Download The cloning of the relevant genes, identification of their

“Genetic diseases. Notions of genetic pathology, chromosomal
abnormalities, diseases by multifactorial etiology,
genetic counseling”
for students of IV courses
have been elaborated
MD, PhD, associate professor, Mariana Sprincean
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Introduction
In an effort to identify individuals and families who might benefit from a
genetic evaluation, it is necessary to have a basic understanding of some general
genetic concepts. In this lesson the students will review the basics about
chromosomes and chromosome abnormalities. There are sections on single gene and
multifactorial disorders. The students will learn about traditional patterns of
inheritance, imprinting, uniparental disomy, and other phenomena that result in
nontraditional patterns of inheritance.
It is important to clarify at the outset the difference between chromosome
abnormalities and single gene disorders. To understood this difference help the
methods of laboratory diagnosis. Chromosome abnormalities are errors that result in
an abnormal chromosome number or an abnormal chromosome structure. These
abnormalities lead to the loss or gain of chromosome material- and we use the
methods of chromosome analysis. All the genes within these chromosomes, however,
are normal. Most chromosome abnormalities are sporadic with a small to negligible
risk of recurrence. Of those that are familial, the risk of recurrence is usually less than
15%.
In the case of single gene disorders, the error lies in a mutation or change
within the DNA sequence. For diagnosis of single gene disorders we using molecular
genetics analyses. Errors that occur within a gene can result in absent, deficient or
abnormal protein products. The chromosomes, or karyotype, of a patient with a single
gene disorder are expected to be normal, 46,XX or 46,XY. Therefore, chromosome
studies are not recommended for patients who are thought to have a single gene
disorder such as cystic fibrosis or muscular dystrophy.
Abnormalities in chromosome structure occur when one or more chromosomes
break and, during the repair process, the broken ends are rejoined incorrectly.
Individuals who inherit a balanced chromosome rearrangement are physically and
intellectually normal; however, they are more likely to produce chromosomally
abnormal gametes. Individuals with balanced translocations often come to clinical
attention following the birth of a child with a chromosome abnormality. They are also
more likely to have miscarriages and may be identified if a chromosome study is
done to determine the cause of the pregnancy losses.
Reference has been made to the dramatic explosion knowledge which has led
to the recognition of over 6000 single gene traits and disorders. The majority of these
are individually extremely rare. Some, however, are relatively common and their
management in families has presented a major challenge for clinical genetics and
closely allied specialities.
The cloning of the relevant genes, identification of their mutational basis and
isolation of their protein products serve to illustrate important genetic principles and
represent major scientific achievements.
Preconception and prenatal risk assessment tools have been developed to
identify factors that might increase a woman's chances of having an adverse
pregnancy outcome. Most tools include questions about a woman's age, health,
nutrition, social situation, previous pregnancies and her use of cigarettes, alcohol and
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drugs. We would like to suggest that by adding a few additional questions the
usefulness of these survey tools can be expanded.
The decision to opt for prenatal diagnosis is often difficult and is influenced by a
couple's feelings about the type of information that is provided through testing and
the available options they feel are appropriate considering their moral, ethical and
religious beliefs. No prenatal test can guarantee a healthy child and there is no
treatment or cure available for the vast majority of conditions for which testing is
possible. Structural defects, such as renal agenesis, may not be apparent on
ultrasound examination when early testing (CVS or EA) is performed. Many
conditions can be identified in the second trimester by detailed ultrasonography in
conjunction with amniotic fluid alpha fetoprotein screening or fetal karyotyping.
The availability of prenatal diagnostic tests may be limited in your area, and
testing options will change over time. It is for this reason that we recommend you
establish a working relationship with the genetics or prenatal diagnostic clinic staff in
your area. They will provide you with information regarding the availability of, and
the risks associated with, specific prenatal tests. Genetics or prenatal center staff are
also available to consult with your patients should they have additional questions or
concerns.
Objectives
The students will be able to know:
1. The basics of genetic pathology.
2. Classification of genetic pathology
3. Mutation (type of mutation, mechanism)
4. Pedigree Analysis (symbols, risk of hereditary)
5. Autosomal dominant condition. Characteristic.
6. Autosomal recessive condition. Characteristic.
7. X-linked inheritance. Characteristic.
8. Multifactorial conditions. General characteristics of diseases with genetic
predisposition.
9. Congenital anomalies. Epidemiology and classification.
10.Teratogen, teratogenic agents, the critical period of exposure is during
organogenesis
11.Differentiate between chromosomal, single gene, and multifactorial disorders.
12.Describe what might cause nontraditional patterns of inheritance.
13.Identify the influence that new mutations and susceptibility genes have on general
health and well being.
14.Human karyotype. Classification of chromosome abnormalities;
15.Numerical abnormalities;
16.Structural abnormalities;
17.Down’s syndrome (trisomy 21): incidence, clinical features, recurrence risk;
18.Turner’s syndrome (45,X): clinical features, chromosome findings;
19.Klinfelter’s syndrome (47,XXY): clinical features, chromosome findings;
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20.Trisomy 13 (Patau’s syndrome) and trisomy 18 (Edward’s syndrome) clinical
features;
21.Portions aneuploidy (cri-du-chat(5p-), Wolf-Hirschhorn (4p) syndromes);
22.Microdeletion syndromes ( the Angelman and Prader-Willi Syndromes, DiGeorge
and Shorintzen syndromes);
23.The fragile X syndrome: incidence, clinical features, the molecular defect.
24.Citogenetic measures (kariotyping, Barr test, FISH);
25.Methods of preparation of metaphase chromosomes:
26.Standard methods of chromosome’s preparations from different cells and tissues
(peripheral blood, chorion villi samples, amniocytes);
27.Practical indication for investigation of sexual chromatin and human
chromosomes.
28.Methods of DNA extraction of different cells and tissues (peripheral blood,
chorion villi samples, amniocytes);
29.Schema and main components of PCR;
30.Preparing the polyacrylamide and agarose gel;
31.English genetics terms glossary.
32.Singel gene (mendelian) inheritance. Definitions, pedigree symbols and
constructions , features- new mutations, reduced penetrance, variable expressivity,
variation in age of onset,
33.Genetic heterogeneity, phenocopy, variation in severity dependent on sex.
34.Biochemical genetics: disorders of aminoacid metabolism-Phenylketonuria,
disorders of steroid metabolism-congenital adrenal hyperplasia, lipoprotein
metabolism- familial hypercholesterolaemia.
35.Neurofibromatosis- incidence, clinical features, mode of inheritance, mapping,
NF1, NF2.
36.Cystic fibrosis- incidence, clinical features, confirmation of diagnosis, mapping,
mutations in the CF gene, gene product, clinical applications.
37.Duchenne muscular dystrophy- incidence, clinical features, mode of inheritance,
confirmation of diagnosis, carrier females, mapping, mutations in the DMD gene,
gene product, clinical applications.
