Methodical recommendations

for practical lesson of medical genetics for 5th year students of medical faculty

Content chapter 2 Propedeutics of the hereditary pathology. Methodic of phenotype

description. Syndromologic analysis. Clinical-genealogical method.

The topic of the lesson: SEMIOTIC OF HEREDITARY DISORDERS.

The purpose of the lesson: to get the practical skills of examination the
patient with the aim of diagnostics of hereditary disorder. To became acquainted with
the structure of medico genetical center.
Student should know:
1. What is hereditary disorder.
2. Classification of hereditary disorders.
3. History data pointing out hereditary pathology.
4. Main congenital anomalies.
5. Tasks of medico-genetic counseling.
6. Organization of medico-genetic aid in Ukraine.
Student should be able to:
1. Reveal most common congenital micro anomalies while examining the patient
or studying the photos of the patients.
2. Analyze the history of the diseases and reveal the symptoms indicating
hereditary pathology.
CONTROL QUESTIONS
1. Aim of the medico-genetic counseling. Principles of organization of
medico-genetic aid to the population.
2. Classification of hereditary disorders.
3. Syndromologic diagnostics in practice.
4. Describing of the phenotype of the patient with hereditary disorder.
5. Definition of congenital micro anomalies and defects and its role in
diagnostics of hereditary disorders.
 6. Main micro anomalies and defects of head face trunk, limbs, skin and its
derivatives.
7. Peculiarities of the clinical features of hereditary disorders.
8. General principles of diagnostics of hereditary disorder.
9. Manifestation of hereditary disorder in different age groups.
10. Main genetic terms: gene, genotype, phenotype, allele genes,
homozygote, heterozygote, dominant gene, recessive gene, recessive character,
proband, siblings.
PRACTICAL WORK
1.To analyze phenotype of the patient, name congenial micro anomalies and
defects.
2. To analyze the case history and name the characters, indicating hereditary
disorder.
3. To study phenotypes of the patients with hereditary disorders, using photos
of the patients with different hereditary diseases. Name the micro anomalies and
congenital defects.

MAIN LITERATURE:
Manuals on medical genetics

ADDITIONAL REFERENCES:

1. Ian.D Young/ Medical genetics. -2nd ed. -Oxford university press. - 304 p.

2. M.R. Speicher, S.E.Antonarakis, F.G. Motulsky. Vogel and Motulsky’s human genetics.
Problems and approaches. 4th addition. – 2010. –981 pp.

MCQs for self -control

1. Minor congenital anomaly is characterized by all of this except:
А. It is a morphological change
В. It doesn’t influence the function.
С. It is not cosmetic defect.
D. It doesn’t require medical correction.
 Е. It is absent in healthy person .

2. Chromosomal disorders are characterized by skin fold in the internal angle of the eye.
This minor anomaly is termed as:
А. Coloboma.
В. Epicanthus.
С. Criptophtalmos.
D. Synophris.
Е. Microblepharon.

3. Blue sclera and gothic palate are features typical for metabolic defects of:
А. Carbohydrates.
В. Lipids.
С. Amino acids.
D. Connective tissue.
Е. Hemoglobin.

4. Coarse face with abundant hair, thick lips is typical for:

А. Cystic fibrosis.
В. Glycogeosis.
С. Phenylketonuria.
D. Mucopolysaccharidosis.
Е. Marfan’s disease.

5. Underdeveloped chin is typical for many chromosomal disorders. This feature is termed
as:
А. Microgenia.
В. Progenia.
С. Prognatia.
D. Microstomia.
Е. Microcoria.

6. Heiloschisis – is:
А. Eyebrows growing together.
В. Short palpebrae.
С. Cleft palate .
D. Cleft lip.
Е. Small mouth.

7. New born girl has claw-like right hand. This defect is termed as:
А. Phocomely.
В. Arachnodactyly.
С. Syndactyly.
D. Camptodactyly.
Е. Ectrodactyly.

8. A 5-months-old girl with Down’s syndrome has lateral deviation of small finger. This
minor anomaly is termed as:
А. Clinodactyly
В. Arachnodactyly.
С. Syndactyly.
D. Camptodactyly.
 Е. Ectrodactyly.

9.. Boy with Marfan’s syndrome has extremely long slender fingers. This minor anomaly
is termed as:
А. Phocomely.
В. Arachnodactyly.
С. Syndactyly.
D. Camptodactyly.
Е. Ectrodactyly.

10. Mongolian eye slant is:

А. Large distance between inner angles of the eyes.
В. Low situated external angle of the eye.
С. Short eye slant.
D. Low situated internal angle of the eye.
Е. Skin fold in the internal angle of the eye.

