(p21;q23) Translocation between chromosomes X
and 7 with break points in respective
chromosomes

Definitions
Euploid
Chromosome numbers are multiples of the haploid set
Polyploid
Chromosome numbers are greaterthan diploid , triploid
Aneuploid
Chromosome numbers are not exact multiples of the haploid set
trisomy; monosomy
Mosaic
Presence of two different cell lines derived from one
zygote(46XX/45X, Turner mosaic
Chimaera
Presence of two different cell lines derived from fusion of two
zygotes (46XX/46XY, true hermaphrodite

47, XXX karyotype in triple X

syndrome

DNA analysis

New techniques in DNA testing are continually being developed, making more single gene disorders amenable to molecular analysis.
Most molecular testing is performed using polymerase chain reaction (PCR). This involves the amplification of specific DNA
sequences, enabling rapid analysis of small samples, which is particularly important in antenatal diagnosis.

The main impact of DNA analysis for genetic counselling is:

confirmation of a clinical diagnosis

detection of female carriers in X-linked disorders, e.g. Duchenne's and Becker's muscular dystrophies, haemophilia A_ B

carrier detection in autosomal recessive disorders, e.g. cystic fibrosis

presymptomatic diagnosis in autosomal dominant disorders, e.g. Huntington's disease, myotonic dystrophy

antenatal diagnosis of an increasing number of Mendelian conditions.

These are accomplished by:

1. Mutation analysis
For an increasing number of disorders, it is possible to directly detect the actual mutation causing the disease. This provides very
accurate results for confirmation of diagnosis, and presymptomatic or predictive testing. Identifying the mutation in an affected
individual may be very time-consuming, but once this has been done, testing other relatives is usually fairly simple. Examples are:

Deletions - large deletion mutations are common in a variety of disorders including Duchenne's and Becker's muscular
dystrophies, alpha-thalassaemia and 21-hydroxylase deficiency (congenital adrenal hyperplasia). They can be tested for relatively
easily.

Point mutations and small deletions - these can be readily identified if the same mutation causes all cases of the
disorder, as in sickle cell disease. For most disorders, however, there is a very diverse spectrum of mutations. About 78% of cystic
fibrosis carriers in the UK possess the F508 mutation, but over 900 other mutations have been identified. Most laboratories test for
a certain number of the most common mutations in their given population.

Trinucleotide repeat expansion mutations - these are readily tested for because the mutation in a given disease is always
the same. The only difference is the size of the repeat sequence, which can be determined from the size of the DNA fragment
containing the repeat.

2. Genetic linkage
If mutation analysis is not available, it may be possible to use DNA sequence variations
(markers) located near to, or within, the disease gene to track the inheritance of this gene through
a family. This type of analysis requires a suitable family structure and several key members need
to be tested to identify appropriate markers before linkage testing can be used predictively

Presymptomatic testing
In many autosomal dominant disorders, onset is during adolescence or adult life and clinical
expression may not be evident at birth. Relatives of affected individuals may request tests to see if
they are likely to develop the disorder in question. Examples include myotonic dystrophy,
Huntington's disease, autosomal dominant polycystic kidney disease and neurofibromatosis.
Assessment may include:

careful examination of individuals at risk, e.g. development of caf-au-lait patches and

axillary freckling in neurofibromatosis

investigations, e.g. renal ultrasound scans in individuals at risk of autosomal dominant

polycystic kidney disease

DNA analysis using linked markers or mutation analysis.

It is generally accepted that presymptomatic tests (e.g. for Huntington's disease and myotonic
dystrophy) and carrier tests (e.g. for cystic fibrosis) should not be performed on healthy children,
as these remove the child's future right to choose whether or not to have this information.
.

Molecular cytogenetics
Fluorescence in situ hybridisation (FISH) is a recently

developed molecular cytogenetic technique, involving

hybridisation of a DNA probe to a metaphase chromosome
spread. Single stranded probe DNA is fluorescently labelled

using biotin and avidin and hybridised to the denatured DNA

of intact chromosomes on a microscope slide. The resultant
DNA binding can be seen directly using a fluorescence
microscope.

Fluorescence in situ hybridisation of normal metaphase

chromosomes hybridised with chromosome 20 probes derived from the
whole chromosome, which identify each individual chromosome 20

Some common reasons for molecular genetic

analysis
Cystic fibrosis

Haemoglobinopathies
Duchenne and Becker muscular dystrophy
Myotonic dystrophy
Huntington disease
Fragile X syndrome
Spinal muscular atrophy
Spinocerebellar ataxia
Hereditary neuropathy (Charcot-Marie-Tooth
Familial breast cancer (BRCA 1 and 2
Familial adenomatous polyposis

Genetic Counselling
One or more sessions
Molecular confirmation of diagnosis in affected relative
Discussion of clinical and genetic aspects of condition, and impact on family
Patient requests test
(interval of several months suggested

Pre-test Counselling
At least one session
Seen by 2 members of staff
(usually clinical geneticist and genetic counsellor
Involvement of partner encouragedFull discussion about Motivation for requesting test
Alternatives to having a test Potential impact of test result
Psychological
Financial
Social (relationships with
partner/family
Strategies for coping with result

Prenatal detection of unexpected

abnormalities
serum biochemical screening and
routine ultrasonography
amniocentesis for chromosomal analysis following
abnormalities on biochemical or ultrasound screening
Prenatal diagnosis of abnormalities anticipated prior to
Pregnancy
ultrasonography for known risk of specific congenital
abnormality because of a previous affected child

chromosomal analysis because of familial chromosome

translocation or previous affected child

Gene therapy

The treatment of most genetic disorders is based on conventional therapeutic approaches.

These may include health surveillance, supportive measures, medical therapy, surgical
procedures, dietary manipulation, replacement of deficient gene products or enzymes and
bone marrow transplantation.

Gene therapy involves the repair, suppression or artificial introduction of genes into genetically
abnormal cells with the aim of curing the disease and is at an experimental stage for most
genetic conditions being studied. There are still many technical and safety issues to be
resolved.

Gene therapy has been initiated in deaminase deficiency (a rare recessive immune disorder),
malignant melanoma and cystic fibrosis, and some clinical benefit has been reported in a few
patients. At present, it is generally accepted that gene therapy should be limited to somatic
(not germ line) cells, so that the risk of adversely affecting future generations is minimised

Down's syndrome trisomy 21

This is the most common autosomal trisomy

and the most common genetic cause of severe
learning difficulties. The incidence (without
antenatal screening) in live-born infants is
about 1 in 650 1.5 per 1000 live-born infants
presentation - antenatal ultrasound screening
or clinical; confirmed on chromosome analysis

The extra chromosome 21 may result from non-disjunction, translocation or mosaicism.

Non-disjunction 94%
In non-disjunction: most cases result from an error at maternal oocytes meiosis
the pair of chromosome 21s fails to separate, so that one gamete has two chromosome 21s and one has
none fertilisation of the gamete with two chromosome 21s gives rise to a zygote with trisomy 21 with47
chromosoms
parental chromosomes do not need to be examined.
The incidence of trisomy 21 due to non-disjunction is related to maternal age However, as the proportion
of pregnancies in older mothers is small, most affected babies are born to younger mothers.
All pregnant women are now offered screening tests measuring biochemical markers in blood samples
and nuchal thickening on ultrasound (thickening of the fat pad at the back of the neck) to identify an
increased risk of Down's syndrome in the fetus.
When an increased risk is identified, amniocentesis testing is offered to check the fetal chromosome
pattern. Although in most instances a normal chromosome pattern will be identified, the possibility of an
abnormal result and the option of termination of pregnancy should be discussed beforehand.
Support and counselling needs to be available.
After having one child with trisomy 21 due to non-disjunction, the risk of recurrence of Down's syndrome
is 1 in 200 for mothers under the age of 35 years, but remains similar to their age-related population risk
for those over the age of 35 years 1 in 385.