38.Sindrom Marfan- incidence, clinical features, mode of inheritance, confirmation
of diagnosis, mapping, clinical applications.
39.Sindrom Ehlers-Danlos- incidence, clinical features, mode of inheritance,
confirmation of diagnosis, mapping, clinical applications.
40.Hemophilia A and B- incidence, clinical features, mode of inheritance,
confirmation of diagnosis, carrier females, mapping, mutations in the gene, gene
product, clinical applications.
41. Primary prevention.
42.Secondery prevention.
43.Sceening program
a. : AFP- alfa fetoprotein,
b. human chorionic gonadotropin,
c. sceening for fetal anomalies using ultrasound,
d. other screening programmes
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44.Diagnostic fetal interventions (obtaining fetal cells).
45.Studies performed on fetal cells: cytogenetics, biochemical test, molecular
analysis.
46.Carrier testing.
47.Presymptomatic diagnosis.
48.Ethical considerations.
GENETIC DISEASES
Genetic diseases represent pathological conditions determined by genetic
factors, occurring as a consequence of errors (mutations ) of the hereditary material.
A genetic disorder results from a chromosomal abnormality or defective gene:
- numerical and structural chromosomal abnormalities,
- single gene disorder,
- multifactorial, or polygenic disorders: isolated and multiple congenital
malformations, etc.
A congenital disease or malformation is any abnormality present at birth,
even if not detected until after birth and encompasses all abnormalities caused by
disturbed prenatal development, regardless of their nature.
Congenital defects are found in 2 to 3% of newborns. And 2 to 3% of
developmental defects not recognized at birth become apparent as the child grows.
Major malformations are found in 25 to 50% of spontaneously aborted embryos,
fetuses and stillborns.
Some genetic disease, including single gene disorders are inherited.
A mutated gene is passed down through a family and each generation of children can
inherit the gene that causes the disease.
Still other genetic disorders are due to problems with the number of packages of
genes called chromosomes. In Down syndrome, for example, there is an extra copy of
chromosome 21.
Hereditary transmission and teratological influence of certain factors during
early periods of ontogenetic development, determines appearance of genotypic and
phenotypic fatal changes to the fetus, and then to the newborn.
Teratogen refers to any agent that causes a structural abnormality following
fetal exposure during pregnancy. Seldom, if ever, have teratogens been identified
following designed epidemiologic studies. Usually an increased prevalence of a
particular birth defect leads to the discovery of a teratogenic agent. For instance,
Minamata disease, an encephalopathy that mimics cerebral palsy, was first
recognized in towns surrounding Minamata Bay in postwar Japan. This localized area
of increased prevalence led to an investigation that pointed to methyl mercury, which
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was discharged into the bay by a local factory, as the offending agent. Ingestion of
contaminated fish during pregnancy was the primary cause for this devastating
condition. Similar results followed the ingestion of grain laced with methyl mercury,
which was used as a fungicide, in Mexico and Iraq.
The sudden appearance of several cases of a rare disorder can also raise
suspicions of teratogenicity. Cases of phocomelia in the early 1960's in Germany and
Australia led to the identification of thalidomide as a human teratogen. Thalidomide
was used to treat morning sickness, resulting in exposure at the stage in development
when the embryo is most vulnerable, the first trimester.
Teratogenic agents include: infectious agents (rubella, cytomegalovirus,
varicella, herpes simplex, toxoplasma, syphilis, etc.); physical agents (ionizing
agents, hyperthermia); maternal health factors (diabetes, maternal PKU);
environmental chemicals (organic mercury compounds, polychlorinated biphenyl or
PCB, herbicides and industrial solvents); and drugs (prescription, over-the-counter,
recreational). It may appear as though there are more suspected teratogens than were
apparent a generation ago. This may be because there has been an increase in the
number of synthetic chemical compounds in use or possibly the clinical recognition
of subtle malformations as teratogenic effects. Examples of the latter would be fetal
alcohol syndrome, fetal hydantoin syndrome, fetal trimethadione syndrome, fetal
warfarin syndrome and smoking associated with low birth weight infants.
There are no absolute teratogens; however, many agents can exhibit
teratogenic effects under certain circumstances. The dose and the time of exposure to
a particular agent often determines the severity of the damage and the type of defect
that occurs. The dose response is obvious: the greater the dose, the greater the effect.
The time of exposure is another important concept, as certain stages of embryonic
and fetal development are more vulnerable than others. In general, the embryonic
stage (first trimester) is more vulnerable than the fetal period (second and third
trimesters). Thalidomide provides a classic example. The critical period of exposure
is during organogenesis (the formation of the organs) from the 35th-8th day after the
last menstrual period. The specificity of the malformations is linked to the time of
exposure: 35-37 days, no ears; 39-41 days, no arms; 41-43 days, no uterus; 45-47
days, no tibia; and 47-49 days, triphalangeal thumbs.
The types or severity of abnormalities caused by a teratogenic agent is also
dependent on the genotype of the pregnant woman and the genotype of the fetus
(genetic susceptibility). For example, variation in maternal metabolism of a particular
drug will determine what metabolites the fetus is exposed to and the duration of
exposure. Differences in placental membranes, placental transport and
biotransformation all affect fetal exposure. The genetic susceptibility of the fetus to a
particular teratogenic agent will also have an effect on the final outcome.
Absolute risk refers to the rate of occurrence of an abnormal phenotype
among individuals exposed to the agent. Chronic alcoholic mothers, for instance,
have a 45% chance of having an infant with fetal alcohol syndrome. Relative risk
refers to the ratio of the rate of the condition among the exposed and the nonexposed.
A relative risk of 2 means that smokers have twice the risk of having a low birth
weight baby as nonsmokers. Keep in mind that a high relative risk may indicate a low
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absolute risk if the condition is rare. For a rare condition with an incidence of 1 in
100,000, a high relative risk of 10 still leads to a very low absolute risk of 1 in
10,000. Finally, attributable risk is the rate of the condition that can be attributed to
exposure to the agent. Ninety percent of phocomelia patients have a history of
thalidomide exposure in utero.
It goes without saying that some pregnant women need to be on medication.
However, there are strategies to prevent or decrease the risk of fetal abnormalities:
the use of the lowest dose possible, the avoidance of combination drug therapies (for
the treatment of seizure disorders), the use of a different agent (heparin instead of
coumadin for thrombophlebitis), the avoidance of first trimester exposures
(preconception diabetes or PKU control), and folic acid supplementation.
Reassurance of a low risk or negligible risk, by itself, is often welcome.
The public awareness of hazardous agents in the home and the workplace, and
awareness of the teratogenic potential of drugs or medications during pregnancy has
led to the establishment of teratogen information services in most states or regions of
the country. This has been facilitated by the availability of national databases
(Reprotox, TERIS), the teratology society organizations (OTIS - Organization of
Teratogen Information Services) and the birth defect/genetics centers in most states.