11. 12-years-old girl with Turner syndrome has widened neck because of wing-like skin
folds. This feature is termed as:
А. Hypertelorism.
В. Hypotelorism.
С. Pterigium coli.
D. Synophris.
Е. Paltoschisis

12. Boy with cri-de-chat syndrome has widely spaced eyes. This minor anomaly is termed
as:
А. Hypertelorism.
В. Hypotelorism.
С. Pterigium coli.
D. Synophris.
Е. Paltoschisis

13. Newborn child with Apert’s syndrome is characterized by egg-shaped skull. Such
shape of the head is termed as:
А. Brachicephaly.
В. Dolychocephaly.
С. Acrocephaly.
D. Scaphocephaly.
Е. Trigonocephaly.

14. 8-years-old girl with mucopolysaccharidosis have flexor contracted fingers. This
feature is termed as :
А. Phocomely.
В. Arachnodactyly.
С. Syndactyly.
D. Camptodactyly.
Е. Ectrodactyly.

15. Excessive development of mammary gland in man is termed as:

А. Hupertelorism.
В. Polytelia.
 С. Polymastia
D. Gynecomastia.
Е. Hyperplasia.

16. Mental deterioration is the typica feature of:

А. Chromosomal disorders with autosomes abnormalities.
В.Chromosomal disorders of sex chromosomes.
С. Chromosomal aberrations.
D. Glycogenosis.
Е. Sphingolipidosis.

17. Combination of microcephaly, microgenia and low situated abnormally shaped

auricles is typical for
А. Chromosomal disorders.
В. Single gene disorders.
С. Metabolic defects of glycosaminoglycans.
D. Amino aciduria.
Е. Metabolic disorders of connective tissue.

18. Slit-like defect of iris is termed as:

А. Coloboma.
В. Hypertelorism.
С. Hypotelorism.
D. Epicanthus.
Е. Atresia.