Translocation 5%
When the extra chromosome 21 is joined onto another chromosome (usually chromosome 14, but
occasionally chromosome 15, 22 or 21), this is known as an unbalanced Robertsonian translocation. An
affected child has 46 chromosomes, but three copies of chromosome 21 material.
In this situation, parental chromosomal analysis is essential since one of the parents carries a balanced
translocation in 25% of cases.
Translocation carriers have 45 chromosomes, one of which consists of the two joined chromosomes
In translocation Down's syndrome: the risk of recurrence is 10-15% if the mother is the translocation
carrier and about 2.5% if the father is the carrier
if a parent carries the rare 21:21 translocation, all the offspring will have Down's syndrome
if neither parent carries a translocation (75% of cases), the risk of recurrence is <1%.
Mosaicism 1%
In mosaicism some of the cells are normal and some have trisomy 21. This usually arises after the
formation of the zygote, by non-disjunction at mitosis. The phenotype may be milder in mosaicism

Characteristic clinical manifestations of Down's syndrome

immediate medical complications - increased risk of duodenal atresia, congenital heart disease
Typical craniofacial appearance Round face and flat nasal bridge
Upslanted palpebral fissures
Epicanthic folds (a fold of skin running across the inner edge of the palpebral fissure)
Brushfield spots in iris (pigmented spots) 70%
Small mouth and protruding tongue
Small low set ears
Flat occiput and third fontanelle
Other anomalies Short neck
Single palmar creases, incurved fifth finger and wide 'sandal' gap between toes
Hypotonia
Congenital heart defects (40%) AVSD (ECCD)
GIT 6% Duodenal atresia 30%
Hirschsprung's disease 3 %
Later medical problems Delayed motor milestones
Moderate to severe learning difficulties
Small stature
Increased susceptibility to infections
Hearing impairment from secretory otitis media 75%
Visual impairment from cataracts 3%, squints, myopia
Increased risk of leukaemia and solid tumours
Risk of atlantoaxial instability
Hypothyroidism 15% and coeliac disease

CLINICAL FEATURES
Growth and development
Short stature
Hypotonia which improves with age
Moderate-to-severe mental
retardation with IQ range of 20
85 e.
Sleep apnea occurring when
inspiratory airflow from
Seizure disorder (510%)
Visual and hearing impairments
Obesity during adolescence
Cataracts
Hearing loss
Age-related increase in
hypothyroidis Neoplasms
Increased risk of senile dementia of
Alzheimer typ

. Behavior
Cheerful

Gentleness
Patience
Tolerance
Anxiety
Autism
Attention deficit hyperactivity disorder
Conduct disorder

Obsessive-compulsive disorder
Tourette syndrome
Depressive disorder during the
transition fromadolescence to

.Skull
a. Brachycephaly
b. Microcephaly
c. Sloping forehead
e. Flat occiput
f. Large fontanels with late closure
g. Patent metopic suture
h. Absence of frontal and sphenoid
sinuses
i. Hypoplasia of the maxillary sinuses

Eyes
Up-slanting palpebral fissures
Bilateral epicanthal folds
. Brushfield spots (speckled iris
. Refractive errors (50%
. Strabismus (44%
. Nystagmus (20%
Tearing from stenotic nasolacrimal ducts
Congenital cataracts (3%

Nose

Flat nasal bridge

. Mouth
. tongue protrusion
Fissured and furrowed tongue
Mouth breathing
. Drooling
. Teeth
Partial anodontia (50%
Tooth agenesis
Malformed teeth
Delayed eruption

. Microdontia (3550%)

. Ears
Small

Congenital heart defects 50%

Common cause of death in the first

two years of life

Endocardial cushion
defect/atrioventricular canal 43%

. Abdomen
Diastasis recti
Umbilical hernia
. Gastrointestinal 12%

Ventricular septal defect 32%

Secundum atrial septal defect
10%

.
Tetralogy of Fallot 6%

. Isolated patent ductus arteriosus

4%
pulmonic stenosis 9%

Duodenal atresia or stenosis

Hirschsprung disease < 1%
TE fistula
Meckel diverticulum
Imperforate anus
Omphalocele

. Genitourinary
Renal malformations

. Skeletal
Atlantoaxial (and
atlantooccipital) instability
Easy fatigability
Short and broad hands
Clinodactyly of the fifth fingers
with a single crease 20%
Hyperextensible finger joints
Increased space between the great
toe and the secondtoe
Acquired hip dislocation 6%

Endocrine
Primarily autoimmune disorder 13
63%
Congenital hypothyroidism 28 times
more common among infants with
Down syndrome
Diabetes
Decreased fertilityAlmost invariably
infertile in male
Decreased fertility in females

. Hematologic

Neonatal leukemoid reactions , pseudoleukemia

increased risk of developing leukemia

Transient myeloproliferative disorder transient leukemia)

Resolves spontaneously in most cases

Develops acute megakaryoblastic leukemia

. Immunodeficiency: 12-fold increased

risk of developing infectious diseases, especially pneumonia,

secondary to impaired cellular immunity

DIAGNOSTIC INVESTIGATIONS
. Serum triple screen
a. -fetoprotein
b. Unconjugated estriol
c. Human chorionic gonadotrophin
. Cytogenetic studies
Clinical diagnosis should be confirmed with
Cytogenetic studies
Karyotyping is essential for determination of recurrence risk
In translocation or isochromosome Down syndrome
karyotyping of the parents and other relatives is
required for proper genetic counseling
fluorescence in situ hybridization FISH for rapid diagnosis and
Successfully applied to both prenatal diagnosis and diagnosis in the
newborn period

Thyroid function tests: TSH and T4 should be obtained at

birth and annually thereafter

. Measurement of IgG
Abd sonar and Skeletal radiography
Echocardiography: this test should be performed on all
infants with Down syndrome for identification of congenital
heart disease, regardless of findings on physical Examination
Auditory brainstem response (ABR) age between 2 m and
3 1/2 years
. Speech evaluation
.

Pediatric vision screening for ophthalmologic disorders

GENETIC COUNSELING
. Recurrence risk
. Patients

sib
Nondisjunction type: 1% or less and robertsonian transln type: 23%
carrier parent with a 21q21q translocation orisochromosome: a 100%
recurrence

riskPatients offspring
Females with trisomy 21: about 1530% are fertile and have a 50%
risk of having an affected child
Males with trisomy 21: no evidence of fathering child

. Prenatal screening
second trimester Maternal serum biochemical markers with Low
maternal serum alpha-fetoprotein and elevated human chorionic
gonadotropin and low unconjugated estriol (uE3) found,
together with maternal age were accepted as a method of prenatal
screening for Down syndrome in the general population

First-trimester free beta-hCG and pregnancy-associated plasma

protein A retrospective screening study achieved rates as high as
those associated with MSAFP, hCG or uE3 in the second trimester

. Prenatal diagnosis
Ultrasonography
Nuchal fold thickening identifies 75% of Down syndrome fetuses
Shortened humerus or femur length detect 31% of cases
Cystic hygroma

Duodenal atresia or stenosis double-bubble sign

Cardiac defects
Echogenic bowel
Renal pyelectasis

Amniocentesis, CVS, or fetal blood sampling for

or metaphase

Chromosome analysis

FISH analysis of interphase cells

Management
Medical care
.a
i. Early intervention programs
a) Physical therapy b) Occupational therapy c) Speech therapy
ii. Hearing evaluation
iii. Thyroid hormone for hypothyroidism
iv. Medical management of congenital heart defects
a) Digitalis and diuretics usually required b) Subacute B endocarditis prophylaxis
v. Prompt treatment of respiratory tract infections and otitis media
vi. Pneumococcal and influenza vaccines for children with chronic cardiac and
respiratory disease
vii. Anticonvulsants for seizures
viii. Provide pharmacologic agents, behavioral therapy, and psychotherapy for
behavioral/psychiatric Disorders
ix. Treat skin disorders
a) Weight reduction b) Proper hygien c) Frequent baths d) Application of antibiotic
ointment e) Systemic antibiotics therapy
x. Prevent dental caries and periodontal disease
Appropriate dental hygiene b) Fluoride treatments c) Good dietary habits (a

Surgical care
i. Presence of Down syndrome alone does not adversely affect the outcome of surgery in the
absence of pulmonary hypertension
ii. Timely surgery of cardiac anomalies necessary to prevent serious complications
iii. Prompt surgical repair of the following gastrointestinal
anomalies: a)TE fistula b) Pyloric stenosis c) Duodenal atresia d) Annular pancreas e)
Aganglionic megacolon f) Imperforate anus
iv. Adenotonsillectomies may be required for obstructive sleep apnea
v. Surgical intervention may be necessary to reduce the atlantoaxial subluxation and to stabilize
the upper segment of the cervical spine if neurologic deficits are significant
vi. Extract congenital cataracts, soon after birth with subsequent correction with glasses or
contact lenses
vii. Anesthetic airway management
a) Adequate evaluation of the airway and neurological status b) Cervical spine radiography
(flexion and extension views) c) Avoid hyperextension of the head during laryngoscopy and
intubation d) Prescribe anticholinergics to control airway hypersecretion e) Aware of other
airway complications (subglottic stenosis and obstructive apnea resulting
from a relatively large tongue, enlarged adenoids, and midfacial hypoplasia

Edwards' syndrome (trisomy 18) and Patau's syndrome

trisomy 13
Although rarer than Down's syndrome particular constellations of
severe multiple abnormalities suggest the diagnosis at birth and
most affected babies die in infancy
The diagnosis is confirmed by chromosome analysis.
Many affected fetuses are detected by ultrasound scan during the
second trimester of pregnancy and diagnosis can be confirmed
antenatally by amniocentesis and chromosome analysis.
Recurrence risk is low, except when the trisomy is due to a
balanced chromosome rearrangement in one of the parents.

