Genetics I: Overview, Cytogenetics I (trans 1)

Question 1

CYTOGENETICS

Answer 1

Study of normal and abnormal chromosomes

Question 2

GENETIC DISORDERS

Answer 2

 Chromosomal or Cytogenetic Disorders

 Mendelian Disorders

 Multigenic Disorders

Question 3

GENETIC DISORDERS - Chromosomal or Cytogenetic Disorders

Answer 3

o Abnormality in number and/or structure of the chromosomes
o Results from genome mutations or chromosomal mutations
o Occur much more frequently (1 in 200 newborn infants)
o Normal karyotype: (2n) 46 XX or 46XY

Question 4

GENETIC DISORDERS - Mendelian Disorders

Answer 4

o Disorders related to mutation in single genes
o Follow one of three patterns of inheritance: autosomal dominant, autosomal recessive, X-linked
o A single-gene mutation may lead to many phenotypic effects (pleiotropy), and conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity)
o Includes many uncommon conditions, such as storage diseases and inborn errors of metabolism
o Most are hereditary and familial

Question 5

GENETIC DISORDERS - Multigenic Disorders

o Implies that both genetic and environmental influences condition the expression of a phenotypic characteristic or disease
o a.k.a. Polygenic Inheritance or Multifactorial Disorders

e. g. Several normal phenotypic characteristics governed by multigenic inheritance: hair color, eye color, skin color, height, intelligence show a continuous variation across all population groups
e. g. DM, hypertension, heart disease

Answer 5

Characterized by:
1. Dosage Effect = more # deleterious gene, more severe expression of the disease
 If you have both diabetic parents, chances of having DM is higher
 If only one parent has DM, manifestations are less severe
2. Range of severity
3. Family clustering w/o mendelian transmission
 Not autosomal recessive, not X-linked recessive, but the family will have the same disorder (in case of DM, food intake & exercise are factors that contribute to the severity of condition)

Question 6

GENETIC DISORDERS - Single Gene Disorder with Non-classical Inheritance Patterns

o Involves single genes but do not follow simple mendelian rules of inheritance

Answer 6

Categories:
 Trinucleotide repeats - triplet repeat mutations (e.g. Fragile X syndrome, Huntington disease and myotonic dystrophy) - Newly discovered disorders so far are associated with neurodegenerative changes
 Mitochondial Inheritance - mutations in mitochondrial genes (e.g. Leber Hereditary Optic Neuropathy)
 Associated with maternal inheritance
 Genomic Imprinting - caused by alterations of imprinted regions (e.g. Prader-Willi and Angelman Syndrome)
 Gonadal Mosaicism

Question 7

DIAGNOSIS OF GENETIC DISORDERS

Answer 7

1. KARYOTYPING
2. G-BANDING (KARYOTYPE BANDING)
3. FLUORESCENT IN-SITU HYBRIDIZATION (FISH)
4. BARR BODY

Question 8

DIAGNOSIS OF GENETIC DISORDERS - KARYOTYPING

Karyotype – standard spread of chromosomes from a cell arrested at metaphase of mitosis
o Uses WBC cell nucleus from blood samples that are stimulated to undergo mitotic activity

 REAGENT: Colcemid – depolymerizes microtubules (Mitotic Spindle inhibitor) to arrest cells in metaphase
 Arranged by pairs, biggest to smallest, and according to the location of the centromeres
 Best way to determine number and structure of the chromosomes

Answer 8

 REAGENT: Colcemid – depolymerizes microtubules (Mitotic Spindle inhibitor) to arrest cells in metaphase
 Arranged by pairs, biggest to smallest, and according to the location of the centromeres
 Best way to determine number and structure of the chromosomes

Question 9

DIAGNOSIS OF GENETIC DISORDERS - G-BANDING (KARYOTYPE BANDING)

 Changes some chromosome structures into black and white, allows identification of translocation
o Analysis of chromosomes by G-banding is the classic approach to identification of changes at the chromosome level
o if karyotype are not banded, translocation of one portion into the other portion cannot be seen
 REAGENT: Giemsa stain