19. How many minor anomalia can be normally present?

А. None.
В. 0 to 3.
С. 0 to 6.
D. 0 to 8.
Е. 0 to 10.
MAIN THEORETICAL INFORMATION
Tasks of the medico genetic counseling.
Medico-genetic counseling it is one of the types of specialized medical aid to
the population, directed on the prevention of birth the children with hereditary
pathology. Basic tasks of the medico-genetic counseling are.
1. Exact diagnostics of hereditary disorder.
2. Determining of the type (mode of inheritance) of hereditary disorder in
that particular family.
3. Calculating of the recurrent risk in that particular family.
4. Determining of the most effective way for prophylaxis.
 5. Explanation of collected and analyzed information and prognosis to the
family.
Medico-genetic aid for the population of Ukraine is provided by specialists of
inter-district medico-genetic consulting rooms, regional medico-genetic centers,
inter-regional medico-genetic centers, Ukrainian scientific center of medical genetic,
scientific research center of hereditary pathology in Lvov, and clinical institutes of
the Health department of Ukraine, medical institutes.
Inter-district medico-genetic centers: Are organized on the territory with
population of 300.000 and more. They are placed in the district and regional hospital.
Pediatricians or obstetricians after special training on medical genetics work in it.
They carry out primary diagnostics of hereditary disorders, consultations of the
families and patients with hereditary disorders, registration and monitoring of the
families with hereditary disorders and congenital defects, control of the mass
screening programs.
Regional medico–genetic consulting centers is organized on the basis of
regional or city hospital, its stuff includes specialists in medical genetics
(pediatricians, obstetricians). Center is equipped with cytogenetic and biochemical
laboratory. Apart from medico-genetic counseling of families with hereditary
disorders and co-coordination of inter-district medical consulting centers work,
management of registries, controlling of mass screening programs specialists of the
center actively reveal the patients with hereditary disorders, carry out prenatal ultra
sound diagnostics, cytogenetic, DNA and biochemical diagnostics of hereditary
diseases.
Inter-regional medico genetic-centers provide the specialized aid for
population in diagnosis, prophylaxis and treatment of patients with hereditary
disorders. Apart from specialists in medical genetic (pediatricians and obstetricians)
stuff of the center includes endocrinologist and neurologists after specialization in
field of medical genetics. In center is well equipped cytogenetic and biochemical
laboratory, ultra sound. Center has high possibilities in diagnostics, treatment and
prophylaxis of hereditary disorders. Specialists of the center organize prenatal
diagnostics and carrying out of mass screening programs in the region.
All specialists of medico-genetic service carry out propaganda of medico-
genetical knowledge to the population.
Specialized centers are organized for diagnostics and treatment of mostly
common hereditary disorders like phenylketonuria, cystic fibrosis, hemophilia,
muscular dystrophy and others.
Classification of hereditary disorders.
What is a hereditary disorder?
Hereditary disorder is a disease caused by changes in genotype (mutation).
Students often define hereditary disorder as a disease, which is transmitted in the
family from generation to generations, a disease that should be obligatory inherited
by children from the parents.
As many hereditary diseases may not inherit, this is not the exact definition.
Hereditary disorder often considerably reduces viability or fertility of the patient or is
the result of fresh dominant mutation. For example, as a rule, child with Down
syndrome has healthy parents. On other side, certain endemic diseases are observed
in parents and children and gives impression of inheritance, but they are not
hereditary (endemic goiter).
Terms “hereditary” and “congenital” diseases are also different. As
congenital are known all diseases and defects, manifesting at birth. Hereditary
disorders are not always congenital. Onset of the disease may be after several months
or even a year (mucopolysaccharidosis, hepatolenticular dystrophy, Huntington’s
disease and others). Some congenital defects are because of teratogenic
environmental effect and are nonhereditary.
“Family disorders” are met among members of one family. It may be either
hereditary (usually autosomal-recessive) or nonhereditary (caused by the same
environmental factor like harmful habits, profession, peculiarities of nourishment and
others).
 Classification of hereditary disorders is based on classification of mutation
and character of interaction with the environment. Under modern classification all
hereditary disorders may be divided into following groups.
1. Single gene disorders (monogenic disease) – caused by single gene
mutation (achondroplasy, phenylketonuria, haemophilia and others).
2. Chromosomal disorders caused by numerical or structural chromosome
mutations (Down syndrome, cat cry syndrome and others).
3. Multifactorial disorders (disorders with hereditary predisposition) are the
result of interaction abnormal genotype of the individual and provoking
environmental factors (cleft lip and palate, clubfoot, arterial hypertension,
schizophrenia and others).
4. Genetic disorders of somatic cells – result of somatic mutation
(retinoblastoma, Wilms tumor and some other tumors, certain sporadic case of
congenital defects).
5. Disorders because of mother-fetus genetic incompatibility (hemolytic
anemia because of Rh-conflict or because of incompatibility on other antigens).
Clinical classification is based on the systems and organs principles: psychic,
neuromuscular, skeletal, facial, cutaneous, respiratory, immunity system disorders
and others.
Syndromologic diagnose in clinical genetics.
Hereditary disorders are caused by changing of the genotype, i.e. mutations.
Mutations result in either failure of embryonic development, or disturbance in certain
link of metabolism. In different people certain hereditary disorder usually manifests
with the same clinical features. As a rule it manifests not only as one symptom, but a
definite complex of symptoms. This pattern of symptoms, caused by the same
pathogenesis is known as a syndrome. Knowing the pattern of the symptoms for
certain hereditary disease one may diagnoses the disorder on the basis of phenotype
analysis. So, diagnostics of majority of hereditary disorders is syndromologic. Many
of the hereditary syndromes are diagnosed only on basic characteristic external
features. In many cases portrait diagnostics is carried out. In portrait diagnostics
special atlases of characteristic syndromes (a visual aid to diagnosis), and computer
diagnostic programs are used.
Description of patient’s phenotype is not enough, exact diagnose is very
important in prognosis of viability, choosing of treatment and calculating of recurrent
risk. For example, at patients with Patau syndrome there is no sense to perform
surgical correction of cleft lip, because this syndrome is lethal. Artesia of esophagus
may be isolated congenital defect or symptoms of lethal Di George syndrome. In first
case surgical treatment is indicated, in the second case it is out of sence. Apart from
that, exact diagnose allows to determine mode of inheritance and this is extremely
necessary for calculating of recurrent risk and choosing of prenatal diagnostics
methods.
Term “syndrome” in clinical genetics often uses as a synonym for word
“disease”. One may say “Down disease”, “Patau disease” and “Down syndrome”,
“Patau syndrome”. For many hereditary diseases term “syndrome” traditionally is
used more often: Klinefelter syndrome, Shereshevsky – Turner syndrome, Russell –
Silver syndrome, Cornelia de Lange syndrome and others.