Teratogens, agents that cause fetal injury with exposure during pregnancy, are
found at home or the workplace. The effect is related to type of agent, dose and
duration and time of exposure. The first half of pregnancy is the most vulnerable.
Public awareness is essential for prevention.
Phenotype and Genotype
Phenotype is the visible trait (all the characteristics physical, morphological,
physiological, biochemical and behavioral) that results in a particular genotype.
Genotype represent the hereditary information, embodied in the genes
contained in chromosomes. Genotype is the combination of alleles that an
individual possesses.
Phenotype is potentially variable.
Genetics is the study of heredity and variation
 The transmission of traits from one generation to the next is called heredity or
inheritance.
 However, offspring differ somewhat from parents and siblings, demonstrating
variation.
Genetic information is transmitted at several levels
 Molecular – AND molecule
 Morfological – Chromosomes
 Cell's - Genetic apparatus
Mutations
A mutation may be defined as a permanent change in the DNA.
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Mutations that affect the germ cells are transmuted to the progeny and may give rise
to inherited diseases. Mutations that arise in somatic cells are important in the genesis
of cancers and some congenital malformations.
Mutations may be classified into three categories:
Genome mutations – involve loss or gain of whole chromosomes (giving rise to
monosomy or trisomy)
Chromosome mutations – result from rearrangement of genetic material and give rise
to visible structural changes in the chromosome.
Gene mutations – may result in partial or complete deletion of a gene or, more often,
affect a single base. For example, a single nucleotide base may be substituted by a
different base, resulting in a point mutation.
Classification of genetic disorders
 Chromosomal disorders (chromosomal abnormalities):
Defect is due to an excess or a deficiency in whole chromosomes or
chromosome segments (trisomy 21,Turner syndrome, Klinefelter syndrome)
 Single gene defects (Monogenic diseases):
Caused by individual mutant genes
 Multifactorial inheritance: Combination of multiple genes and environmental
factors. (Complex disease: diabetes mellitus, Crohn’s disease, Multiple
sclerosis)
 Mitochondrial disorders
 Somatic mutations (cancer)
1. Autosomal dominant disorders (neurofibromatosis, tuberous sclerosis,
polycystic kidney disease, familiar polyposis coli, hereditary
spherocytosis,
Marfan
syndrome,
osteogenesis
imperfecta,
achondroplasia, familiar hypercholesterolemia)
2. Autosomal recessive disorders (cystic fibrosis, phenylketonuria,
homocystinuria, hemochromatosis, sickle cell anemia, thalassemia,
alkaptonuria, neurogenic muscular atrophies)
3. X-linked disorders - (Duchenne muscular dystrophy, glucose-6phosphate dehydrogenase deficiency, hemophilia)
Genetic disorders
 Multifactorial (common)
- “Environmental” influences act on a genetic predisposition to produce a
liability to a disease.
- One organ system affected.
- Person affected if liability above a threshold.
 Single gene (1% liveborn)
- Dominant/recessive pedigree patterns (Mendelian inheritance).
- Can affect structural proteins, enzymes, receptors, transcription factors.
 Chromosomal (0.6% liveborn)
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- Thousands of genes may be involved.
- Multiple organ systems affected at multiple stages in gestation.
- Usually de novo (trisomies, deletions, duplications) but can be inherited
(translocations).
Human genome
46 chromosomes
 22 pairs of autosomes
 XY male
 XX female
Chromosomes
 Normal human cells contain 23 pairs of chromosomes
 This includes one pair of sex chromosome XX or XY
 During cell division we can identify chromosomes
 Haploid: set of 23 chromosomes
 Diploid: normal number of 46 chromosomes
 Aneuploidy: less than an even multiple of 23 usually is 45 or 47 and rarely 48,49
 Triploidy: 69 chromosomes
 Mosaicism
 Abnormal in deletion and translocation (balanced and unbalanced)
Chromosome abnormalities account for 50% of all spontaneous miscarriages
and are present in 0,5-1,0% of all newborn infants.
Chromosomal aberrations (cytogenetic disorders)
- alternations in the number or structure of chromosomes
- autosomes or sex chromosomes
- studied by cytogenetics
- cytogenetic disorders are relatively frequent (1:160 newborns; 50% of spontaneous
abortions)
Incidence
 Mosaicism
 The earlier the abortion the more likely to be chromosomal
 50% of spontaneous abortion are chromosomal abnormal
 Mostly triploidy. 45 XO, trisomy 16
 98% of fetus with turner abort
 Generally 6/1000 the incidence of chromosomal abnormalities
 Maternal Age
 At 25 years, 17% of eggs may have chromosomal abnormalities. At 40 years,
up to 74% may contain abnormalities.
 Spontaneous Abortion (Miscarriage)
 Two-thirds of all pregnancies are lost. These miscarriages are called
spontaneous abortions.
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 Genetic mutation causes an estimated 60% of these spontaneous
abortions.
Numerical abnormalities
 polyploidy (3n or 4n) - spontaneous abortion
 aneuploidy
- trisomy (2n+1) - 47 - compatible with life
- monosomy (2n-1) - autosomal - incompatible
with life - sex chromosomal –
compatible with life
euploidy - normal 46 (2n)
Structural abnormalities
 breakage followed by loss or rearrangement
 deletion, translocation
Generally:
 loss of chromosomal material is more dangerous than gain
 abnormalities of sex chromosomes are better tolerated than autosomal
 abnormalities of sex chromosomes sometimes symptomatic in adult age (e.g.
infertility)
 usually origin de novo (both parents and siblings are normal)
Down syndrome (trisomy 21)
DS is the most common autosomal syndrome and shows a strong association
between increasing incidence and advancing maternal age. 95% of all cases are
caused by trisomy 21. Chromosome studies are necessary in all cases so that the rare
but important cases due to unbalanced familial Robertsonian translocations can be
identified.
The incidence in newborns is about 1 in 700, the most common cause is meiotic
nondisjunction of genetic material.
Clinical symptoms
• mental retardation (IQ 25-50)
• small nose, flat face, epicanthal fold
• congenital heart defectspathology
• neck skin folds
• single palmar crease
• skeletal muscle hypotonia
• dental anomalies
• hypermobility of joints
• increased risk of acute leukemias
• mortality 40% until 10Y (cardiac complications)
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Less frequent chromosomal disorders
 Trisomy 13 (Patau syndrome) 1:15000
 Trisomy 18 (Edwards syndrome) 1:8000
Trisomy 13 (Patau syndrome)
Dysmorphic –
cleft lip, cleft palate, holoprocencephaly, postaxial polydactyly
1 in 10,000 livebirths
- Holoprosencephaly
- Polydactyly
- Flexion of the fingers
- facial clef ting
- heart defects
- Scalp defects
- Microcephaly
- Polycystic kidneys
Symptoms:
- Mental and physical retardation
- Skull and facial abnormalities
- Defects in all organ systems
- Cleft lip & large triangular nose
- Extra digits
- Average life expectancy: 6 months (but ½ die in the first month)
Trisomy 18 (Edwards syndrome)
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Symptoms:
• low birth weight
• multiple dysmorphic features
• chin, ears, single palmar crease, clenched hands
• malformations of the brain, heart, kidneys, and other organs
• average life expectancy:
2-4 months, rarely survive beyond 1 year.