Answer 9

CHROMOSOME NOMENCLATURE
Written by order of left to right
1. CHROMOSOME NUMBER
2. ARM - Short arm : p (“petite”) Long arm : q
3. REGION : start at centromere, labeled using numerals
4. BAND
5. SUB-BAND

Question 10

DIAGNOSIS OF GENETIC DISORDERS - FLUORESCENT IN-SITU HYBRIDIZATION (FISH)

Answer 10

 Uses DNA probe + Fluorescent dye
 Advantage of not having to wait for mitosis, can be done on Interphase nuclei
 DNA probe binds to a complementary sequence targeted for identification
 APPLICATION: Rapid diagnosis using any cell (e.g. pre-natal samples, lymphocytes, or archival tissue sections) for trisomy or monosomy.
 REAGENT: Fluorescent dye

Question 11

DIAGNOSIS OF GENETIC DISORDERS - BARR BODY

 Genetic material bleb protruding from the nucleus
 PRINCIPLE: Lyon’s Hypothesis: Only 1 X chromosome is active, second X is inactive and undergoes pyknosis to become the Barr body
o Inactivation of the second X occurs at random on the 16th day of embryonic life. This inactivation will then persist in all cells down the cell line.
 Identification of Barr body is the simplest of the four methods, limited to identifying sex chromosomes only
o Peripheral smear - identify if patient is Male (no Barr body) or Female (1 Barr body).
o Buccal Smear (squamous cells): Used in cytogenetic applications, to check for mutations
 It is a condensed chromatin at the periphery of the nuclear border
APPLICATION: Klinefelter’s syndrome – 47,XXY (male) or 47,XXX (female) = 1 BB on male patient, 2 BB on female patient with Klinefelter’s

Answer 11

Barr bodies. Presence of hyperchromatic blebs (see arrows) outside of the nuclei on the female (XX) patient. Note their absence in the normal male

Question 12

TYPES OF MUTATIONS

Answer 12

1. Gene mutations
2. Chromosome Mutations

Question 13

TYPES OF MUTATIONS - Genome Mutations

o “buo-buong chromosome nawawala.” (Whole chromosomes are lost)
o Only single nucleic acid mutations or several nucleic acids are involved, not affecting the structure of your chromosomes.
o Causes an abnormality in the chromosomal number

Answer 13

Two types:

• Non-disjunction
• Anaphase Lag

Question 14

TYPES OF MUTATIONS - Genome Mutations

**Non-disjunction

 main cause of genome mutation
 Occurs in gamete formation (meiosis). Either sperm or ova may undergo non-disjunction.
 Failure of the chromosome to separate in anaphase.

Answer 14

 Non disjunction can also occur during mitosis (after fertilization). The end effect will be production of abnormal chromosome in one of the chromosomes.
 If the non-disjunction occurred in mitosis, the product is a mosaic.
 A mosaic is an individual wherein the chromosome numbers are different from one part of the body to another (e.g. the chromosome number of a cell from the left hand is different the chromosome number of a cell from the right hand) indicating that there is not just a single cell line.

Question 15

TYPES OF MUTATIONS - Genome Mutations

**Non-disjunction

Answer 15

Non-disjunction in the meiosis during gametogenesis. The chromosome (encircled in red) fails to separate, producing one cell with a double set (trisomy) and another with an absent chromosome (monosomy).

Question 16

TYPES OF MUTATIONS - Genome Mutations

**Non-disjunction

Answer 16

Meiotic non-disjunction occurring in the mother (in Meiosis I). In this case, the father’s normal sperm combines with the mother’s gamete containing an extra set of chromosomes, resulting in trisomy. If the father’s sperm had combined with the ovum lacking a chromosome, this would result to a monosomy.