Description of the phenotype of the patient with hereditary disorder

Phenotype is the totality of external and internal signs of the organism.
While describing phenotype of the patient one should pays attention on congenital
defect and minor anomalies.
Congenital defect (or congenital abnormality) is a structural defect of prenatal
origin, present at birth, seriously interfering function, health or viability. As
synonyms of “congenital defect” terms “defects of development”, “malformations”
“birth defects” are used.
Minor anomalies (stigmas of disembryogenesis) are unusual morphologic
features that are of no serious medical or cosmetic consequence. So, these are
morphologic changes of an organ, which don’t require any medical correction.
Number of minor anomalies in healthy child is from 0-6. Following are met
more often: epicanthal folds, high palate, flat nasal bridge, deformation of ear auricles
and others. In hereditary diseases their number increases (in single gene disorders 8 –
15). Presence of multiple minor anomalies suggests a generalized disorder of early
embryogenesis under hereditary or teratogenic factors. The more minor anomalies are
present the more likely is the hereditary disorder. Specific pattern of minor anomalies
forms unique phenotype of the patient. Its recognition is very important in clinical
diagnoses of hereditary disorder.
Examination of the patient starts with the measurement of height, weight and
head circumference. Obtained data is compared with normal age parameters.
Height: - hereditary disorder often accompanies by growth deficiency starting
in embryonic or postembryonic period. Smallness of body is termed as microsomia or
dwarfism. Abnormally large size of the body is observed rarely and termed as
macrosomia or gigantism (Beckwith- Wiedemann syndrome).
Sometimes facial or cranial asymmetry (hemifacial hypertrophy) or
asymmetry of the body (Russell–Silver syndrome) is observed.
Weight: hereditary disease often manifests in embryonic period that results
in hypotrophy and hypoplasia of newborn. Hypoplasia is inappropriate for gestation
age weight and height of the newborn. Hypotrophy is small weight of the child with
normal height. Decrease in body weight observes in chromosomal disorders, inborn
errors of metabolism, congenital defects of digestive tract and others. Rarely obesity
may be observed (Prader–Willi syndrome and some others).
List of main congenital defects and minor anomalies
1. HEAD, FACE, NECK.
a) abnormal size of the head with more than of 10% deviation comparatively
with age norm: microcephalia (-5cm) or macrocephalia (+5cm).
Hydrocephalus (excessive accumulation of fluid in cerebral ventricles) differs
from macrocephalia with disproportional enlargement of cerebral parts of the
cranium – face is relatively small, large prominent forehead, dilatation of
subcutaneous veins, possible divergence of cranial sutures, enlargement of fontanels.
b) unusual cranial configuration: brachycephalia (disproportionate shortness
of head, flat face), dolichocephalia (disproportionately long head), scaphocephalia
(prominent forehead and occiput), trigonocephalia (triangular configuration of the
skull due to premature synostosis of the cranial bones), acrocephaly or oxycephalia or
turricephaly (tower skull – abnormally high, conically shaped) Premature synostosis
of cranial bones (craniosynostosis) leads to the different deformations of the skull,
like cloverleaf skull.
c) Low (or high) anterior and posterior hairlines.
d) unusual face: Bird-like face (Marfan syndrome), doll face
(glycogenosis), coarse face (mucopolysaccharidosis – abundant thick hair of the
eyebrows, thick lips), triangular face (Russell – Silver syndrome).
e) Small or very high forehead, bulging or sloping forehead.
f) Defect of eyes.
Anophthalmos – absence of one or both eyes; cryptopthalmus – congenital
absence of the eyelids with skin passing continuously from forehead onto cheek over
a rudimentary eye; buphthalmos – enlargement of the eyeball; microphthalmos –
small size of the eyeball.
Anomaly of eyelids: distichiasis or tristichiasis – the presence of two or three
rows of eyelashes on the eyelids; coloboma – slit-like defect, epicanthus - fold of skin
extending from the root of the nose to the inner termination of the eyebrow;
microblepharon – small vertical size of the palpebra, leading to lagophthalmos
(inability to close the eyes), blepharophimosis – shortening of the eye lids and eye
slit; ptosis – drooping of the eyelid, synophrys – the growing together of the
eyebrows.
Blow sclerae; micro- and macrocornea – abnormal size of cornea; coloboma
of cornea; aniridia – absence of iris; heterochromia – irregular distribution of pigment
in one eye or in two eyes, cataract – a loss of transparency of the lens of the eyes;
leukoma – albugo, a dense, opaque, white opacity of the cornea; enophthalmos –
deep position of the in orbital area; exophthalmos – protrusion of the eyeballs.