Edwards SYNDROM

(trisomy 18)
1 in 8000
IUGR Low birthweight
Prominent occiput
Small mouth and chin
Short sternum
Flexed, overlapping fingers
Vertical talus
Rocker-bottom feet
Profound MR
Cardiac 60%and renal malformations
90% die < 1yr

Trisomy 18
karyotype
(47,XY,+18).

Trisomy 18 shown Translocation trisomy

by FISH
18 karyotype
[46,XX,+18,der(13)t(1
3;18

trisomy 18 showing small eyes, microstomia,

low-set/malformed ears, and short neck

infant with trisomy 18 showing

micro/retrognathia, short
neck, and characteristic finger
grasping pattern.

Typical hand grasping pattern

(left) and rocker-bottom feet
with prominent calcaneus
(right) observed in trisomy 18.

DIAGNOSTIC INVESTIGATIONS
Conventional cytogenetic study to detect full
trisomy,mosaic trisomy, or rare translocation

Echocardiography for cardiac anomalies

Barium swallow for gastrointestinal anomalies

Ultrasound for genitourinary anomalies
. Skeletal radiography

GENETIC COUNSELING
. Prenatal

diagnosis

Prenatal screening in families without history of trisomy 18 using maternal serum markers
Low human chorionic gonadotrophin (hCG) and Low unconjugated estriol (uE3) in
maternal

serum during mid-trimester: useful predictors for an increased risk for trisomy 18.
Possible future first-trimester biochemical screening for trisomy 18 with reduced levels
of pregnancy associated plasma protein A (PAPP-A) and free beta-human chorionic
gonadotropin (beta-hCG) at 813 weeks gestation. to achieve a detection rate of 76.6%
Prenatal ultrasonography
the majority of fetuses with trisomy 18 have detectable structural abnormalities
Oligohydramnios/polyhydramnios (12%)

Intrauterine growth retardation 29%

Two-vessel umbilical cord (40%) . Micrognathia

Thickened nuchal skin fold

. Cystic hygroma or lymphangiectasia (14%) . Omphalocele (20%) . Esophageal atresia

Cardiac defects (37%):

Renal anomalies (9%.

. Limb

Amniocentesis or CVS by conventional cytogenetic or FISH techniques

. Management

Medical care of trisomy 18 infants

Treat infections as Otitis media and Upper respiratory infection
bronchitis pneumonia Urinary tract infections
Nasogastric and gastrostomy supplementation for feeding problems
Orthopedic management of scoliosis secondary to hemivertebrae
Primarily medical management of congenital heart disease
Diuretic and digoxin for congestive heart failure
Referral for early intervention including physical and occupational therapy
Psychosocial management: discuss implications, possible outcomes, and available
supportive services in the community
Surgical care of trisomy 18 infants: Because of the extremely poor prognosis,
surgical repair of severe congenital anomalies such as esophageal atresia or
congenital heart defects is not likely to improve the survival rate of infants and
should be discussed with Family

Patau's syndrome (trisomy 13)

1 in 14 000 live births,

Structural defect of brain

Scalp defects
Small eyes (microphthalmia) and other eye
defects
Cleft lip and palate
Polydactyly
Profound MR
Cardiac 80% and renal malformations
90% die < 1yr

Trisomy 13 karyotype (G-banded)

Trisomy 13 shown by FISH analysis of

interphase cells with three copies of
the green signal representing three
chromosome 13s and two copies of the
red signal representing
two chromosome 21s

Translocation trisomy 13 [t(13q;14q)].

child with
trisomy 13
associated with
premaxillary
dysgenesis,
hypotelorism,
cleft nose, and
smooth philtrum.

trisomy 13
trisomy 13 showing microcephaly, showing scalp
microphthalmia, cleft lip/palate,
defect on the
and Omphalocele
vertex.

Postaxial polydactyly of the hand and the feet in

an infant with trisomy 13

DIAGNOSTIC INVESTIGATIONS
. Cytogenetic studies

Conventional technique or FISH of interphase cells for rapid diagnosis

Parental karyotyping in case of translocation trisomy 13
Echocardiography for cardiovascular anomalies
EEG: hypsarrhythmia
. CT/MRI for central nervous system anomalies
Radiography
Wide anterior fontanell
Presence of a cervical ri
Absence of the 12th rib
Cranial bone abnormalities in case of holoprosencephaly
Clefting of the vertebral bodie
Agenesis of the nasal bones

GENETIC COUNSELING
. Recurrence risk for Patients, sib Trisomy 13: about 1 in
4000
Familial translocation: 515%
Patients offspring: not surviving to reproductive age

Prenatal diagnosis
Prenatal ultrasonography: prevalence of ultrasound
abnormalities 91%
Chromosome analyses by CVS, followed by amniocentesis

Management

Feedings
Nasal Oral gastric tube feeding or Gastrostomy feeding
Nissan fundoplication for gastroesophageal reflux
Early intervention programs
Seizure control
Monitor apneic spells
Treat infections
Symptomatic treatment for heart failure
Cardiac operation rarely performed

Turner's syndrome 45, X

Usually (>95%) this results in early miscarriage. Increasingly detected by ultrasound
antenatally when fetal oedema of the neck, hands or feet or a cystic hygroma may be
identified. In live-born females, the incidence is about 1 in 2500. although short stature
may be the only clinical abnormality in children.

Treatment is with: growth hormone therapy

oestrogen replacement for development of secondary sexual characteristics at the time
of puberty (but infertility persists).
In about 50% of girls with Turner's syndrome, there are 45 chromosomes, with only one
X chromosome. The other cases have a deletion of the short arm of one X chromosome,
an isochromosome that has two long arms but no short arm, or a variety of other
structural defects of one of the X chromosomes. The incidence does not increase with
maternal age and risk of recurrence is very low.

Clinical features of Turner's syndrome

Lymphoedema of hands and feet in neonate, which may persist
Spooned shaped nails
Short stature - cardinal feature
Neck webbing or thick neck
Wide carrying angle (cubitus valgus)
Widely spaced nipples
Congenital heart defects (particularly coarctation of the aorta)
Delayed puberty
Ovarian dysgenesis resulting in infertility, although pregnancy may be possible with invitro fertilisation (IVF) with donated ova
Hypothyroidism
Renal anomalies
Pigmented moles
Recurrent otitis media
Normal intellectual function in most

CLINICAL FEATURES
Skeletal manifestations
Short stature (100%): Intrauterine growth retardation Progressive decline in growth velocity in
childhood Lack of pubertal growth spurt Delayed growth cessation
Cubitus valgus Hypoplastic nails Short 4th metacarpals

craniofacial features
Down slanting of the palpebral fissures Epicanthal folds ptosis and strabismu
Midfacial hypoplasia High arched palate Micrognathia Teeth Crowding Malocclusion

Neck
Short and broad neck Webbed neck (pterygium coli) with low posterior
hairline from the resolution of the cystic hygroma

. Chest
Shield chest Increased internipple distance

. Congenital heart defects30%

Coarctation of the aorta Bicuspid aortic valve Aortic stenosis

. Vascular anomalies
Multiple intestinal telangiectasia Hemangiomas Lymphangiectasia
Protein-losing enteropathy
. Peripheral
. Nail

lymphedema in the newborn infant involving dorsum of the hands and feet

dysplasia

Redundant skin with Multiple pigmented nevi

. Gonadal dysgenesis
Sexual infantilism: Primary amenorrhea (the rule) Some of these women even give birth5%
Delayed pubertal development in most patients
A high frequency of miscarriage reported among the spontaneous pregnancies of women with
Turner syndrome
. Genitourinary lesions
Horseshoe and ectopic kidneys . Ureteropelvic obstruction A double collecting system

. Hypertension (common even without cardiac or renal malformations

Conductive and sensorineural hearing losses

. Autoimmune disease
Autoimmune hypothyroidism Diabetes mellitus in 5% of patient
inflammatory bowel disease Rheumatoid arthritis

Psychosocial aspects
Significantly higher verbal level than performance level t difficult among verbal subtests
Difficulty in performance Reading Figure drawing Geometry . Arithmetic
. Presence of Y chromosome material
.A high risk of developing gonadoblastoma and dysgerminoma
Requiring preventive removal of the dysgenetic gonads

. Mosaic patients with a structurally abnormal X chromosome

Classic phenotype X-derived marker in majority of case Usually a large ring X
chromosome

DIAGNOSTIC INVESTIGATIONS
. Endocrine study
Very low estrogen levels . Elevated pituitary gonadotrophins after puberty
.