1 in 8,000 live births
• Microcephaly
• Mental and physical retardation
• Poor muscle tone
• Defects in all organ systems
• Heart defects
• Coloboma
• Horseshoe kidney
• Flexion of the fingers
The phenotypes associated with sex chromosome trisomies are less severe than
those associated with autosomal trisomies.
Turner syndrome
• Most common monosomy : 45,X
• Great variability in phenotype
• Most frequently results from loss of paternally derived sex chromosome (X)
• Mosaicism frequent (presence of two or more cell lines, each with a different
karyotype
(Examples: mos 45,X/46,XX mos 45,X/46,XY)
Infancy
• Swelling of the nape of the neck, webbing
• Edema of dorsum of the hand and foot
• Cystic hygroma
• Congenital heart disease
• Preductal Coarctation of the aorta & bicuspid aortic valve most
important cause of mortality
Pterygium coli
Excess neck skin
Lymphedema
Individuals are very short, they are usually infertile
Failure of secondary sex characteristics to develop Genitalia-infantile
Characteristic body shape changes include:
• a broad chest with widely spaced nipples,
• a webbed neck.
IQ and lifespan are unaffected
Mental status – normal.
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Diagnosis
• Shortness of stature <150 cm in height
• Amenorrhea-single most important cause of primary amenorrhea
(33% of cases of primary amenorrhea )
• Hypothyroidism -auto antibodies to the thyroid gland
• Glucose intolerance, Obesity & Insulin resistance
• Ovaries - atrophic fibrous strands
Cytogenetic analysis is decisive for the diagnosis Turner syndrome
 X-chromatin test is negative;
= simple and inexpensive test screening
 chromosome analysis – essential for diagnosis
 homogeneous monosomy X (50-60%)
 mosaics 45,X/46,XX (25%);
 X chromosome structural abnormalities: isochromosomes, deletions, ring crs.
KLINEFELTER SYNDROME (47,XXY)
 often asymptomatic except for sterility, learning disabilities
 small testes; low testosterone levels
 poorly developed male 2o sexual charact.
 some female characteristics:
 enlarged breasts, elongated limbs, increased incidence of
“female” diseases: breast cancer, scoliosis, osteoporosis
 hormone therapy improves symptoms
 47,XXY (85%),
 mosaics 46,XY/47,XXY or polisomy XY (48, XXXY, 49,XXXXY) – 13%.
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Changes in Chromosome Structure
 Changes in the numbers of genes
 deletions
 duplications
 Changes in the location of genes
 inversions
 translocations
 transpositions
 Robertsonian changes
Deletions
Loss of a (generally small) segment of chromosome
 Arise through spontaneous breakage
 some chromosomes have fragile spots
 radiation, UV, chemicals, viruses may increase breakage
 May arise through unequal crossing over
Abbreviations
Deletions in Humans
 Wolf-Hirschhorn syndrome (4p-)
 Cri-du-chat syndrome (5p-)
 Angelman syndrome
 Micro deletion of chromosome 15
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 Prader-Willi syndrome
 Micro deletion of chromosome 15
 DiGeorge syndrome
 Micro deletion of chromosome 22
Wolf-Hirschhorn (4p-) Syndrome
 FREQUENCY 1/50,000 BIRTHS
 2F : 1M SEX PREDILECTION
Greek warrior helmet appearance of the nose,
Microcephaly, Hypertelorism, Distinct Mouth, Short philtrum, Micrognathia,
Mental retardation, IUGR/postnatal growth retardation, Hypotonia,
Seizures, Feeding difficulties.
50% to 75%
Distinctive EEG abnormalities
Skeletal anomalies
Abnormal teething
Ptosis 25% to 50%
Heart defects
Hearing defects
Eye/optic nerve defect
Stereotypies
Cleft lip/palate
Structural brain anomalies
Genitourinary tract defects
Cri-du-chat syndrome
46,XX,5p46,XY,5p(Involves a missing piece of the short arm of chromosome 5 (5p-))
 Mental retardation
 Microcephaly
 Round face
 Congenital Malformations
 Laryngeal anomaly leading to cry sounding like cat (infants)
Prader-Willi and Angelman Syndromes (microdeletion of 15)
Prader-Willi
lack of muscle tone in newborn
poor swallowing reflex
as adult - gross obesity
 mean I.Q. ~ 50
Angelman Syndromes
 developmentally delayed
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



jerky movements
stiff, fixed smile
uncontrolled laughter
abnormal E.E.G., epilepsy
Prader-Willi syndrome
Clinical Features
PWS can be thought of as a Two-stage Disorder
Stage 1 – Infancy Stage
 Low birth weight and subsequent failure to thrive
 Severe muscle weakness (hypotonia), excessive sleepiness
 Suck/swallow problems, reflux, respiratory problems
 Subtle dysmorphic facial features such as “triangle” shaped mouth, narrow
forehead, almond-shaped eyes
 Underdeveloped sexual organs (small labia majora in girls, small penis &
undescended testes in boys)
 Delayed motor/physical milestones
Stage 2 – Hunger Stage
 Between ages 2-6, hyperphagia symptoms begin
with a preoccupation with food and/or compulsion
to eat
 Voracious appetite begins as brain does not
receive/process signals of feeling “full”
 Slow metabolic rate causes rapid weight gain
 Low energy level makes it difficult to exercise
 Emotional labiality and behavioral manifestations
Chromosome 22q11 Deletion Syndrome
DiGeorge syndrome (Velocardiofacial syndrome)
 Most common autosomal deletion syndrome (incidence ~1:3,000.
 Compare to Cri-du-chat 1:20-50,000)
 Well recognized syndrome diagnosed by geneticists, cardiologists,
otolaryngologists
 Significant number diagnosed in adulthood
 Abnormalities of palate including clefts (velo)
 Cardiac malformations (frequently septal defects)
 Unusual facial features
1. Long face
2. Flattened cheeks
3. Dark circles under eyes
4. Prominent nose
Other Features

Learning disabilities/Mental retardation
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



Long slender fingers
Neuropsychiatric abnormalities
Can be associated with DiGeorge sequence (T-cell immune deficiency,
hypercalcemia)
Caused by deletion 22q11.2
In addition to reviewing a patient's family, medical and developmental history,
observations made during a clinical evaluation might also lead you to conclude that
your patient should be referred for a genetic consultation. While major malformations
are obvious at birth and often result in an immediate referral for a genetic evaluation,
minor malformations may go unnoticed as they have no clinical consequence.