Mongoloid (external angle over the internal), or anti-mongoloid (external
angle below the internal) slant of palpebral fissures.
 Hypotelorism – narrow spaced eyes; hypertelorism – widely spaced eyes.
Distance between internal angle of the eye normally is equal to the length of the eye
slit.
In hereditary disease also is met glaucoma, divergent or convergent
strabismus, short or long sight, blindness.
g) Anomaly in structure of nose and jaws;
Nasal bridge: depressed, flat, broad, narrow, bulging of the nasal root (Greek
warrior helmet);
Nose: saddle-like, beak-like, potato, small nose with turned-up nostrils.
Hemihypoplasia of the nose, hypoplasia of nasal porch. Distortion of the nasal
septum, hypoplasia and notching of alai nasi, colobomus of nasal wings.
Upper jaw may be underdeveloped (micrognathia) – or vice versa, large, with
abnormal forward projection (prognathism), abnormally small lower jaw is termed as
microgenia, and its overgrowth with forward position of the chin – basilar
prognatism.
Long or short philtrum (distance between the nose and upper lip).
i) Mouth and oral cavity.
Macrostomia and microstomia – large or small size of the mouth; abnormally
thick or thin lips are also the symptoms of hereditary pathology. Cheilo- or
palatoschisis – middle, one or double sided cleft lip or palate.
Changes in number of the teeth: adentia – absence of teeth, oligodentia – less
number of teeth), abnormal shape (conical teeth). Macro- and microdentia –change in
size of teeth, diastema – a space between two adjacent teeth;
amelogenesis imperfecta – enamel dysplasia. Multiple caries. High (gothic) palate.
Macroglossia and microglossia - large tongue.
j) Auricle.
Process of formation of external ear in embryonic development is very
sensitive to the changes of genotype and action of teratogenic factors.
Due to hereditary and congenital pathologies often observed large
(macrotia) or small (macrotia) auricles, high or low position of auricles, large everted
auricules. Normally lower wall of auditory canal is situated on the line between wing
of the nostril and mastoid process of the temporal bone. Often are met: attached ear
lobule, thick ear lobule, preauricular tags or fistulas, stenosis or atresia of auditory
canal, hypo-and hyperplasia of different auricular structures.
Hearing impairment or deafness may also be observed.
k) Neck: - short, wing-like skin fold - pterygium, central or lateral cervical
cysts.
2. TRUNK:
a) deformation of chest and vertebrae column: scoliosis – lateral curvature
of the spine; kyphosis – abnormal curvature of the spine with the convexity
backward(usually in the thoracic region); lordosis – anterioposterior curvature of the
spine, generally lumber, with the convexity looking anteriorly; kyphoscoliosis; flat
spine – absence of physiological curvatures; cobbler’s chest, funnel chest, keeled
(chicken) chest.
b) changes in nipples or mammary gland: absence of nipples – atelia; extra
nipples – polytelia; widely spaced nipples – hypertelorism of nipples; gynecomastia –
excessive development of the male mammary glands.
c) hernias of linea alba, umbilical, inguinal, inguinoscrotal hernias.
d) abnormalities of sexual organ:
in males epispadia and hypospadia – a malformation in which the urethra
opens on the dorsum or on the under surface of the penis; macro- or microphalos-
Crypthorchism – the failure of descent of a testis; in females – hypertrophy of
clitoris; hypo- or hyperplasia of large and small pudendal lips; atresia of vagina.
3. LIMBS
Phocomelia - absence of a proximal parts of the limbs or of the whole limbs;
brachymelia - shortness of limbs; brachydactylia - shortness of fingers; isodactylia -
equal length of fingers; arachnodactylia - long slender fingers; syndactylia
(symphalangism) any degree of webbing or fusion of fingers or toes; clinodactyly –
deflection of one or more fingers; large distance between first and second toes; flat
foot - arches of the foot are flattened; rockerbottom foot - flat foot with prominent
heel; polydactylia – more then five digits; ectrodactylia – congenital absence of one
or more fingers and toes with hand or foot like lobster’s claw;
4. SKIN AND ITS DERIVATIVES (hair, nails, skin glands):
hyperkeratosis – hypertrophy of the horny layer of the epidemis; ichthyosis –
congenital disorder of keratinisation characterized by dryness and fishskin-like
scaling of the skin; albinism - absence or decrease amount of the melanin in skin and
hair; partial hyperpigmentation of skin – nevi (birthmarks); partial hypopigmentation
of skin – leukoderma; angidrosis – dry skin because of sweat glands absence;
hypohydrosis – insufficient function of sweat glands; hyperhydrosis – excessive
function of sweat glands; hypertrichosis - growth of the hair in excess of the normal;
hypotrichosis – a deficiency of hair on the head and body; hirsutism – presence of
excessive bodily and facial hair in women; alopecia – complete or partial absence of
hair on the scalp; hypoplasia of nails; anonychia – absence of nails.

