Genetics I: Overview, Cytogenetics I (trans 1) Flashcards
CYTOGENETICS
Study of normal and abnormal chromosomes
GENETIC DISORDERS
Chromosomal or Cytogenetic Disorders
Mendelian Disorders
Multigenic Disorders
GENETIC DISORDERS - Chromosomal or Cytogenetic Disorders
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
GENETIC DISORDERS - Mendelian Disorders
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
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
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)
GENETIC DISORDERS - Single Gene Disorder with Non-classical Inheritance Patterns
o Involves single genes but do not follow simple mendelian rules of inheritance
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
DIAGNOSIS OF GENETIC DISORDERS
- KARYOTYPING
- G-BANDING (KARYOTYPE BANDING)
- FLUORESCENT IN-SITU HYBRIDIZATION (FISH)
- BARR BODY
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
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
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
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
DIAGNOSIS OF GENETIC DISORDERS - FLUORESCENT IN-SITU HYBRIDIZATION (FISH)
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
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
Barr bodies. Presence of hyperchromatic blebs (see arrows) outside of the nuclei on the female (XX) patient. Note their absence in the normal male
TYPES OF MUTATIONS
- Gene mutations
- Chromosome Mutations
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
Two types:
- Non-disjunction
- Anaphase Lag
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.
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.
TYPES OF MUTATIONS - Genome Mutations
**Non-disjunction
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).
TYPES OF MUTATIONS - Genome Mutations
**Non-disjunction
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.
TYPES OF MUTATIONS - Genome Mutations
**Non-disjunction
Meiotic non-disjunction occurring in the mother (in Meiosis II). In this case, meiotic nondisjunction occurs in Meiosis II
TYPES OF MUTATIONS - Genome Mutations
**Non-disjunction
Mitotic non-disjunction in a fetus. A few cells would be monosomic whereas some would be trisomic. Happens during embryogenesis.
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
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
TYPES OF MUTATIONS - Chromosome Mutations
o Loss of genetic material
o Causes an abnormality in the structure
o Severity of manifestation depends on the volume of genetic material lost
TYPES OF MUTATIONS - Chromosome Mutations
**Inversion
2 breaks in a single chromosome with rearrangement of genetic material
TYPES OF MUTATIONS - Chromosome Mutations
**Isochromosomes
when 1 arm is lost and the remaining arm is duplicated
TYPES OF MUTATIONS - Chromosome Mutations
**Deletions
2 breaks within the chromosome arm followed by a loss of a chromosomal material between the breaks and fusion of the broken ends
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.
CAUSES OF MUTATION
Increasing age
Chromosomal instability
Ionizing radiation
Drugs
Viruses
IMPORTANT CANCER GENES
- Oncogenes
- Tumor suppressor genes
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
- 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) - 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
IMPORTANT CANCER GENES - Tumor suppressor genes
Form a network of checkpoints that prevent uncontrolled growth
Tumor suppressor genes control the proliferation of the cell
- RB gene
Retinoblastoma (RB) protein
13q14 (point mutation)
“governor of the cell cycle”
Function: inhibitor of G1/S transition during cell cycle progression - WT-1 gene
11p13
Wilm’s tumor-1
Function: transcription factor - DCC gene – 18q21
- APC gene
5q21
Adenomatous polyposis coli protein
“gatekeeper of colonic neoplasia”
- p53
Cancer suppressor gene
17p13.1
“guardian of the genome”
Function: cell cycle arrest and apoptosis in response to DNA damage - NF-1 gene
17q11.2
neurofibromin-1 protein
Function: inhibitor of RAS/MAPK signaling - BRCA gene
17q
Function: repair of double stranded breaks in DNA
**p53 gene protective for breast and colon cancer
Effect of Translocation in Oncogenesis
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)
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)
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
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.
Causes of Down’s Syndrome
- Meiotic non-disjunction (90%)
- Translocation (4%)
- Mosaic (1%)
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)
Meiotic non-disjunction of gametes in one of the parents.
TRISOMY 21 (DOWN’S SYNDROME) - Translocation (4%)
t(21→ 22 or 14) - Robertsonian translocation of long arm of chromosome 21 to another acrocentric chromosome (e.g. 22 or 14)
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)
Mitotic dysfunction in Trisomy 21.
FISH of Trisomy 21
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).
TRISOMY 21 (DOWN’S SYNDROME) - Clinical Features
- Mental Retardation – always present but variable in degree; patients cannot enter a regular school
- 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
- 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 - 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
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
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
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%)
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)
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)
Physical Characteristics
o Microcephaly
o Micropthalmia
o Cleft lip and palate (usually bilateral)
o Hands and feet: polydactyly, rocker bottom feet
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.
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
CHROMOSOME 22q11.2 DELETION SYNDROME
REMEMBER
PATCH 22
Parathyroid hypoplasia
Abnormal facies
Thymic hypoplasia
Cardiac and Cleft palate
Hypocalcemia
from deletion of band q11.2 of chromosome 22
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
- KLINEFELTER’S SYNDROME
- TURNER’S SYNDROME
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
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
SEX CHROMOSOME DISORDERS - KLINEFELTER’S SYNDROME
Clinical Symptoms
- 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
- Gynecomastia
- Female distribution of hair
Reduced facial, body, and pubic hair - 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 - Eunuchoid bodily habitus
increase in length between the soles and the pubic bone - elongated body
SEX CHROMOSOME DISORDERS - KLINEFELTER’S SYNDROME
Confirmatory lab findings
- Positive X chromosome in buccal smear (male w/ a barr body)
- Oligospermia or azoospermia
- Increase urinary excretion of FSH
- Decrease in serum testosterone
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
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
- 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) - Mosaicism
Two or more cell lines one of which is 45 XO
Don’t completely express classical phenotype → wide range of clinical severities
SEX CHROMOSOME DISORDERS - TURNER’S SYNDROME
Clinical manifestations in adolescent
- 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. - 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
- Infertility
- Webbing of the neck
Due to distended lymphatic channels (in infancy) - Lymphedema
- Broad chest and wide spaced nipples
- Low posterior hairline
- Pigmented nevi
- 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%)
REMEMBER
Klinefelter’s:
Excessive X chromosome - male patient with no male characteristics
Turner’s
Lacking an X chromosome - female patient lacking female characteristics
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
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
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.
Other Sex-linked Chromosomal Abnormality
Pseudohermaphrodite (PH)
o Divergent gonad vs phenotypic sex
o More common than true hermaphrodites
- 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)
- 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