Question 17

TYPES OF MUTATIONS - Genome Mutations

**Non-disjunction

Answer 17

Meiotic non-disjunction occurring in the mother (in Meiosis II). In this case, meiotic nondisjunction occurs in Meiosis II

Question 18

TYPES OF MUTATIONS - Genome Mutations

**Non-disjunction

Answer 18

Mitotic non-disjunction in a fetus. A few cells would be monosomic whereas some would be trisomic. Happens during embryogenesis.

Question 19

TYPES OF MUTATIONS - Genome Mutations

**Anaphase Lag

 A chromosome lags behind before the nuclear membrane is formed.
 Such that during the occurrence of cell membrane/nuclear membrane, that lagging chromosome is lost on the next cycle.
 Sperm/ova produces monosomic individuals
 One homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus

Answer 19

Anaphase lag in a cell, resulting in one normal cell and one monosomic cell. Note the lengths of the middle centromeres. In the cell at the left it is shorter while in the right it is longer

Question 20

TYPES OF MUTATIONS - Chromosome Mutations

Answer 20

o Loss of genetic material
o Causes an abnormality in the structure
o Severity of manifestation depends on the volume of genetic material lost

Question 21

TYPES OF MUTATIONS - Chromosome Mutations

**Inversion

Answer 21

2 breaks in a single chromosome with rearrangement of genetic material

Question 22

TYPES OF MUTATIONS - Chromosome Mutations

**Isochromosomes

Answer 22

when 1 arm is lost and the remaining arm is duplicated

Question 23

TYPES OF MUTATIONS - Chromosome Mutations

**Deletions

Answer 23

2 breaks within the chromosome arm followed by a loss of a chromosomal material between the breaks and fusion of the broken ends

Question 24

TYPES OF MUTATIONS - Chromosome Mutations

**Translocation - A segment of the chromosome is transferred to another chromosome

Can be classified as:

a. Balanced – no loss of genetic material (“If you look at the karyotype, parang walang nangyari”)
b. Robertsonian - between 2 acrocentric chromosomes. There is loss of genetic material. “New heterochromatic” chromosome may be lost in next genetic cycle.

Answer 24

Question 25

CAUSES OF MUTATION

Answer 25

 Increasing age
 Chromosomal instability
 Ionizing radiation
 Drugs
 Viruses

Question 26

IMPORTANT CANCER GENES

Answer 26

1. Oncogenes
2. Tumor suppressor genes

Question 27

IMPORTANT CANCER GENES - Oncogenes

 Mutant or overexpressed versions of proto-oncogenes that function autonomously without a requirement for normal growth promoting signals
 Proto-oncogenes, on the other hand, are normal cellular genes whose products promote cell proliferation.

**Oncogenes promote the development of the tumor

Answer 27

1. Philadelphia chromosome
    First ever gene that was related to a malignancy
    Translocation between chromosome 9 and 22
    Seen in CML (chronic myelogenous leukemia)
    t(9;22)
2. Burkitt’s lymphoma
    t(8;14)(q24;q32)
    The affected genes are MYC 8q24 and IGH 14q32
    It is a very aggressive tumor of B cells that usually arises at extranodal sites

Question 28

IMPORTANT CANCER GENES - Tumor suppressor genes

 Form a network of checkpoints that prevent uncontrolled growth

 Tumor suppressor genes control the proliferation of the cell

1. RB gene
    Retinoblastoma (RB) protein
    13q14 (point mutation)
    “governor of the cell cycle”
    Function: inhibitor of G1/S transition during cell cycle progression
2. WT-1 gene
    11p13
    Wilm’s tumor-1
    Function: transcription factor
3. DCC gene – 18q21
4. APC gene
    5q21
    Adenomatous polyposis coli protein
    “gatekeeper of colonic neoplasia”

Answer 28

5. p53
    Cancer suppressor gene
    17p13.1
    “guardian of the genome”
    Function: cell cycle arrest and apoptosis in response to DNA damage
6. NF-1 gene
    17q11.2
    neurofibromin-1 protein
    Function: inhibitor of RAS/MAPK signaling
7. BRCA gene
    17q
    Function: repair of double stranded breaks in DNA