Terms, used for description of the phenotype

Agenesis - absence, failure of formation or imperfect development of any

part;
aplasia - congenital absence of an organ or tissue;
hypoplasia - a) underdevelopment of tissue or an organ, usually due to a
decrease in the number of cells, b) mass and growth of newborn, of corresponding
with the period of gestation;
hypertrophy - an increase in number of cells in tissue or organ, excluding
tumor formation whereby the bulk of the part or organ is increased;
macrosomia — abnormally large size of the body;
pachy – prefix is used to mark the thickness of definitive part of the organ
For example: pachygyria - unusually thick convolutions of the cerebral cortex related
to defective development; pachydactyly - enlargement of fingers or toes;
heterotopy - a displacement of parts of the organs, tissues;
ectopy - congenital displacement of any organ or part of the body;
 duplicitas - doubling of part;
multiplicity of definitive organs is marked with Greek prefix - poly- or Latin
- multi-. For example: polydactyly —the presence of more then five digits an either
hand or foot, polygyria — a condition in which the brain has an excessive number of
convolutions;
atresia - congenital absence of a normal opening or normally patent lumen;
stenosis - a narrowing of any canal;
-pagus - suffix is used to mark conjoined twins. For examples craniopagus
conjoined twins with fused sculls, thoracopagus — conjoined twins with fusion in the
thoracic region;
syn- prefix is used to mark fusion or adhesion of the organs. For example:
syndactylity - any degree of webbing or fusion of fingers or toes, syncheilia —a more
or less complete adhesion of the lips;
persistence - obstinate continuation of existence the embryonic structures
that normally should vanish;

hydro- prefix is used to mark excessive accumulation of fluid dilating the

organ. For example: hydrocephalus - excessive accumulation of cerebrospinal fluid in
cerebral ventricles; hydronephrosis - dilation of the pelvis and calices of one or both
kidneys resulting from obstruction to the flow of urine;
inversion - mirror disposition of internal organs.

Main peculiarities of clinical manifestations of hereditary disorders

Despite a great variety of clinical symptoms all hereditary disorders have
common specific features, which are explained by the action and interaction of genes.
1. Familial character of disease, as a rule, indicates the hereditary disorder.
At the same time presence of the disease only in one person in the family, does not
exclude hereditary character of the disease, as parents of the patient may be
heterozygous carriers of recessive pathological gene. Dominant single gene disorders
may be the result of fresh mutation. Chromosomal disorders usually are also caused
by mutations.
 2. Chronic, progressive, recurrent course.
Pathologic genotype effects constantly. This explains chronic progressive
course (with age of the patient severity of the disease increases). Especially this is
characteristic for storage disorders with reduced catabolism of macromolecules.
3.Congenital character of disease is typical, but not for all of the hereditary
diseases. All chromosomal diseases and nearly 25% of single gene disorders
manifests from the moment of birth. Other starts at different age, from few days to
senile period. On the other side, congenital disease not always is hereditary (for
example, fetal alcohol syndrome, diabetic embryopathy and others).
4. Multiple affection - participating in pathological process of many organs or
even of system of organs makes to think about hereditary pathology. Multiple
affection is explained with pleyotropic action of genes (influence of one gene on the
formation of many signs).
5. Pattern of specific symptoms does not characterizes all hereditary diseases.
But if they are present, it recognition permits to diagnose hereditary pathology in
time. Examples of such specific symptoms are: mice odor of urine and sweat in
phenylketonuria, mewing-like crying of newborns in chromosomal “cat cry”
syndrome and others.
6. Hereditary disorders are resistant for the most traditional methods of
therapy. At present times methods of treatment for some hereditary diseases are
proposed, but they are very much differentiated from methods of treatment for
common non-hereditary diseases.

General principles of clinical diagnostics for hereditary

diseases.