Karyotype analyses

45X Observed in 50% of cases or Maternal origin of the X chr in twothirds of cases
Structurally abnormal sex chromosome, such as Xq or
Mosaicism with a second cell line containing a normal or abnormal X or Y
Determination of the chromosomal origin of sex marker chromosomes

Fluorescence in situ hydridization FISH

.i

PCR to identify the presence or absence of specific Y sequences

Electrocardiography for cardiovascular malformations

Renal ultrasound for renal anomalies
Radiography
Other investigations
Blood pressure measurement for hypertension
Thyroid function
Audiology for conductive and sensorineural hearing loss
Orthodontic evaluation
Orthopedic evaluation
Glucose intolerance

GENETIC COUNSELING
Recurrence risk Patients sib: low and Patients offspring: rarely pass to offspring
due to infertility

Prenatal diagnosis
. Maternal serum screening
Ultrasonographic screening
i. Fetal hydrops
ii. Increased nuchal translucency
iii. Fetal cystic hygroma
iv. Coarctation of the aorta
v. Left-sided cardiac defects
vi. Lymphedema
vii. Renal anomalies
viii. Intrauterine growth retardation
ix. Polyhydramnios

c. Amniocentesis or CVS for chromosome analysis

Management
Psychosocial counselinge

Estrogen replacement therapy

i. To induce near normal pubertal development
ii. To prevent osteoporosis
iii. To reduce the risk of developing cardiovascular disease

Growth hormone with or without anabolic steroids for short stature

Pregnancies among women with Turner syndrome
i. A high risk of miscarriages among spontaneous pregnancies
ii. A high incidence of cardiac abnormalities, even fatal aortic dissection

Five girls with 45,X O syndrome illustrating the variability of features such as webbed
neck and broad chest.

45,X newborn with classic facial features (epicanthal folds,

down-slanting palpebral fissures, flat nasal bridge, receding chin, lowset/
posteriorly rotated ears) and excessive nuchal skin folds. severe lymphedema of the dorsum
ofhand and feet and toe nail hypoplasia

45,X karyotype.

Klinefelter's syndrome 47, XXY

This disorder occurs in about 1-2 per 1000 live-born males. For clinical features,
Recurrence risk is also very low.
Clinical features of Klinefelter's syndrome
Infertility - most common presentation
Hypogonadism with small testes
Pubertal development apparently normal (some males benefit from testosterone
therapy)
Gynaecomastia in adolescence
Tall stature
Intelligence - usually in the normal range, but may have educational and psychological
problems

47

, XXY karyotype in Klinefelter syndrome

Translocations
Reciprocal translocations
An exchange of material between two different chromosomes is called a reciprocal
translocation

When this exchange involves no loss or gain of chromosomal material, the translocation is 'balanced'
and has no phenotypic effect. Balanced reciprocal translocations are relatively common, occurring in 1 in
500 of the general population. A translocation that appears balanced on conventional chromosome
analysis may still involve the loss of a few genes or the disruption of a single gene that results in an
abnormal phenotype, often including learning difficulty. Studying the chromosomal breakpoints in such
individuals has been one way of identifying the location of specific genes.

Unbalanced reciprocal translocations contain an incorrect amount of chromosomal material and cause a
combination of dysmorphic features, congenital malformations, developmental delay and learning
difficulties. In a newborn baby, the prognosis is difficult to predict, but the effect is usually severe. The
parents' chromosomes should be checked to determine whether the abnormality has arisen de novo, or
as a consequence of a parental rearrangement. Finding a balanced translocation in one parent indicates
a recurrence risk for future pregnancies and antenatal diagnosis by chorionic villus sampling or
amniocentesis should be offered as well as testing of relatives

Robertsonian translocations
Robertsonian translocations occur when two of the acrocentric
chromosomes (13, 14, 15, 21, or 22) become joined together.

Balanced translocation carriers have 45 chromosomes but no

significant loss of overall chromosomal material and they are
almost always healthy. In unbalanced translocation karyotypes
there are 46 chromosomes with trisomy for one of the
chromosomes involved in the translocation. This may lead to
spontaneous miscarriage (chromosomes 14, 15, and 22) or
liveborn infants with trisomy (chromosomes 13 and 21).
Unbalanced Robertsonian translocations may arise
spontaneously or be inherited from a parent carrying a
balanced translocation.

Balanced Robertsonian
translocation affecting
chromosomes 13and 14 (c

Deletions
Deletions are another type of structural abnormality. Loss of part of a chromosome
usually results in physical abnormalities and learning difficulties. The deletion may
involve loss of the terminal or, less commonly, the interstitial part of a chromosome.
An example of a deletion syndrome involves loss of the tip of the short arm of
chromosome 5, hence the name 5p- or monosomy 5p. Because affected babies
have a high-pitched mewing cry in early infancy, it is also known as cri du chat
syndrome. Parental chromosomes should be checked to see if one parent carries a
balanced chromosomal rearrangement.
An increasing number of syndromes are now known to be due to chromosome
deletions too small to be seen by conventional cytogenetic analysis. These
submicroscopic deletions can be detected by FISH (fluorescent in-situ hybridisation)
studies using DNA probes specific to particular chromosome regions. DiGeorge's
syndrome is due to a deletion of chromosome 22 at band 22q11 Williams' syndrome
is another example of a microdeletion syndrome due to loss of chromosomal
material on the long arm of chromosome 7 at band 7q11

Cri du chat syndrome

associated with deletion of
short arm
of chromosome 5

Fluorescence in situ hybridisation with

a probe from the
DiGeorge critical region of
chromosome 22q11, which shows
hybridisation to only one chromosome
22 (red signal), thus indicatingthat the
other chromosome 22 is deleted in
this region

Fluorescent in-situ hybridisation (FISH) demonstrating a microdeletion on chromosome

22 associated w DiGeorge's syndrome. Hybridisation signals are seen on one
chromosome 22 but not on the other chromosome 22 because of the presence of a
deletion. ith

Examples of syndromes associated with

microdeletions
Syndrome
DiGeorge
Velocardiofacial
PraderWilli
Angelman
William
MillerDieker (lissencephaly)
WAGR (Wilms tumour aniridia)
RubinsteinTaybi
Alagille
Trichorhinophalangeal
SmithMagenis

Chromosomal deletion
22q11
22q11
15q11-13
15q11-13
7q11
17p13
11p13
16p13
20p12
8q24
17p11

Mendelian inheritance
Disorders with these patterns of inheritance, described by Mendel in are
rare individually, but collectively numerous, with over 15 000 single gene
traits or disorders described. For many disorders the Mendelian pattern
of inheritance is known. If the diagnosis of a condition is uncertain, its
pattern of inheritance may be evident on drawing a family tree
(pedigree), which is an essential part of genetic evaluation

 The term Mendelian inheritance applies when a characteristic

or set of characteristics is due to the information contained in a
single gene pair. The characteristic may be "usual" or it may not: it
could be a feature of a genetic condition.
Autosomal recessive inheritance,
Autosomal dominant inheritance,
X-linked recessive inheritance and
X-linked dominant inheritance.
Some genetic conditions are due to faulty genes that do not
follow the Mendelian patterns of inheritance.
Multifactorial inheritance,
Mitochondrial inheritance and
Genetic imprinting.