However, it is the recognition of these minor malformations that might lead to the
early detection of a genetic condition and prompt intervention for the child and
family.
Assessing a person's body proportion (the length of the arms and legs relative
to the trunk) may provide important information. The midpoint of the body is at about
the level of the umbilicus in the newborn. As a child grows, this shifts downwards so
that by maturity the midpoint is at the upper border of the symphysis pubis. The ratio
of the upper segment (head to symphysis pubis) to the lower segment (symphysis
pubis to floor) is about .92, indicating that the legs are slightly longer than the trunk.
The arm span is usually equal to the standing height.
Achondroplasia (a-absence, chondro-cartilage, plasia-growth) is a common
form of dwarfism. Since achondroplasia affects mainly cartilaginous bones (arms and
legs), the sitting height is normal while the standing height is short. Associated
features include trident fingers, prominent forehead, a large skull, and saddle-shaped
nose (on side view). This is an autosomal dominant disorder. Another form of
dwarfism that was formerly included in the spectrum of achondroplasia is dystrophic
(twisted limb) dwarfism. However, this is now recognized as a distinct entity with
associated clubfeet, "cauliflower" ears and "hitchhiker" thumbs. Diastrophic
dwarfism is an autosomal recessive disorder.
As discussed in the previous section on Mendelian inheritance, an autosomal
dominant disorder due to a new mutation can mimic an autosomal recessive disorder
(in both cases an affected child would have normal parents). If a child has
achondroplasia secondary to a new mutation, the risk of recurrence in future sibs
would be negligible. In dystrophic dwarfism, the risk of recurrence for a couple
would be 25%. This difference in risk recurrence clearly illustrates the importance of
an accurate diagnosis (made possible by the different minor malformations associated
with each disorder) in risk counseling.
The converse of short stature is tall stature, a clinical feature seen in patients
with Marfan syndrome. Individuals with this condition are taller than average, with
long arms and legs relative to trunk. Affected individuals may also have lax joints,
arachnodactyly (spider-like long fingers), cardiovascular abnormalities, including
aneurysm (ballooning or dilatation) of the aorta and aortic insufficiency (dilatation of
the ring at the base of the aortic valve allowing a backflow of blood), and dislocated
lens.
17
When all three cardinal features are present, the diagnosis is relatively easy to make.
A family history showing first or second degree relatives with features of this
condition is also helpful in making the diagnosis in the proband. Problems in
diagnosis arise in young children who do not have a family history of Marfan
syndrome, as the syndrome is not yet fully developed or expressed. This points to the
importance of follow-up. As more clinical features develop with age, the diagnosis
becomes definitive over time.
Facial features provide important clues to diagnosis. Measurements are taken
of the inner canthal distance, outer canthal distance and interpupillary distance
(between the inner corners of the eye, the outer corners of the eye and the pupils,
respectively). These measurements are then compared with established norms. The
palpebral fissures (eye slits) should be on a horizontal plane rather than upslanting or
downslanting. The length of the palpebral fissure is usually equal to the distance
between the inner corners of the eyes. Hypotelorism refers to eyes that are close
together. Hypertelorism refers to eyes that are far apart. Epicanthic fold refers to a
fold of skin that overlies the inner comer of the eye. The nose can be variously
described as short or long (from root to tip) with a high, low or wide nasal bridge, or
upturned nares. Measuring from the nasal bridge to the upper lip, the nose should
equal 2/3 to 3/4 of this length. The ears may be low-set, posteriorly rotated or
prominent. Normally, the ear should be transected by an imaginary horizontal line
drawn from the outer corner of the eye. The lips can have a full or thin vermilion
border, a tented shape, down-turned comers or a cleft. The philtrum, on the upper lip,
is bounded by ridges that run from under each nostril marking the fusion of the
premaxilla and the lateral maxillary processes. The philtrum may be flat. The palate
can be intact, high arched, or cleft. The chin can be prominent (prognathic) or small
(micrognathia).
There are also established norms for head size as it increases with age.
Microcephaly refers to a head circumference less than the 2nd percentile.
Macrocephaly refers to a head circumference greater than the 98th percentile. The
head shape can also be abnormal because of craniosynostosis (early closure of the
skull sutures). The head shapes include brachycephaly (short front to back),
scaphocephaly (long front to back), and trigonocephaly (triangular shape). These are
best assessed by looking directly downwards at the top of the head.
The diagnosis of fetal alcohol syndrome is partly based on craniofacial features
which include microcephaly, telecanthus, narrow palpebral fissures, thin lips and a
flat philtrum, with or without cleft lip or palate. Facial abnormalities figure
prominently in the diagnosis of malformation syndromes because the modeling of the
face (and for that matter, the hands and the feet) is a complicated process that occurs
over time, is governed by numerous genes, and is subject to extraneous influences.
Abnormalities of the hands (and feet) include brachydactyly (short fingers, the
length of the third finger is normally equal to the width of the palm), arachnodactyly
(long fingers), clinodactyly (incurved digits, usually the fifth), syndactyly (fusion of
digits, usually third and fourth for the fingers and second and third for the toes),
polydactyly (extra digits), and other asymmetric abnormalities of the fingers and toes
18
with or without dysplastic nails. All fingers have two creases except for the thumb
which has one. Occasionally the fifth digit has only one crease because of a small
middle phalanx. The palm has two horizontal creases and an oblique crease created
by thumb to finger apposition. These creases are usually present by the twelfth week
in utero. In Down syndrome, because of short hand and finger bones, it is not
uncommon to have a single flexion crease on the palm (simian line) and the fifth
fingers along with brachydactyly and clinodactyly of the fifth fingers.
Skin and hair abnormalities are important. Pigmentary abnormalities such as
hemangioma (strawberry birthmarks), cafe-au-lait spots (brown spots), and streaks or
whorl-like pigmentation need to be noted. Hair abnormalities such as localized areas
of alopecia (absent hair on the scalp), synophrys (fused eyebrows), a low posterior
hairline on the nape of the neck, a white forelock or hirsutism (excess hair) over the
face, shoulders or lower back can serve as important diagnostic clues.
Abnormalities of the spine are usually major malformations that are readily
apparent at birth such as anencephaly (absent skull and brain), encephalocele (cranial
defect with the brain extruding into an external sac), and myelomeningocele (spine
defect with the spinal cord and membranes extruding into an external sac). A milder
form of spine abnormality, spine bifida occulta, refers to a hidden spine defect
apparent only because a tuft of hair is present on the overlying skin along with a
waddling or abnormal gait. This belongs to a group of conditions referred to as neural
tube defects which has been discussed previously in the section on multifactorial
traits and prenatal diagnosis.