Peculiarity of clinical genetics is that object for examination is not a

particular patient, but whole family. Gathering information about a family starts with
proband. Proband is the patient or member of the family that brings the family under
study. It may be child, adult person or couple. Children of same parents are termed as
sibs (siblings). Family in narrow meaning is a couple and their children, but
sometimes may include other relatives.
 At present time for medico-genetic counseling often come families having
already sick child. In this case medico genetic counseling is known as retrospective.
Diagnostics of hereditary diseases, as a rule has two stages:
1) general clinic examination of the patient, genealogic and laboratory, when
required. (ultra-sound, x-rays examination, endocrinologic, immunologic and other
assays).
2) In suspicion on certain hereditary disorder - special genetic studies like
(cytogenetic, DNA, special biochemical and other assays).
Examination of the patient is carried out in accordance with ordinary
scheme. While taking family history one should pay attention on following
moments.
1. Surname, name, and paternal name of the parents. Maiden surname of
mother should also be ascertained. Coinciding of surnames in paternal and maternal
family may indicate consanguineous marriage. In such marriages risk to have a child
with recessive disorder increases.
2. Age of proband (including date and month of birth). Hereditary disorders
may manifest in different age. Age of the parents at the moment of proband birth is
also important. With paternal age increases probability of fresh dominant mutations
(for example – achondroplasy and neurofibromatosis). With maternal age increases
risk of chromosomal abnormalities.
3. Nationality. Some rare hereditary disorders are relatively common in
certain nationalities. Ethnic backgrounds of the parents may be an indication for
specific carrier testing or genetic screening.
For example are common:
a) in Ashkenazi Jews and Canadians of French origin - Tay-Sachs disease;
b) in Greeks and other inhabitants of Mediterranean region - Beta-
thalassaemia.
c) in Afro-Americans – cycle-cell anemia.
d) in inhabitants of south – eastern Asia - alpha-thalassaemia.
e) in inhabitants of northern Europe and of south of Ukraine – cystic fibroses.
 4. Residence of the family to exclude endemic diseases and influence of the
environmental factors.

5. Residence of maternal and paternal families. If in few generations all

members of the family live in the same small village there is a high probability of
consanguineous marriages.
6. Work conditions. Possible contact with mutagens and teratogens factors
should be taken into account.
7. Kind of military service of the father, possible contacts with mutagen
factors during this period.
8. Chronic diseases of mother. Disorders of cardiovascular and respiratory
systems often leads to fetal hypoxia, which is one of teratogenic factors; diabetes
mellitus causes the risk of diabetic embryofetopathy; treatment for epilepsy includes
many teratogenic anticonvulsants; maternal compensated phenylketonuria if woman
do not keep a diet during the pregnancy, cause phenylpyruvic embryofetopathy.
9. Pathologic obstetric history.
Spontaneous abortions or stillbirth in anamnesis may indicate balanced
chromosomal mutation in either paternal or maternal organisms. Both parents also
may be carriers of the same recessive pathological gene (each person has 4-5
recessive lethal genes in average). Sometimes dominant lethal mutations form de
novo.
10. Loaded family anamnesis. Presence in the consulted family or family of
close relatives children with heredity disorders or congenital defects, and neonatal
death because of unknown reasons indicates hereditary pathology. In all cases of
stillbirth and neonatal deaths is necessary to get the conclusion of pathologist if
possible.
11. Pathologic obstetric symptoms in pregnancy, which ends by giving birth
to proband (patient).
a) Risk of spontaneous abortion is characteristic for chromosomal and many
single gene disorders;
 b) Intrauterine growth retardation may be revealed with ultrasonographic
measurements of head and abdomen circumference. Possible reasons of growth
retardation are: chromosomal syndromes; single gene disorders; intrauterine fetal
infection (cytomegalovirus, rubella, syphilis); ionizing or non-ionizing radiation;
multiple pregnancy; aplasia of pancreas. Growth delay also may be due to the
influence of some maternal factors (smoking, alcohol and others).
Intrauterine growth retardation needs to be distinguished from syndromes
hereditary dwarfism.
c) oligohydramnios is the symptom of different renal disorders with
inadequate fetal urine output and may be teratogenic mechanical factor by itself.
d) polyhydramnios is observed in different defects of gastrointestinal tracts
with swallowing failure.
e) decreased motility of fetus is characteristic for arthrogryposis (limitation of
range of joint motion and contractures present at birth).