**p53 gene protective for breast and colon cancer

Question 29

Effect of Translocation in Oncogenesis

Answer 29

BCR-ABL fusion gene, aka Philadelphia chromosome. The ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22 where it fuses with the BCR gene. The resultant gene encodes a constitutively active, oncogenic BCR-ABL tyrosine kinase. Increased tyrosine kinase activity leads to increased production of transcription factors for proliferation leading to uncontrolled mitosis. It is associated with chronic myelogenous leukemia (CML)

Question 30

CYTOGENETIC DISORDERS

AUTOSOMAL CONDITIONS
A. Trisomy 21 (Down’s Syndrome)
B. Trisomy 18 (Edward’s Syndrome)
C. Trisomy 13 (Patau’s Syndrome) – most die in utero or right after birth
D. Chromosome 22q11.2 deletion (DiGeorge Syndrome)

Answer 30

 The lower the number of chromosome, the larger the volume of genes, the more severe the affectation.
 Chromosome 1 is the biggest, while chromosome 22 is the smallest based on size.
 Most cases of cytogenetic disorders are trisomy since if it is monosomy, the baby dies due to loss of too much genetic material

Question 31

TRISOMY 21 (DOWN’S SYNDROME)

 Most common chromosomal disorder
 Major cause of mental retardation
 Maternal age is a strong influence on the incidence of trisomy 21.
 Incidence rate (IR) of 1:1500 live births for mothers <20 years old
 Increased IR of 1:25 live births for mothers whose age is >45 years.

Answer 31

Causes of Down’s Syndrome

1. Meiotic non-disjunction (90%)
2. Translocation (4%)
3. Mosaic (1%)

Question 32

TRISOMY 21 (DOWN’S SYNDROME) - Meiotic non-disjunction (90%) in either parent (who are normal in all respects; normal karyotype)

 Most common cause
 Maternal age affects this disorder
 Occurs in gametogenesis (either oogenesis or spermatogenesis)

Answer 32

Meiotic non-disjunction of gametes in one of the parents.

Question 33

TRISOMY 21 (DOWN’S SYNDROME) - Translocation (4%)

Answer 33

 t(21→ 22 or 14) - Robertsonian translocation of long arm of chromosome 21 to another acrocentric chromosome (e.g. 22 or 14)

Question 34

TRISOMY 21 (DOWN’S SYNDROME) - Mosaic (1%)

 Non-disjunction occurred during the development of the baby
 Individual with >1 cell line
 Having a mixture of cells w/ 46 & 47 chromosomes
 Results from mitotic non-disjunction of chromosome 21 during an early stage embryogenesis
 Severity depends on the timing of non-disjunction.
o If it happens during the 2-cell stage, half of the cells will have normal set of chromosomes, while the other half will have Trisomy 21.
o If it happens during a later cell stage, only few cells will have Trisomy 21.
 Variable and milder symptoms (depending on the proportion of abnormal cells)

Answer 34

Mitotic dysfunction in Trisomy 21.

Question 35

FISH of Trisomy 21

Answer 35

This is an example of a translocation Down’s. Notice that the pink dot is translocated to the green dot. If you count the number of chromosomes, it is just the same (2 green and 2 pink).

Question 36

TRISOMY 21 (DOWN’S SYNDROME) - Clinical Features

1. Mental Retardation – always present but variable in degree; patients cannot enter a regular school
2. Facial profile
    Oblique palpebral fissures (lateral canthus slanted upwards) – eyes appear to be positioned upwards
    Flat face
    Epicanthic folds - fold in the eye that goes across the inner canthus. Most common striking characteristic.
    Dysplastic ears - set lower than normal, folded or misplaced downwards. Any abnormality of the ear may be present. Not as specific as the epicanthic fold.
    Protruding tongue
    Abundant neck skin
    Broad/flattening of nasal bridge