The shape, size and symmetry of the chest and breast bone is often altered in
skeletal dysplasias. Pectus carinatum (forward projection of the sternum resembling
the keel of a boat) or pectus excavatum (an indention at the lower part of the chest)
are two common alterations. The position of the nipple is normally directly below the
mid point of the collar bone. Widely spaced nipples and a broad chest are features
seen in Turner syndrome. Breast development in males or the lack of development in
females may be useful clues to an underlying genetic syndrome.
The abdomen may show abdominal wall defects including omphalocele (a
dilated umbilical ring with intestine herniating into the cord), and gastroschisis (a
muscle and skin defect with the intestine externalized and the umbilical cord to one
side). Should these abnormalities be noted on an ultrasound examination in
pregnancy, it is important to know that an omphalocele is often associated with a fetal
chromosome abnormality and an amniocentesis is recommended. Umbilical or
inguinal hernias are associated with a number of known genetic conditions.
Hepatosplenomegaly is a common finding in children with storage diseases.
The genitalia should be definitively male or female. Large testes are seen in
males with fragile X syndrome, and small testes are common in Prader-Willi
syndrome. Delayed development of the secondary sexual characteristics is common
in both Turner syndrome and Klinefelter syndrome. Ambiguous genitalia is observed
in children with a number of different genetic disorders. It should result in a genetics
referral in the newborn period to rule out life threatening congenital adrenal
hyperplasia (CAH).
19
It is important to emphasize that a solitary minor malformation should not cause
undue concern. Single minor malformations are seen in 13.4% of newborns, and only
3% of these children will have a major malformation. However, two minor
malformations are seen in 0.8% of newborns and are associated with an 11% chance
of a major malformation, and three or more minor malformations are seen in 0.5% of
newborns and are associated with a 90% chance of a major malformation. The
presence of a number of major and minor malformations in a child with failure to
thrive, short stature, microcephaly or developmental delay is highly suggestive of a
chromosomal disorder or a malformation syndrome and should result in a genetic
consultation.
In addition to noting minor malformations, it is also important to assess an
individual's psychomotor development during a physical examination by careful
observation or the use of formal assessment tools. If a delay is noted, it is important
to document whether a skill was acquired then lost. The loss of ability may be
associated with a number of inborn errors of metabolism or adult onset
neurodegenerative disorders.
Syndrome describes a group of major and minor abnormalities that are
associated frequently enough to be clinically recognizable as a specific entity. When
attempting to understand the relationship between a diverse set of major and minor
abnormalities, it often helps to consider the underlying developmental pathology.
These include malformation, deformation and disruption.
Malformation refers to a primary defect in the cells or tissue forming an organ
or organ system. The defect may be caused by an abnormality in a gene, a group of
genes, or a chromosome. A number of syndromes fall into this category:
chromosomal abnormalities such as Down syndrome, trisomy 18, cri-du-chat
syndrome; single gene disorders such as Apert syndrome and Marfan syndrome; and
multifactorial traits such as congenital heart defects and cleft lip and palate.
Deformation refers to intrinsic or extrinsic biomechanical forces acting on the
fetus to cause a structural abnormality. A prolonged breech presentation can cause
congenital dislocation of the hip, clubfeet and a flattened, elongated "breech head".
These are usually benign and, with the constraints removed, can be corrected. Realize
that a primary malformation can lead to a secondary deformation. An obstructed
urethra causing oligohydramnios (deficient amount of amniotic fluid which is mainly
fetal urine) leads to flattened facial features and arthrogryposis (fixed joints). The risk
of recurrence will depend upon the initiating event.
Disruption refers to the breakdown of a normally formed tissue or structure.
Limbs can be amputated by an amniotic band. Porencephalic cysts (fluid filled
cavities within the brain) can follow a blood clot within a cerebral blood vessel.
When a cascade of effects can be shown to occur as the result of a primary
defect the term sequence has been used. An example is the oligohydramnios sequence
just described which can lead to dilated ureters and enlarged cystic kidneys. Another
example is the Robin sequence, where a very small jaw leads to the upward
displacement of the tongue which prevents the palate from closing, leading to
mierognathia, cleft palate, and glossoptosis (posteriorly displaced tongue that can fall
back and obstruct respiration and swallowing).
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Monogenic (mendelian) disorders
mutation of 1 gene, mendelian type of inheritance
today about 5000 diseases
Autosomal dominant
Autosomal recessive
X-linked
Biochemical and molecular basis of single-gene disorders
1. Enzyme defects and their consequences
2. Defects in receptors and transport systems
3. Alterations in structure, function or quantity of nonenzyme proteins
4. Genetically determined adverse reactions to drugs.
Some single gene disorders
Commonly used pedigree symbols
21
Single gene disorders
- High risks to relatives
- Dominant/recessive pedigree patterns
- Some isolated cases due to new dominant mutations
- Structural proteins, enzymes, receptors, transcription factors
Characteristics of Autosomal Dominant Disorders
 each affected person has an affected parent (exceptions!)
 each child of an affected parent has 50% risk to inherit trait.
 unaffected family members do not transmit phenotype to children (exceptions
again).
males and females equally likely to transmit the trait, to children of either sex. In
particular, male-to-male transmission does occur (in contrast to sex-linked dominant
inheritance).
 phenotype appears in every generation
 new mutations relatively common
Marfan syndrome
 Abnormal protein fibrillin and impairment of collagenous and elastic tissue decreased firmness of connective tissue.
 Principal clinical manifestations
1. Skeleton slender:
 elongated habitus,
 long legs, arms and fingers (arachnodactyly) - El Greco
 high, arched (Gothic) palate
 hyperextensibility of joints,
 spinal deformities, pectus excavatum, pigeon breast,
2. ocular changes
 dislocation or subluxation of the lens (weakness of suspensory ligaments)
3. cardiovascular system
• fragmentation of elastic fibers in tunica media - aorta
• aneurysmal dilatation - aortic dissection - rupture (35-45% of pts.)
• incompetence (dilatation) - aortic valve
• tricuspidal and/or mitral valve - floppy valve
Achondroplasia
Gene mutation in FGFR3, Хр 4p16.3.
-
short limbs,
a normal-sized head and body,
normal intelligence
Apert syndrome: AD – FGFR2 mutation
Clinical symptoms
22
Craniofacial dysmorphy:
clover shaped cranium,
high forehead, flat occiput, hypertelorism, deep nasal root, small, beaked nose, cleft
palate
Syndactyly, small muscular VSD
Familial hypercholesterolemia
 (= subgroup of hyperlipoproteinemia)
 most frequent mendelian disorder - 1:500
 mutation of gene encoding LDL-receptor (70% of plasma cholesterol)
 heterozygotes 2-3× elev. of plasma cholesterol levels
 homozygotes 5× elevation of plasma cholesterol levels
 heterozygotes asymptomatic until adulthood - xanthomas along tendon sheets,
coronary AS
 homozygotes - xanthomas in childhood, death due to MI by the age of 15Y
Neurofibromatosis (NF 1)
Recklinghausen diseases - common disorder of
the nervous system.