AUTOSOMAL MUTATIONS:
Recessive mutations:
If the body can still work normally with less than the usual amount of the correct
gene product available, the person will be unaffected by having a gene in which
one copy is faulty and the other correct..
The person is an unaffected "carrier" of the faulty gene copy.
In these cases, the mutation causing the gene copy to be faulty is hidden or
"recessive" to the unchanged information in the correct copy of the gene.
Dominant mutations
If the body cannot work normally with less than the usual amount of correct
gene product, that person will show the effects of the faulty gene by being
affected with a genetic condition, even though only one copy of the gene is
faulty.
In these cases, the mutation making the gene copy faulty appears to override or
"dominate" the unchanged information in the correct copy of the gene: it is
described as a dominant mutation.

Autosomal dominant inheritance

This is the most common mode of Mendelian inheritance. An affected

individual carries the abnormal gene in the heterozygous state on one
of a pair of autosomes (chromosomes 1-22). Male and female
offspring each have a 1 in 2 (50%) chance of inheriting the abnormal
gene from an affected parent This is straightforward, but complicating
factors include the following.

CHARACTERISTICS:
Vertical pattern in pedigree affected individuals present in
each generation.
Any child of an affected individual has an 50% chance of
inheriting the disorder.
Phenotypically normal family members do not transmit the
condition.
Males and females are equally affected.
Significant number of patients are due to new mutations.
VARIABLE EXPRESSIVITY:
Wide variations in the phenotype.
Reduced penetrance obligate carrier does not show any
phenotypic manifestations.
Also sometimes a non penetrant may show somatic or germ
line mosaicism.

Variation in expression
Within a family, some affected individuals may manifest the disorder mildly and others more severely. For
example, a parent with tuberous sclerosis may have mild skin abnormalities only, but his or her affected child
may have, in addition, epilepsy and learning difficulties
.

Late onset disorders

Dominant disorders may have a late or variable age of onset of signs and symptoms.
People who inherit the defective gene will be destined to become affected, but may
remain asymptomatic well into adult life. Young adults at risk may not know whether
they have inherited the disorder and be at risk of transmitting it to their children at the
time they are planning their own families. The possibility of detecting the mutant gene
before symptoms become apparent has important consequences for conditions such
as Huntington disease and myotonic dystrophy
Non-penetrance
Refers to the lack of clinical signs and symptoms in an individual who must have inherited the abnormal gene.
An example of this is otosclerosis, in which only about 40% of gene carriers develop deafness
No family history of the disorder
May be due to: A new mutation in one of the gametes leading to the conception of the affected person. This
is the most common reason for absence of a family history in dominant disorders, e.g. >80% of individuals with
achondroplasia have normal parents.
Gonadal mosaicism - very occasionally a healthy parent harbours the mutation only in a number of gametes
in the gonad. This can account for recurrences of autosomal dominant disorders in siblings born to apparently
normal parents. It has been described in congenital lethal osteogenesis imperfecta.
Non-paternity - if the apparent father is not the biological father.

Homozygosity
In the rare situation where both parents are affected by the same autosomal dominant disorder, there is a 1 in
4 risk that a child will be homozygous for the mutant gene.

AUTOSOMAL DOMINANT INHERITANCE:

Characteristics of autosomal dominant

inheritance

Males and females equally affected

Disorder transmitted by both sexes
Successive generations affected
Male to male transmission occur
s

Examples of autosomal dominant disorders

May hgline spherocytosis
Gilbert and mild c najjar syn
OS weber sy

eliptocytosis

VWD

Ehlers-Danlos syndrome

Marfan's syndrom

noonan syn

Acute intermittent porphyria Tuberous sclerosis

Osteogenesis imperfecta

Achondroplasia

Gardener syn Polyposis coli

P jager syndrom

Neurofibromatosis
Otosclerosis
Familial adenomatous polyposis

Familial hypercholesterolaemia Familial breast cancer F magrine

At telengactasia
Spinocerebellar ataxia
disease

Huntington disease

Myotonic dystrophy

Facioscapulohumeral dystrophy CharcotMarieTooth

Estimation of risk in mendelian disorders

Many autosomal dominant disorders have onset in adult lifeand are not
apparent clinically during childhood. In suchfamilies a clinically unaffected
adolescent or young adult has ahigh risk of carrying the gene, but an
unaffected elderly
relative is unlikely to do so. The prior risk of 50% fordeveloping the disorder
can therefore be modified by age. Data are available for Huntington disease
andfrom whichage-related risks can be derived for clinically
unaffectedrelatives. In example 1 the risk of developing Huntington disease
for individual B is still almost 50% at the age of 30.Risk to offspring C is
therefore 25%.d

Autosomal recessive inheritance

Many hundred disorders resulting from this type of inheritance are known

An affected individual is homozygous for the abnormal gene, having inh

Consanguinity It is thought that we all carry at least one abnormal recessive

gene. Fortunately, our partners usually carry a different one. Marrying a cousin or
other relative increases the chance of both partners carrying the same abnormal
autosomal recessive gene, inherited from a common ancestor. A couple who are
cousins therefore have a small increase in the risk of having a child with a
recessive disorder
inherited an abnormal allele from each parent, both of whom are unaffected
heterozygous carriers. For two carrier parents, the risk of each child, male or
female, being affected is 1 in 4 (25%) All offspring of one affected individuals will
be carriers
Recessive gene frequencies may vary between racial groups. When the gene occurs
sufficiently frequently and the gene or its effect can be detected, population-based
carrier testing can be performed and antenatal diagnosis offered for high-risk
pregnancies. Disorders that can be screened for in this way include cystic fibrosis
in north Europeans, sickle cell disease in black Africans and Americans,
thalassaemias in Mediterranean or Asian ethnicity and Tay-Sachs disease in
Ashkenazi Jews

CHARACTERISTICS:
Horizontal pattern in pedigree siblings of the proband.
Males and females are equally affected.
Parents of an affected child are asymptomatic heterozygote
carriers of the gene.
Recurrence rate of a siblings of an affected child is 25%.
Consanguinity and genetic isolates runs a higher risk for this
inheritance.
HARDY WEINBERG FORMULA:
P2 + 2pq + q2 = 1.
where p is the frequency of one allele and q is that of
another. pq is therefore the carrier frequency.

Variability
Autosomal recessive disorders usually demonstrate full
penetrance and little clinical variability within families.
Haemochromatosis is unusual in that not all homozygotes
develop clinical disease
New mutations
New mutations are rare in autosomal recessive disorders and it
can generally be assumed that both parents of an affected child
are carriers

Uniparental disomy
Occasionally, autosomal recessive disorders can arise through a
mechanism called uniparental disomy, in which a child inherits
two copies of a particular chromosome from one parent and
none from the other

Heterogeneity
Genetic heterogeneity is common and involves multiple alleles
at a single locus as well as multiple loci for some disorders.
Allelic heterogeneity implies that many different mutations can
occur in a disease gene. It.

AUTOSOMAL RECESSIVE INHERITANCE :

Characteristics of autosomal recessive

inheritance
Males and females equally affected
Both parents are unaffected carrier
Two out of three unaffected siblings are carriers
Increased incidence of parental consanguinity in rare
disorders

Examples of autosomal recessive disorders

ongenital adrenal hyperplasia
Cystic fibrosis
Friedreich's ataxia
Galactosaemia
Glycogen storage diseases
Hurler's syndrome
Oculocutaneous albinism
Phenylketonuria
Sickle cell disease
Tay-Sachs disease
Thalassaemia
Werdnig-Hoffmann disease
Haemochromatosis
Homocystinuria
Hurler syndrome

Estimation of risk in mendelian disorders

In general, doubling the square root of the disease incidence gives a
sufficiently accurate estimation of carrier frequency in a given
population. The risk for cystic fibrosis is The unaffected sibling of a
person with cystic fibrosis has a carrier risk of 2/3. The unrelated
spouse has the population risk of around one in 22 for being a carrier.
Since the risk of both parents passing on the mutant gene is one in
four if they are both carriers, the risk to their child would be2/3 1/22
1/4 = 1/132

If aconsanguineous couple have a child affected by an autosomal

recessive condition other marriages within the family may be at
increased risk for the same condition. The risk can be defined by
calculating the carrier risk for both partners
Risk of affected child
* 1/2* 1/4 = 1/16

When an affected person has children, the risk of recurrence is

again determined by the chance that the partner is a carrier. In
non-consanguineous marriages this is calculated from the
population carrier frequency. In consanguineous marriages it is
calculated from degree of the relationship to the spouse. The
affected parent must pass on a gene for the disorder since they
are homozygous for this gene and the risk to the offspring is
therefore half of the spouses carrier risk 1 1/4 1/2 = 1/8

X INACTIVATON:
To correct the potential imbalance between males and
females the cells have a system to ensure that only one copy
of most (see later) of the X chromosome genes in a female
cell are "active". Most of the other X chromosome copy is
"inactivated" or switched off Lyonization.
X-inactivation only occurs in the somatic cells, since both X
chromosomes need to be active in the egg cells for their
normal development..
This system of inactivation in the body cells is usually
random.
The relative proportion of cells with an active maternal or
paternal X chromosome varies from female to female (even
between identical twins).