Answer 36

3. Motor abnormality
    Loss of Moro reflex (startle reflex) - initiated by a banging sound like clapping of hands. They do not react to loud or banging sounds.
    Poor motor activity
    Muscle hypotonia
4. Hands and Feet
    Simian crease – straight single palmar crease (normal in 3% of population)
    Short broad hands
    Gap between 1st and 2nd toe
    Dysplastic middle phalanx
    1 crease on the 5th finger – only 2 phalanges are present

Question 37

TRISOMY 21 (DOWN’S SYNDROME) - Associated Diseases

Congenital Heart Disease - About 40% of the patients have this

o Most common are defects of the endocardial cushion, including:
 Ostium primum
 Atrial septal defects
 Atrioventricular valve malformations
 Ventricular septal defects
 Tetralogy of fallot
 Patent ductus arteriosus

**Cardiac Problems are responsible for the majority of the deaths in infancy and early childhood

GIT
 Check if (+) meconium within 24 hours
 Atresia of the esophagus and small bowel, stenosis, imperforate anus may also be present

Answer 37

Premature Alzhemier Disease
 Normally occurs 60 years of age, but in Trisomy 21, occurs 30-40 years old.

Acute Leukemia
 Children with trisomy 21 have 10-fold to 20-fold increased risk of developing acute leukemia.
 Both acute lymphoblastic leukemia and acute myeloid leukemia can occur.

Decreased Immune Response
 Frequent and/or serious infections particularly of the lungs, and thyroid autoimmunity

Question 38

TRISOMY 18 (EDWARD’S SYNDROME)

 1:5,000 – 10,000 livebirths
 Severe malformation involving the heart and the kidneys
 Very few live beyond 1 year (<13%)
 Severe mental retardation
 Severe cardiac and renal anomalies (95%)

Answer 38

Physical Characteristics:
o Prominent occiput
o Micrognathia
o Short neck, hands & feet
o Overlapping fingers (2nd finger over the 3rd finger)
o Rocker bottom feet (appear like bottom of rocking chair)

Question 39

TRISOMY 13 (PATAU’S SYNDROME)

 Microcephaly and mental retardation
 Severe malformation
 Most die after birth and rarely live to a year
 Severe cardiac and renal anomalies (more severe)

Answer 39

Physical Characteristics
o Microcephaly
o Micropthalmia
o Cleft lip and palate (usually bilateral)
o Hands and feet: polydactyly, rocker bottom feet

Question 40

CHROMOSOME 22q11.2 DELETION SYNDROME

 Deletion of chromosome 22q11.2 (band q11.2 on the long arm of chromosome 22)
 1: 4000 livebirths

**Chromosome 22q11.2 deletion has two manifestations. One is those patients with DiGeorge Syndrome, the PATCH 22 (Hypocalcemia being the most important, so the manifestations are seizures and cyanosis; tetany) and the other is those patients with Velocardiofacial syndrome wherein the most prominent feature is mental retardation associated with facial dysmorphism.

Answer 40

Disorders:
1. DiGeorge syndrome
 Thymic hypoplasia
o With resultant T-cell immunodeficiency
o Associated with absent T-lymphocyte
 Parathyroid hypoplasia
o Gives rise to hypocalcemia
o Another problem is seizures
 Cardiac manifestation
2. Velocardiofacial Syndrome
 Facial dysmorphism
o Prominent nose
o Retrognathia
 CV abnormality
 Learning disability
 Cleft palate (high arch palate)

**High risk for:
o Psychotic illnesses
 Schizophrenia
 Bipolar disorder
 Attention deficit disorders

Question 41

CHROMOSOME 22q11.2 DELETION SYNDROME

Answer 41

REMEMBER

PATCH 22
Parathyroid hypoplasia
Abnormal facies
Thymic hypoplasia
Cardiac and Cleft palate
Hypocalcemia
from deletion of band q11.2 of chromosome 22