1. Multiple benign fleshy tumors (neurofibromas) in the skin.
2. Multiple flat, irregular pigmented skin lesions known as café au lait spots.
3. Small benign tumors (hamartomas) on the iris of the eye – Lisch Nodules
4. Less frequently, mental retardation, CNS tumors,
diffuse plexiform neurofibormas and the development
of cancer of the NS or muscle.
Huntington’s Disease
HD is a neurodegenerative disease characterized by progressive dementia and
abnormal movements.
Symptoms: develop btwn. 35-50 yrs. old
- Depression
- Personality changes
- Mood swings
- Memory loss
- Involuntary movements
- Progressive dementia
Characteristics of Autosomal Recessive Disorders
 majority of mendelian disorders
 only homozygotes are affected, heterozygotes (parents) are only carriers
 25% of descendants are affected
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 if the mutant gene occurs with low frequency - high probability in
consanguineous marriages
 onset of symptoms often in childhood
 frequently enzymatic defect
 testing of parents and amnial cells
Phenylketonuria
General description:
- Autosomal-recessive
- Absence of enzyme phenylalanine-hydroxylase (PAH) Phe ->Tyr.
- Increase of plasmatic Phe since birth - rising levels - impairs brain development.
- After 6M - severe mental retardation - IQ under 50
- Decreased pigmentation of hair and skin - absence of Tyr
- EARLY SCREENING TEST!!!
PKU Test (blood taken from baby’s heel)
Treatment: Special diet
in first 7 years of life
Cystic fibrosis
 Cystic fibrosis is a heterogeneous recessive genetic disorder with features that
reflect mutations in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene.
 1:2000 live births - most common lethal genetic disease in white population
 defect in the transport of chloride ions across epithelia - increased absorption
of Na+ and water to the blood
 widespread defect in the exocrine glands - abnormally viscid mucous
secretions
 blockage of airways, pancreatic ducts, biliary ducts
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 Pancreatic abnormalities (85%) - dilatation of ducts, atrophy of exocrine part,
fibrosis
 Pulmonary lesions - dilatation of bronchioles, mucus retention, repeated
inflammation, bronchiectasis, lung abscesses, emphysema and atelectasis
(100%), cor pulmonale chronicum
 GIT - meconium ileus (newborns) (25%), biliary cirrhosis (2%)
 Male genital tract - sterility (obstruction of vas deferens, epididymis, seminal
vesicles) (95%)
Clinical symptomatology
 recurrent pulmonary infections
 pancreatic insufficiency, malabsorption syndrome (large, foul stool),
hypovitaminosis A, D, E, K, poor weight gain
 high level of sodium in the sweat - "salty" children - mother's diagnosis
 death usually in 3. decade due to respiratory failure
Gaucher disease (AR) defect of glucocerebrosidase, mutation 1q21-31
defect of glucocerebrosidase - 3 types (type 1 - survival, type 2 - lethal, type 3 intermediate) accumulation of glucocerebroside (Glc-ceramide) - kerasin
Gaucher cells - spleen (red pulp), liver (sinuses), bone marrow
Wilson’s Disease
• Progressive lenticular degeneration
• Autosomal recessive disorder
• Affects copper metabolism
• Leads to organ damage, specifically of the liver and brain, due to buildup of
copper
• Easily treated if diagnosed early
• Difficult to diagnose.
Signs and Symptoms
Generally begin between 1st – 3rd decade
Very variable and nonspecific
Liver disease – more common in adolescents (ages 8-16)
“Neuropsychiatric disease” – more common in young adults (very rare before age
12).
Ehlers-Danlos syndrome
 similar to Marfan syndrome
 genetic defect of collagen fibrils - several types - both autosomal dominant and
recessive
 hyperextensibility of skin, hypermobility of joints - contortionist!
 joint dislocations, vulnerability
 rupture of large vessels, colon, cornea
Albinism - Autosomal-recessiv inheritance, complete lack of melanin.
Patients are unable to produce skin or eye pigments, and thus are light-sensitive.
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Niemann-Pick disease
 defect of sphingomyelinase
 accumulation of cholesterol and sphingomyelin in spleen, liver, BM, LN, lungs
- massive visceromegaly
 CNS (foamy cells) - severe neurological deterioration
 death during first 4-5 years
Mucopolysacharidoses
 MP synthesized in the connective tissue by fibroblasts - part of the ground
substance
 several clinical variants (I-VII)
 involvement of liver, spleen, heart (valves, coronary arteries), blood vessels
 Symptoms: coarse facial features (gargoylism), clouding of the cornea, joint
stiffness, mental retardation
 usually death in childhood (cardiac complications)
 most frequent Hurler syndrome and Hunter syndrome (X-linked)
X-linked diseases
 transmitted by heterozygous mother to sons
 daughters - 50% carriers, 50% healthy
 sons - 50% diseased, 50% healthy
 Children of diseased father - sons are healthy, all daughters are carriers
Hemophilia A (defect of Factor VIII)
Hemophilia B (defect of Factor IX)
Muscle dystrophy (Duchen disease)
Hemophilia A is the oldest known hereditary bleeding disorder.
 Caused by a recessive gene on the X chromosome.
 The severity of hemophilia is related to the amount of the clotting factor in the
blood. About 70% of hemophilia patients have less than one percent of the
normal amount and, thus, have severe hemophilia.
 One can bleed to death with small cuts.
Duchenne muscular dystrophy
 Sex-Linked Disorders in Humans
 Duchenne muscular dystrophy, affects about one out of every 3,500 males
born in the Republic of Moldova.
 People with Duchenne muscular dystrophy rarely live past their early 20s.
 The disease is characterized by a progressive weakening of the muscles and loss
of coordination.
 Researchers have traced the disorder to the absence of a key muscle protein
called dystrophin and have tracked the gene for this protein to a specific locus on
the X chromosome.
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Congenital malformations
 structural defects present at birth - some may become apparent later!
 etiology is either genetic or environmental
 viral infections (rubella, CMV) - during first 3M
 other infectious (toxoplasmosis, syphilis, HIV)
 drugs (thalidomide, alcohol, cytostatics)
 irradiation
 in 40-60% is the cause unknown!