 However, rarely, some women have more cells where the X

chromosome carrying the faulty gene is active so that these
women do show some of the symptoms of these conditions. In
these rare cases the X - inactivation has been "skewed"
rather than random.
In other rare cases, women have a structural change of one of
their X chromosomes : their X chromosome may be missing a
small part (deleted) or rearranged in some way. Usually it is
this changed X chromosome that is inactivated rather than the
correct copy.
In other rare cases, women have a special type of
chromosome rearrangement in their cells called a
translocation where the X chromosome is attached to one of
the numbered chromosomes (autosomes). In the cells of
these women, on the other hand, it is the correct copy of the X
chromosome that is usually inactivated, rather than the
rearranged (translocated) X chromosome copy.

X CHROMOSOMAL MUTATIONS:

Recessive mutations:
A female who has a mutation in a gene on one of her X chromosome copies but a
correct copy of the gene on the other X chromosome, is a "carrier" of the gene
mutation (X-linked genetic carriers).
Due to the process whereby one of the female's X chromosome copies is
inactivated, some of her cells will contain the X chromosome on which the correct
copy of the gene is located; other cells will contain the X chromosome on which
the faulty gene is located.
Females who are "X-linked genetic carriers" will therefore usually have only half of
her cells containing the information for the correct gene product.
Dominant mutations:
Some gene products must be present in all the cells of the woman for the body to
work normally.
A mutation in a gene on the X chromosome that impairs the cell's ability to make
this type of product will therefore show an effect and so the mutation is described
as "dominant"

X-linked recessive inheritance

Over 400 disorders have been described in which an abnormal recessive gene is
carried on the X chromosome
In X-linked recessive inheritance:
males are affected
females can be carriers but are usually healthy occasionally a female carrier shows
mild signs of the disease manifesting carrier
each son of a female carrier has a 1 in 2 (50%) risk of being affected
each daughter of a female carrier has a 1 in 2 (50%) risk of being a carrier
daughters of affected males will all be carriers
sons of affected males will not be affected, since a man passes a Y chromosome to
his son.
The family history may be negative, since new mutations and gonadal mosaicism
are fairly common. Identification of carrier females in a family requires interpretation
of the pedigree, looking for mild clinical manifestations and doing specific
biochemical or molecular tests. Identifying carriers is important because a female
carrier has a 50% risk of having an affected son regardless of who her partner is,
and X-linked recessive disorders are often very severe.

Characteristics of X linked recessive

inheritance
Males affected almost exclusively
Transmission through carrier females
Male to male transmission does not occur
All daughters of affected males are carriers

CHARACTERISTICS:
Males > females.
Heterozygote female carriers are usually unaffected.
From an affected man to all his daughters and any of his daughters
sons have 50% chance of inheriting the disease.
Never from father to son.
Series of carrier females and affected males are related through
carrier females.
A significant amount cases are due to new sporadic mutations.
FEMALE INHERITS THE DISEASE:
Homozygous state.
Turner syndrome.
Skewed X inactivation.

Examples of X linked recessive disorders

Anhidrotic ectodermal dysplasia
Becker muscular dystrophy
Choroideraemia
Colour blindness
Duchenne muscular dystrophy
EmeryDreifuss muscular dystrophy
Fabry disease
Fragile X syndrome
G-6-P-D deficiency
Haemophilia A, B
Hunter syndrome (MPS II)
Ichthyosis (steroid sulphatase deficiency)
LeschNyhan syndrome
Menkes syndrome
Ocular albinism
Ornitine transcarbamylase deficiency
Retinitis pigmentosa (some types)
Testicular feminisation syndrome

X LINKED RECESSIVE:

X-linked dominant inheritance

X-linked disorders where the mutation has a dominant

effect are rare. Both males and females are affected,
e.g. a variant of vitamin D-resistant rickets. In some
disorders male lethality is expected and only affected
females will be seen, e.g.
Rett's syndrome and
incontinentia pigmenti
VIT Dresistance rickets Glotz syndrom
Alcardel syndrom
menk kinky hair

CHARACTERISTICS:
All of the daughters and none of the sons of an affected man
have this condition.
Both male and female offsprings of affected woman have 50%
chance of inheriting the condition.
Affected females are twice as common as affected man but
have a milder manifestations.
Hypophostemic rickets.
Incontinentia pigmenti.

X LINKED DOMINANT:

Y-linked inheritance

Y-linked traits are extremely rare. Y-linked inheritance

would result in only males being affected, with transmission
from an affected father to all his sons. Y-linked genes
determine sexual differentiation and spermatogenesis, and
mutations are associated with infertility.

Possible causes of sporadic cases

Autosomal dominant
Autosomal recessive
X linked recessive
Chromosomal
Polygenic (multifactorial)
Non-genetic

Risks to offspring of carriers

Recessive mutations: no risk unless partner is a
carrier
Dominant mutations: 50% risk applies to late onset
disorders
X linked recessive: 50% risk to male offspring

Unusual genetic mechanisms

trinucleotide repeatation
This is a class of unstable mutations caused by
expansions of trinucleotide repeat sequences inherited
in Mendelian fashion.
Fragile X syndrome and myotonic dystrophy
spinocerebellar ataxia and Friedreich's ataxia.
Spinocerebellar ataxia
These disorders follow different patterns of inheritance
but share certain unusual properties due to the nature of
the underlying mutation.
Clinical anticipation is often seen,
with the disorders becoming more severe in successive
generations of a family
and new mutations being exceedingly rare

Fragile X syndrome
The prevalence of severe learning difficulties in males due to fragile X syndrome is about
1 in 4000 This condition was initially diagnosed on the basis of the appearance of a gap
(fragile site) in the distal part of the long arm of the X chromosome.
Diagnosis is now achieved by molecular analysis of the CGG trinucleotide repeat
expansion in the relevant gene (FMR1). PCR

Although it is inherited as an X-linked recessive disorder, a high proportion of obligate

female carriers have learning difficulties (usually mild to moderate) and around one-fifth
of males who inherit the mutation are phenotypically normal but may pass the disorder
on to their grandsons through their daughters. These unusual findings are explained by
the nature of the mutation, which occurs in 'pre-mutation' and 'full mutation' forms. The
normal copy of the gene contains fewer than 50 copies of the CGG trinucleotide repeat
sequence and is stable when transmitted to offspring. Genes with the pre-mutation
contain 55-199 copies of the repeat sequence. This expansion causes no intellectual
disability in male or female carriers, but is unstable and may become larger during
transmission through females. Genes with the full mutation contain more than 200
copies of the repeat sequence. This affects gene function, causing the clinical features
of fragile X syndrome in virtually all males and around half of the female carriers. These

Clinical findings in males in fragile X syndrome

Moderate-severe learning difficulty (IQ 20-80, mean 50)

Fragile X syndrome is the second most common genetic cause of

severe learning difficulties after Down's syndrome

Macrocephaly

Macro-orchidism - postpubertal

Characteristic facies - long face, large everted ears, prominent

mandible and broad forehead, most evident in affected adults.