Question 42

SEX CHROMOSOME DISORDERS

 More common compared to autosomes
 More benign
 Subtle, complaints related to sexual development and fertility
 Rarely diagnosed at birth
 Two factors that are peculiar with sex chromosomes:
(1) Lyonization of X chromosomes: Lyon hypothesis - one X chromosome of females, maternal or paternal, is randomly inactivated during development
(2) The small amount of genetic information carried by the Y chromosome

Answer 42

1. KLINEFELTER’S SYNDROME
2. TURNER’S SYNDROME

Question 43

SEX CHROMOSOME DISORDERS - KLINEFELTER’S SYNDROME

 Most common cause of hypogonadism in males
 Testicular dysgenesis
 Most frequent genetic disorder of sex chromosome
 Incidence Rate - 1:660 Live births
 Associated with a higher frequency of several disorders, including breast cancer (seen 20 times more commonly than in normal males), extragonadal germ cell tumors, and autoimmune diseases such as systemic lupus erythematosus

Answer 43

 Only rarely are patients fertile, and presumably such persons are mosaics with a large proportion of 46,XY cells
 Classic case 47XXY
o Produced by non-disjunction during meiosis
o Others: 48XXXY or 49 XXXXY

Question 44

SEX CHROMOSOME DISORDERS - KLINEFELTER’S SYNDROME

Clinical Symptoms

1. Testicular atrophy and azoospermia - absence of spermatogenesis leading to development of female characteristics
    Markedly reduced testicular size, sometimes to only 2 cm in greatest dimension
    Serum testosterone levels are lower than normal, urinary gonadotropin levels are elevated
    The sterility is due to impaired spermatogenesis, sometimes to the extent of total azoospermia.
    Histologic examination: hyalinization of tubules (ghostlike structures on tissue section)
    Leydig cells are prominent - as a result of either hyperplasia or an apparent increase related to loss of tubules

Answer 44

2. Gynecomastia
3. Female distribution of hair
    Reduced facial, body, and pubic hair
4. Mental retardation
    you don’t see this in Turner’s syndrome
    Degree of mental impairment: Mild to no deficit
    Associated with the number of extra X chromosomes
5. Eunuchoid bodily habitus
    increase in length between the soles and the pubic bone - elongated body

Question 45

SEX CHROMOSOME DISORDERS - KLINEFELTER’S SYNDROME

Confirmatory lab findings

Answer 45

1. Positive X chromosome in buccal smear (male w/ a barr body)
2. Oligospermia or azoospermia
3. Increase urinary excretion of FSH
4. Decrease in serum testosterone

Question 46

SEX CHROMOSOME DISORDERS - TURNER’S SYNDROME

 Characterized by primary hypogonadism in phenotypic females, results from partial or complete monosomy of the short arm of the X chromosome.
 Gonadal Dysgenesis

Answer 46

Types:
1. 45 XO - high post natal mortality
 Monosomic individual, absence of one x chromosome in females
 Chances of mortality is higher in Turner’s than Klinefelter’s

2. Defective 2nd X chromosome
   46 Xp-, 46,Xi(Xq), 46 Xq-, 46,Xr(X)
    Deletion of the small arm → formation of an isochromosome of the long arm: 46Xi(X)(q10)
    Deletion of portions of both long and short arms → ring chromosome formation: 46Xr(X)
    Deletion of portions of the short or long arm: 46Xdel(Xq),46Xdel(Xp)
3. Mosaicism
    Two or more cell lines one of which is 45 XO
    Don’t completely express classical phenotype → wide range of clinical severities