Four major factors that induce congenital malformations:
1. Chromosomal abnormalities,
2. Abnormalities of individual genes,
3. Intrauterine injury by drugs, radiation, maternal infection, or environmental
factors,
4. Environmental factors acting on a genetically predisposed embryo.
Etiology of Congenital Malformations in Humans:
Maternal Infections
o Toxoplasmosis - Hydrocephalus, blindness, mental retardation
o Varicella - Skin scarring, limb reduction defects, muscle atrophy, mental
retardation
o Cytomegalovirus - Growth and developmental retardation, microcephaly,
hearing loss, occular abnormalities
o Herpes (Primary) - Pregnancy loss, growth retardation, eye abnormalities
o Herpes (Active) - Vertical transmission at delivery
o Chemicals
 Maternal Disorders
o Insulin Dependent Diabetes Mellitus - Congenital heart defects, caudal
deficiency, neural tube defects, limb defects, holoprosencephaly, pregnancy loss
o Hypo/Hyperthyroidism - Goiter, growth and developmental retardation
o Phenylketonuria - Pregnancy loss, microcephaly, mental retardation, facial
dysmorphism, congenital heart defects
o Hypertension - Intrauterine growth retardation
o Autoimmune Disorders - Congenital heart block, pregnancy loss
o Reproductive Toxins, Therapeutic Radiation - Growth and developmental
retardation, microcephaly
o Cigarette Smoking - Pregnancy loss, low birth weight
o Hyperthermia - Neural tube defects
o Chronic Alcoholism Growth and developmental retardation, microcephaly,
craniofacial dysmorphism
Congenital abnormalities account for 20-25% of perinatal deaths.
Now, many genetic and other disorders can be diagnosed early in pregnancy.
Prenatal diagnosis uses various noninvasive and invasive techniques
27
Mitochondrial Disorders
This type of inheritance, also known as maternal inheritance, applies to genes in
mitochondrial DNA. Because only egg cells contribute mitochondria to the
developing embryo, only mothers can pass on mitochondrial conditions to their
children.
An example of this type of disorder is
Leber's Hereditary Optic Neuropathy.
Disorders with multifactorial inheritance (polygenic)
 influence of multiple genes + environmental factors
 relatively frequent
 Diabetes mellitus (see Endocrine pathology)
 Hypertension (see Circulation)
 Gout (discussed here + see Crystals)
 Schizophrenia (Psychiatry)
 Congenital heart disease - certain forms (see Heart)
 Some types of cancer (ovarian, breast, colon) (see Neoplasms)
 often familial occurrence - probability of disease is in 1st degree relatives about
5-10%; 2nd degree relatives - 0,5-1%
Genetic Counseling
Genetic counseling is the process through which a geneticist provides
information about genetic conditions, diagnostic testing, and risks in other family
members, within the framework of nondirective counseling.
- the process by which patients or relatives at risk of a disorder that may be hereditary
are advised of the consequences of the disorder, the probability of developing or
transmitting it, and of the ways in which this may be prevented, avoided or
ameliorated.
 communication process
 address individual concerns relating to development / transmission of
hereditary disorder
 consultand = individual who seeks genetic counseling
 strong communicative and supportive element so that those who seek
information are able to reach their own fully informed decisions without undue
pressure or stress
What Information should be provided?
- medical diagnosis and its implications in terms of prognosis and possible treatment
- mode of inheritance of disorder and the risk of developing and/or transmitting it
- choices or options available for dealing with the risks
Prenatal diagnosis
Prenatal diagnosis is recommended in the following cases:
 The pregnant woman is 35 years or older at the time of delivery.
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She or her parents have had a previous child with a chromosomal abnormality.
She has a history of recurrent abortions, or her husband's previous wife
experienced several miscarriages.
A history of parental consanguinity is present.
The couple is known to be carriers of a chromosomal translocation.
The pregnant woman is affected with type 1 diabetes mellitus, epilepsy, or
myotonic dystrophy.
She is exposed to viral infections, such as rubella or cytomegalovirus.
The mother is exposed to excessive medication or to environmental hazards.
In her or her spouse's family, a history of Down syndrome or some other
chromosomal abnormality is present.
A history of single gene disorder is present in her or her spouse's family.
Invasive and Noninvasive techniques
• amniocentesis - analysis of amniotic fluid
• cytogenetic analysis (karyotype - e.g. Down)
• biochemical analysis (α-fetoproteine, β HCG)
• analysis of various specific genes (CF gene - PCR)
• sex of the fetus (X-linked disorders - hemophilia)
Noninvasive techniques
 Fetal visualization - Ultrasound
 Screening for neural tube defects (NTDs) - Measuring maternal serum alphafetoprotein (MSAFP)
 Screening for fetal Down syndrome
 Measuring MSAFP
 Measuring maternal
unconjugated estriol
 Measuring maternal
serum beta-human chorionic
gonadotropin (HCG)
Fetal visualization - ultrasound is a noninvasive procedure for imaging fetal
anatomy. It is harmless to both the fetus and the mother.
Ultrasound can evaluate gestational age, as well as identify twins;
fetal position; placental location;
fetal growth, development, and movement; and any structural birth defects.
It also can assess amniotic fluid volume.
Nuchal Translucency
 Timing: 11-14 wks EGA
 NT measurement > 3. 5 mm associated with increased risk of
- Chromosomal abnormalities
- Structural anomalies
- SAB, SGA, stillbirth
29
 Down syndrome detection rate 64-70%
 Many fetal organ systems and anatomical lesions, including some
genitourinary, gastrointestinal, skeletal, and central nervous system
abnormalities and congenital cardiopathies, can be visualized by ultrasound
between 16-20 weeks' gestation.
 Ultrasound also is used to guide invasive sampling, such as amniocentesis and
various fetal biopsies.
Biochemical analysis
(α-fetoproteine, β HCG)
 Maternal serum screening for alpha-fetoprotein can indicate the presence of a
neural tube defect (anencephaly, spina bifida) or other abnormalities.
 The MSAFP test has the greatest sensitivity between 16-18 weeks' gestation,
but it also can be performed between 15-22 weeks' gestation.
Invasive techniques
Amniocentesis is a procedure in which a needle is placed into the amniotic cavity
and a fluid sample is withdrawn. This fluid can be analyzed biochemically and also
provides cells for culture and genetic analysis (cytogenetic & molecular
investigations).
Chorionic villus sampling (CVS) involves aspirating a tissue sample directly
from the placenta to obtain cells
for genetic analysis.
Literature:
1. Emery’s elements of medical genetics. Robert F. Mueller, Ian D. Young,
churchill livingstone, 1995
2. Chromosomes abnormalities and genetic counselling. Gardner RJM, Sutherland
G.R., 1989, Oxford University Press, Oxford.
3. Molecular biology in medicine – Timothy M. Cox, John Sinclair , 1997.
4. Basic Dysmorphology. Virginia P. Johnson, MD, Carol Christianson, MS
University of South Dakota, School of Medicine. Peer Review Status: Internally
5. Internet
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