Symptoms of hereditary disorder, which can be revealed during the examination

of the patient

While examining the patient it is necessary to pay attention on following

symptoms, indicating hereditary disorder and congenital abnormality.
IN NEWBORNS
1. Congenital malformations may be hereditary (monogenic, chromosomal,
multifactorial) or because of different teratogenic factors.
2. Prematurity of the newborn is typical for mane chromosomal disorders.
3. Hypotrophy or hypoplasia at birth is the symptoms of many chromosomal and
single gene disorders.
4. Macrosomia is observed in Beckwith-Wiedemann syndrome, diabetic
embryofetopathy and others.
5. Minor congenital anomalies (more than 6).
6. Muscular hypotony, and hyporeflexia are the symptoms of neuromuscular single
gene disorders, Down syndrome and others.
7. Convulsions are the symptom of inborn errors of metabolism, defects CNS.
8. Microgenitalism or malformation of genitalia are symptoms of congenital adrenal
hyperplasy, many single gene and chromosomal syndromes.
9. Acid – alkali misbalance (alkalosis or acidosis) are the symptoms of inborn errors
of metabolism.
IN INFANTS
1. Growth retardation is observed in inborn errors of metabolism, chromosomal
disorders, may be a symptom of hereditary dwarfism. Influence of different
teratogenic factors like alcohol and others may cause as prenatal as postnatal growth
delay.
2. Psychomotor retardation. It is a sign of chromosomal disorder if combined with
congenital defects and minor anomalies. Is common in amino acidurias (inborn errors
of amino acid metabolism). May be the symptom of neuromuscular congenital
disease.
3. Mental deterioration is the symptom of storage disease (sphingolipidosis,
leukodistrophy and others).
4. Microcephaly may inherits like recessive disorder or is a symptom of many single
gene and chromosomal syndromes. Sometimes is caused teratogenic factors
(intrauterine infection, hypoxia and others).
5. Macrocephaly may be familial feature or the result of hereditary pathology (fragile
X syndrome, mucopolysaccharidosis, achondroplasia and others).
6. Deviation in physical development.
a) Hypertrophy and asymmetry of face and cranium (syndrome of
hemifacial hypertrophy and others).
b) Hypertrophy and asymmetry of limbs (Russel-Silvers syndrome and
others).
c) Promoted physical growth (Beckwith – Wiedemann syndrome and
others).
 d) Disproportion of trunk and limbs (in Marfan syndrome and
homocystinuria – long slender limbs, in achondroplasy - shortening of
proximal parts of limbs and others).
e) Shortening of trunk in bone anomalies of vertebrae column.
7. Diffuse or local pigmentation defects. Stains on skin of coffee with milk color is
characteristic for neurofibromatosis, hypopigmented stains for tuberose sclerosis,
skin like geographic maps for, plural pigmentation of________________ in
syndrome Basal celled____________ For albinism, ectoderm displasia,
phenylketonuria general hypopigmentation is typical.
8. Unusual smell of sweat and urine is characteristic for many inborn errors of
metabolism (maple syrup disease or FKU with mousy odor).
IN CHILDREN OF PRESCHOOL AGE
1. Mental retardation exhibits very clear in children of school age. Usually it is
preceded by psychomotor delay.
Basic reasons for mental retardation

ETIOLOGY EXAMPLES
Autosomal dominant disorder Tuberose sclerosis, myotonic dystrophy

Autosomal recessive disease Phenylketonuria, mucopolysaccharidose

X-linked disorder Fragile X syndrome, stenosis of

Multifactorial Non-specific mental retardation,

hydrocephlia

Chromosomal disease Down syndrome, Prader – Willi and other’s

Terratogenic influence Fetal alcohol syndrome, congenital rubella

 Sporadic case Prenatal hypoxia, intra-cranial hemorrhage

Syndromes with unknown etiology Cornelia de Lange syndrome

2. In this age at first may manifest some congenital errors of metabolism
(mucopolysaccharidosis) or neuromuscular disorders (muscular dystrophy) e.t.c.
3. Chronic anemia may be a result of hemoglobinopathies (thalessaemia) or
disturbances in metabolism of erythrocytes (glucose–6-phosphate dehydrogenase
deficiency).
IN ADOLESCENT AND ADULT AGE.
1. Hypogenitalism and hypogonadism. Primary amenorrhea may be observed in
syndrome of testicular feminization, primary amengrrhea and underdevelopment of
secondary sexual characters are observed in Shereshevsky-Turner syndrome (45 XO),
underdevelopment of secondary sexual characters in boys with Klinefelter syndrome
(47, XXY).
2. Early pubescence may be observed in Beckwith-Wiedemann, Poland, Albright
syndromes and others. This also may be a symptom of the tumor of pituitary, adrenal
gland or ovary.
3. Some hereditary disease of nervous system manifests at this age: Friedreikch’s
disease, Huntington’s disease and others. Epilepsy may start in adolescent period.
4. Hereditary nephritis and polykistosis of kidneys may manifest. One of the first
clinical signs may be arterial hypertension.
5. In people with genetic predisposition in this or in more early age may be
malignant tumors.
6. Early onset of middle-age disorders (ischemic heart disease or arterial
hypertension) may be the result of single gene disorders (familial
hypercholesterinemia).
7. Infertility may the result of balanced structural chromosomal mutation,
presence of lethal gene or chromosomal disorder (Shereshevsky-Turner syndrome, or
congenital defect of the uterus in women). Male infertility because of oligospermia
often observed in Kleinefelter syndrome, cystic fibrosis, deletion of the Y
chromosome.
8. Chronic miscarriage is observed in balanced chromosomal abnormalities of in
both parents.