Question 47

SEX CHROMOSOME DISORDERS - TURNER’S SYNDROME

Clinical manifestations in adolescent

1. Short stature
    Significant growth retardation
    Turner phenotype: short stature homeobox (SHOX) gene at Xp22.33 - remain active in both X chromosomes, unique in having an active homologue on the short arm of the Y chromosome
   - Thus, both normal males and females have two copies of this gene.
   - Extra copies of SHOX may be a cause of the increased stature in normal individuals or other sex chromosome conditions
   - One copy of SHOX gives rise to short stature.
   - One copy of SHOX can explain growth deficit in Turner syndrome.
2. 1o amenorrhea
    Fetal ovaries develop normally early in embryo embryogenesis, but the absence of the second X chromosome leads to an accelerated loss of oocytes, which is complete by age 2 years - “menopause occurs before menarche”
    Morphologic examination: transformation of the ovaries into white streaks of atrophic fibrous stroma devoid of follicles (streak ovaries)
    Fail to develop normal secondary sex characteristics; the genitalia remain infantile, breast development is minimal, and little pubic hair appears

Answer 47

3. Infertility
4. Webbing of the neck
    Due to distended lymphatic channels (in infancy)
5. Lymphedema
6. Broad chest and wide spaced nipples
7. Low posterior hairline
8. Pigmented nevi
9. Coarctation of the aorta
    Cardiovascular abnormalities are the most common cause of death in childhood
    Other congenital malformations: horseshoe kidney, bicuspid aortic valve
    Not as consistent (less than 10%) compared to a patient with Down’s Sydrome (40 - 50%)

Question 48

REMEMBER

Klinefelter’s:
Excessive X chromosome - male patient with no male characteristics

Turner’s
Lacking an X chromosome - female patient lacking female characteristics

Answer 48

Remember:
Y chromosome - physical & sexual development is supposedly male
 Doesn’t contain any genetic value except for production of the male characteristics
 Development of testes -> male hormones

Question 49

Other Sex-linked Chromosomal Abnormality

Terms:
 Genetic sex – determined by presence or absence of Y chromosome
 Gonadal sex – based on histologic characteristics of gonads
 Ductal sex – depends on the presence of derivatives of the Mullerian or Wolffian ducts
*Wolffian = male: Mullerian = female
 Phenotypic sex – based on the appearance of external genitalia
 Multi-X Syndrome
o Occurs in women who inherit three (or more) X chromosomes
o Aka “super-females” or “metafemales”
o Phenotypically normal (generally are an inch or so taller than average with unusually long legs and slender torsos)
o Tendency of mental retardation with increase of each X (like in Klinefelter’s)
o Amenorrhea and menstrual irregularity

Answer 49

 Double Y males – 47 XYY (Jacobs Syndrome)
o Aka “super-males”
o Phenotypically normal
o Excessively tall (usually >6ft) and prone to acne due to increased testosterone
 True Hermaphrodite
o Presence of both testicular and ovarian tissue in a patient
o Affected individuals may have ether a female or a male phenotype with variable degrees of sexual ambiguity
o In some cases, there is a testis on one side, ovary on the other; in some, combination called ovotestes (more common)
o Definitely mosaics because one line is 46XX and other line is 46XY
o The diagnosis has traditionally been applied only if an individual has (1) histologically verified ovarian follicles or proof of their prior existence (e.g., corpora albicantia) and (2) seminiferous tubules or spermatozoa.

Question 50

Other Sex-linked Chromosomal Abnormality

Pseudohermaphrodite (PH)
o Divergent gonad vs phenotypic sex
o More common than true hermaphrodites

1. Female PH – ovaries with excessive androgenic stimulation
    Genetic sex: XX, normal internal genitalia but ambiguous external genitalia
    Ovaries with excessive androgenic stimulation
    No vagina or uterus; short penis
    During conception, mother was exposed to high androgenic stimulation → Fetal adrenal affected by congenital adrenal hyperplasia (autosomal recessive trait)

Answer 50

2. Male PH - testis but w/ defects in androgen receptors, Xq12
    Possess Y chromosome, gonads are exclusively testes but external genital are either ambiguous or completely female
    With testis but with defects in androgen receptors (short arm of X chromosome) at Xq12 → body of the baby cannot interpret that there is actually testosterone available.
    Xq12 – Location of gene encoding the androgen receptor and its mutation results to “Complete androgen insensitivity syndrome (testicular feminization)”
    Not enough testosterone produced or testosterone receptors are inactive