Other features - mitral valve prolapse, joint laxity, scoliosis, autism,

hyperactivity

chromosome spread showing a fragile X chromosome

Mitochondrial or cytoplasmic inheritance

. In mt DNA disorders, the mutation is usually present in only a
proportion of the mitochondria, so that cells have a mixture of
normal and mutant mt DNA. Mutations in mt DNA cause several
disorders such as
MEALS AND MEERF
Leber's hereditary optic neuropathy and
various mitochondrial myopathies and
Encephalopathies.
Mitochondrial DNA mutations show only maternal transmission,
since only the egg contains cytoplasm and mitochondria.
Disorders due to mt DNA deletions are usually not transmitted to
offspring. Sperm do not contain mitochondria, so a father with a
disorder due to a mitochondrial DNA mutation will not have
affected children

Imprinting and uniparental disomy

It has been shown that some genes are actively expressed only if they have
been derived from a parent of a given sex.
This phenomenon is called 'imprinting'. An example involves
Prader-Willi syndrome
(learning difficulties, hypotonia, obesity).
(that is, bands 11-13 on the long arm of chromosome 15). Normally,
only the paternal copy of the Prader-Willi gene is active.
Failure to inherit the active paternal gene will give rise to the syndrome.
Failure to inherit the maternal copy of this gene has no effect, since it is
inactive.Coincidentally, the gene for Angelman syndrome
(severe learning difficulty, ataxia, characteristic facial appearance, epilepsy)
is also found in the same chromosome region and is also subject to
imprinting. In this case it is the maternal gene that is the active one. Failure to
inherit the maternal gene will therefore cause Angelman syndrome. There are
two main ways that a child can fail to inherit the active gene for either
syndrome
:

Parental chromosomes are normal, and a deletion occurs as a

new mutation in the child. If the deletion occurs on the paternal
chromosome 15, the child has Prader-Willi syndrome.
If the deletion affects the maternal chromosome 15, the child
has Angelman syndrome.
Uniparental disomy . This is when a child inherits two copies
of a chromosome from one parent and none from the other
parent.
In Prader-Willi syndrome the affected child has no paternal
(but two maternal) copies of chromosome 15q 11-13. In
Angelman syndrome the affected child has no maternal (but
two paternal) copies of chromosome 15q11-13. This can be
detected with DNA analysis.

Prader-Willi syndrome

DIAGNOSTIC INVESTIGATIONS
. Cytogenetic studies

Microscopic or submicroscopic del(15)(q11-q13

confirmed by fluorescence in situ hybridization FISH probe 6080%
Paternally derived chromosome 15 that is deleted

Balanced chromosomal rearrangement with break in 15q11-q13

Molecular analyses for Uniparental disomy

GENETIC COUNSELING
low recurrence risk 1% .

Prenatal diagnosis
For High risk pregnancies

Management
Manage feeding problems with special nipples or gavage feeding if needed to assure
adequate nutrition, o avoid failure to thrive, and to improve hypotonia

Early intervention programs with speech, physical, and occupational therapies

,
.

Dietary control

. Management of endocrine problems

Growth hormone replacement in patients with deficient growth hormone
Testosterone treatment in males to improve changes in voice and body hair, beard growth,
genital size, body mass and strength, and selfimage
Treatment with estrogen, cycling hormones or birth control pills in females has resulted in
increasing breast size and menstrual periods

Management of

scoliosis as in the general population

Behavioral management
Psychiatric management

Treatment of complications resulting from excessive obesity

CLINICAL FEATURES of Angelman syndrome

Normal newborn phenotype
Seizur . Developmental delay
Profound speech impairment
Movement or balance disorder
Typical behavioral pattern happy baby
DIAGNOSTIC INVESTIGATIONS
Normal metabolic, hematologic, and chemical laboratory profiles
. Normal brain imagings (MRI, CT) with occasional mild cortical atrophy and
dysmyelination
Abnormal EEG
Cytogenetic studies
. To detect visible chromosome rearrangement
Fluorescence in situ hybridization (FISH) to identify 15q11-q13 microdeletions

GENETIC COUNSELING
Recurrence risks
risk likely to be extremely low <1%

Management

Physical therapy for unstable or nonambulatory

children
Occupational therapy for improving fine motor and
oral-motor control
Speech and communication therapy
Consistent behavioral modifications
Seizure control difficult with antiepileptic drugs,
especially in childhood with Sodium valproate as
monotherapy or in combination with clonazepam or
other benzodiazepines
Experience with the newer antiepileptic drugs very
limited

Silver-Russell Syndrome
GENETIC/BASIC DEFECTS

Sporadic occurrence in majority of cases

Maternal uniparental disomy (UPD) for chromosome 7 about 710% of case

Diagnostic criteria:
Presence of three major features plus one or more minor features is generally required
for a positive diagnosis.

a. Major criteria
Low birth weight intrauterine growth retardation)
Proportionate short stature postnatal growth retardation)
Small triangular face
Fifth finger clinodactyly

b. Minor criteria
Relative macrocephaly Ear anomalies Skeletal asymmetry
Brachydactyly of the fifth fingers Bilateral camptodactyly
Syndactyly Transverse palmar crease Downward slanting corner of the mouth
Muscular hypotrophy/hypotonia Motor/neurological delay
Irregular spacing of the teeth Caf-au-lait spots

DIAGNOSTIC INVESTIGATIONS
Increased serum or urinary gonadotropin levels in the prepuberty
. Hypoglycemi
Growth hormone studies
Delayed bone age and Limb asymmetry

Chromosome analysis to define chromosome basis

e

GENETIC COUNSELING
Recurrence risk Not increased

Prenatal diagnosis by ultrasonography

. Management
Growth deficiency by Optimize caloric intake and Consider nasogastric or
gastrostomy feeding for severe gastroesophageal reflux
Consider growth hormone treatment in patients with growth hormone
deficiency
Dental cares for overcrowding of teeth
Orthopedic management for asymmetry of legs
Early intervention programs including physical therapy for developmental
delay
Special education for learning disabilities
Psychological counseling

Beckwith-Wiedemann Syndrome
GENETICS/BASIC DEFECTS
Sporadic (85% and Paternally derived 11p15.5 duplications
CLINICAL FEATURES
. Prenatal and postnatal overgrowth (gigantism)e and Macroglossia (cardinalfeature
Ear-lobe grooves Omphalocele cardinal feature Visceromegaly
Benign and malignant tumors Wilms tumor most frequent and Hypoglycemia
DIAGNOSTIC INVESTIGATIONS
. Transitory neonatal hypoglycemia )
Neonatal polycythemia (20%)
Hypercholesterolemia, hyperlipidemia, hypothyroidism,
. Periodic abdominal ultrasonography for organomegaly and tumor
Radiography
Advanced bone age
Chest radiography to rule out rare neural crest tumors such neuroblastoma
. Echocardiography for suspected cardiac abnormality
. Chromosome analysis

Five infants with Beckwith syndrome BWS showing hemangioma,

macroglossiaand umbilical hernia.

GENETIC COUNSELING
. low

recurrence risk
Prenatal diagnosis
Maternal serum alpha fetoprotein screening: may be elevated in a
fetus with omphalocele
. Prenatal Ultrasonography
Cytogenetic studies
Molecular analysis
Management
. Early detection and close monitoring for hypoglycemia
Partial tongue resection for cosmetic purpose and to relieve airway
obstruction
Management of abdominal wall defects, gastrointestinal, and renal
anomalies
Orthopedic follow-up of hemihyperplasia
. Management of embryonal neoplasms

Polygenic or multifactorial inheritance

There is a spectrum in the aetiology of disease, from environmental factors (e.g. trauma) at one
end to purely genetic causes (e.g. Mendelian disorders) at the other. Between these two
extremes are many disorders which result from the additive effect of several genes (hence
the term polygenic) with or without the influence of environmental or other unknown factors
(i.e. multifactorial). The two terms are often used interchangeably
Normal traits such as height and intelligence are also inherited in this way.
The risk of recurrence of a polygenic disorder in a family is usually low and is most
significant for first-degree relatives. Empirical recurrence risk data are used for genetic
counselling.
increase the risk to relatives are:

having a more severe form of the disorder, e.g.

bilateral cleft lip and palate than in unilateral cleft lip alone

close relationship to the affected person,

multiple affected family members,

sex difference in prevalence,

.
The phenotype (clinical picture) of a disorder may have a heterogeneous (mixed) basis in
different families; for example, hyperlipidaemia leading to atherosclerosis and coronary
heart disease can be due to a single gene disorder such as autosomal dominant
hypercholesterolaemia, but some forms of hyperlipidaemia are polygenic and result from an
interaction of the effect of genes on various lipoproteins.

Conditions with multifactorial inheritance

Congenital malformations

Neural tube defects (anencephaly and spina bifida)

Congenital heart disease

Cleft lip and palate

Pyloric stenosis

Congenital dislocation of the hip

Talipes

Hypospadias
Adult life

Atherosclerosis and coronary heart disease

Diabetes mellitus

Asthma

Epilepsy

Hypertension

CHARGE Association
Sporadic in most cases
possible genetic causation high withIncreased paternal age

CLINICAL FEATURES
Coloboma (8090%) of the iris
Heart disease (cardiovascular malformations) 85%
Choanal Atresia (5060%
Growth and mental Retardation (70100%
Genital anomaly (7080
Ear anomalies/deafness (90%
DIAGNOSTIC INVESTIGATION
. Audiology, tympanometry, BAER, and CT of temporal bones for evaluation of hearing
Dilated fundoscopic exam for colobomas
. Nasal pharyngeal feeding tube and evaluation of choanal atresia
. Echocardiography and Ultrasound for renal anomalies
. CT scan and/or MRI for brain
Chromosome analysiss

Molecular genetic analysis for CHD7 gene mutation

boy with typical CHARGE association at ages 11 (front

view) and 15 (lateral view). The patient had bilateral colobomas, choanal atresias, growth
and mental retardation, hypogonadism, andear anomalies with hearing loss.

VATER (VACTERL) Association

GENETICS/BASIC DEFECTS
1

Etiologic heterogeneity Isolated cases

CLINICAL FEATURES
Vertebral anomalies
Anal and urachal anomalies
Cardiac anomalies
Tracheoesophageal fistula
.Esophageal atresia
. Renal anomalies
Limb defects

DIAGNOSTIC INVESTIGATIONS
. Radiography for vertebral and limb defects
. Echocardiography for congenital heart defects
. GI investigation for TE fistula or esophageal atresia
Renal ultrasonography for renal dysplasia
Urological evaluation of urogenital defects
. Chromosome analysis

GENETIC COUNSELING
low recurrence risk gene disorder
. Prenatal diagnosis by ultrasonography revealing multiple conenital
Anomalies

Management
Medical care
Surgical care
i. TE fistula and/or esophageal atresia
ii. Major cardiac defects
iii. Urogenital anomalies
iv. Skeletal and limb defects

child with VATER association showing club hands and radial

Aplasiaabnormally rotated left lower limb

Williams Syndrome
Association of the elastin (ELN) gene disruption by chromosome translocation or partial
deletion involving chromosome 7q11.23 Sporadic new deletion in most cases
CLINICAL FEATURES
. Characteristic dysmorphic facies, frequently referred to as elfin facies 100%

Cardiovascular diseases
Supravalvular aortic stenosis (80%
Variable mental retardation (75%

Behavioral problems
Idiopathic infantile hypercalcemia (15%
Ocular findings
Dental abnormalities
Chronic otitis media
Difficulty feeding
. Gastroesophageal reflux/vomiting

DIAGNOSTIC INVESTIGATIONS
Radiography. Echocardiography for cardiac lesions and Ultrasonography
Blood calcium levels Serum creatinine Thyroid function test
. Ophthalmologic evaluation Urinalysis to detect hypercalcinuria Renal ultrasound for possible
nephrocalcinosis
Full cytogenetic studies andFluorescence in situ hybridization (FIS

GENETIC COUNSELING
recurrence risk low <1%
Prenatal diagnosis by amniocentesis or CVS

Management
Management of hypercalcemia
AvLimit high calcium food
ovoid preparations containing vitamin D
Supravalvular aortic stenosis (a life-threatening
surgically correctable
Early dental care
Early daily learning activities and strategies

Williams syndrome showing periorbital fullness,

stellate lacy iris pattern, flat nasal bridge, short nose with bulbous
tip,wide mouth, and full cheeks and lips

Noonan Syndrome
Autosomal dominant inheritance and Caused by mutation in the gene PTPN11 (proteintyrosine phosphatase, nonreceptor-type 11
CLINICAL FEATURE

Growth
normal birth weight but can be short stature Pubertal growth spurt often reduced or absent .
Craniofacial features:
Strabismus Refractive errors
Congenital heart defects (2/3rd of cases) Pulmonary valvular stenosis (50%)
Hypertrophic cardiomyopathy (2030% Pulmonary artery branch stenosis)

pectus deformity
Bleeding diathesis
Behavioral and developmental abnormalities
DIAGNOSTIC INVESTIGATIONS
. Echocardiography Electrocardiography A wide QRS complex LAD Giant Q wave
Radiography: pectus deformity
Renal ultrasound for renal anomalies. Coagulation studies when needed
Chromosome analysis: normal karyotype
Molecular genetic testing FOR Mutations in the gene PTPN11

GENETIC COUNSELING
Recurrence risk 50%if a parent is affected Low risk (<1%) if not affected

Prenatal diagnosis.
Ultrasonic AND Molecular genetic testing of fetal DNA

Management
a. Plotting of growth parameters on growth charts for Noonan syndrome
b. Ophthalmological care
c. Cardiac management of congenital heart defects
d. Hearing evaluation and management
e. Physical and occupational therapies
f. Speech therapy for articulation deficiencies
i. Hearing aids for sensorineural hearing loss
j. Orthopedic management of musculoskeletal abnormalities
k. Growth hormone treatment of short stature:s
l. Successful pregnancy possible in women with Noonan syndrom

Noonan syndrome
showing variousfeatures:
down slanting palpebral fissures,
hypertelorism, short andwebbed neck with
a low posterior hair line, pectus, and
cubitus valgus

Marfan Syndrome
Autosomal dominant and New mutation in about 2530% of the cases
Caused by a wide variety of mutations in the fibrillin-1 gene located on
chromosome 15q
CLINICAL FEATURES

Skeletal system
tall and thin with respect to the family profile. Limbs are disproportionately
long compared with the trunk (dolichostenome and Arachnodactyly is a very
common feature Pectus carinatum excavatum
Reduced upper-to-lower body segment ratio
Positive (Steinberg) signs Scoliosis
ectopia lentis (usually superior temporal dislocation
Dilatation of the ascending aorta and Dissection
Mitral valve prolapse
Spontaneous pneumothorax

DIAGNOSTIC INVESTIGATIONS
. Annual physical examination including blood pressure measurement
. Slit lamp examination for lens dislocationn
Electrocardiogram
Pelvic and Chest X-ray Computed tomography
CT and magnetic resonanceimaging (MRI
Aortograph
Molecular analysis of FBN1 mutations
GENETIC COUNSELING
Prenatal diagnosis
Fetal echocardiography Ultrasonography

Management
-blockers and Calcium antagonists and (ACE) inhibitors
Life style changes Avoid competitive and collision/contact sports
Surgical intervention recommended for Pneumothorax
Management of scoliosis Pectus repair Ocular management

Marfan
syndrome
showing a
slender/tall
habitus,
typical
facies,
arachnodact
yly, and toe
anomalies.

DIGEORGE SYNDROME;
INHERITANCE :Autosomal dominant
Short stature 20% of adults
Obesity 35% of adults

HEAD AND NECK :

Micrognathia
Hearing deficits
Short palpebral fissures
Blunted nose
High arched palate

Low-set ears
Hypertelorism
Strabismus
Short philtrum

Heart
Tetralogy of Fallot
Truncus arteriosus
Interrupted aortic arch Right aortic arch
Ventricular septal defect Patent ductus arteriosus

Umbilical hernia
:
Unilateral renal agenesis
Hydronephrosis
:
Mild to moderate learning difficulties
development
Late-onset speech development
Tetany
disorder:
:
Parathyroid hypoplasia
Thymic hypoplasia
Hypothyroidism) :
infection

Cholelithiasis
Renal dysplasia
Scoliosis
Delayed psychomotor

Seizure

Attention deficit

Parathyroid absence
Thymic aplasia
T cell deficit Susceptibility to

LABORATORY ABNORMALITIES :
Neonatal hypocalcemia
T-cell deficit
85-90% DGS patients have deletion of 22q11.2
Other cytogenic abnormalities have been associated
MOLECULAR BASIS
A contiguous gene syndrome involving deletion
of the DiGeorge syndrome chromosome region
(DGCR) involving mutations in
TUP-like enhancer of split 1 (TUPLE1, 600237) and
DiGeorge critical region gene 2 (DGCR2),
1