Rarest form of CAH Two genes Mutations -Type I (placenta, skin, mammary gland) -Type II (adrenal gland and gonads) -46,XY DSD – male is hypomasculinized -46,XX DSD – clitoromegaly -Adrenal hyperplasia
3B-hydroxysteroid dehydrogenase deficiency
MC cause of CAH
Autosomal recessive
Impaired synthesis of cortisol from cholesterol in adrenal cortex
Virilization in all individuals (androgen excess)
Salt-wasting (due to lack of aldosterone)
Deficiency of cortisol
21-hydroxylase deficiency
Males:
- Premature body hair loss
- Enlarged penis with small testes
- Decreased sperm count
- Short stature
Females:
- Premature adrenarche/menarche
- Menstrual abnormalities
- Balding
- Excess hair growth
- PCOS
M & F:
- Premature growth of body hair
- Body odor
- Early rapid growth
- Acne
Non-classical 21-hydroxylase deficiency
Difference between “classic” and “mild/non-classical” forms of CAH:
“Classical” CAH:
- Virilizing form
- Salt-wasting (newborns at risk for life-threatening crises)
“Mild/non-classical” CAH:
- Later onset
- MC than classic – may have normal height, but short when compared to parents
- Moderate enzyme deficiency – limited glucocorticoid response to stress
Prenatal virilization in females
Postnatal virilization in males and females
Salt-wasting (in 75%)
Cortisol deficiency (in 100%)
Classic 21-hydroxylase deficiency
Prenatal virilization absent
Postnatal virilization variable
Salt-wasting absent
Cortisol deficiency rare
Non-classical 21-hydroxylase deficiency
Dx confirmation for CAH involves the molecular genetic testing of:
CYP21A2
Dx confirmation for CAH may also involve biochemical findings such as elevated serum:
17-OHP
17-OHP unable to be converted to 11-deoxycortisol
( >20,000 ng/dL = classic)
(2,000 – 15,000 ng/dL = non-classical)
Tx for classic 21-hydroxylase deficiency CAH:
Glucocorticoid replacement therapy
- Increased during periods of stress
- Salt-wasting pts – Rx 9a-fludrohydrocortisone and NaCl
An infant with a sibling affected with CAH does not have elevated 17-OHP. What is the probability that this infant is a carrier?
66%
Excess adrenal androgens in utero:
- Before 12 weeks:
- After 12 weeks:
Excess adrenal androgens in utero:
- Before 12 weeks: Labioscrotal fusion, clitoral enlargement
- After 12 weeks: Clitoral enlargement
Excess adrenal androgens after birth:
- Precocious puberty
- Untreated males:
- Untreated females:
Excess adrenal androgens after birth:
- Precocious puberty
- Untreated males: progressive penile enlargement and small testes
- Untreated females: clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, reduced fertility
Second MC cause of CAH Most mutations abolish activity Females: -Ambiguous or masculinized external genitalia -Virilization during childhood Males: -Normal external genitalia -Virilization early DOC and 11B-deoxycortisol are increased (NO salt-wasting) HTN*** (distinguishes from 21-OHD)
11B-hydroxylase deficiency
What are the two genes associated with 11B-hydroxylase?
CYP11B1
CYP11B2
In the zona glomerulosa, 11B-hydroxylase has 3 enzyme activities:
- 11B-hydroxylase
- 18-hydroxylase
- 18-oxidase
All activities are coded for by which gene?
CYP11B2
18-hydroxylase and 18-oxidase are involved in the conversion of corticosterone to:
Aldosterone
HMG octamer mutations ->
No binding to DNA ->
No male differentiation ->
46,XY female
What gene is mutated?
SRY
The Pseudoautosomal Region (PAR) pairs and recombines with X-chromosome. SRY is near but not in PAR. Therefore, Recombination may translocate this gene to the X-chromosome, resulting in 46,XX but phenotypically demonstrating:
46,XX with male phenotype
What is required for SRY expression and gonads/adrenal development (sex determination, sex differentiation, steroidogenesis, lipid metabolism)?
Steroidogenic Factor 1 (SF1)
Congenital adrenal hypOplasia and hypogonadotropic hypogonadism is due to a mutation or deletion in which gene?
DAX1
(normally down-regulated in developing testes but not in ovary)
-Duplication in males -> 46,XY females
-Duplication in females -> no effect
Dosage sensitive sex reversal-Adrenal sensitive sex reversal on the X Chr (DAX1 gene) is important in development of the ovary and down regulation in developing testes. What happens if it is duplicated in males? MoA?
Duplicated DAX1 -> 46-XY female
SRY may inhibit DAX1, but in duplicated state, there may be insufficient SRY to repress DAX1 expression
- Result of SOX9 mutations -> Mullerian ducts do not degenerate (ovary development occurs)
- Associated with sex reversal due to gonadal dysgenesis in 46,XY
- Bowing of long bones
- Shortened long bones
- Skeletal dysplasia
Campomelic dysplasia
“bent limbs”
WT1 and SF1 expression are required for which gene to be expressed?
SRY
SRY expression in Sertoli cells up-regulates which gene?
SOX9
SRY mutations
SOX9 mutations
DAX1 mutations
All result in:
Sex reversal
- Abnormality of anterior urethral development in which the urethral opening is ectopically located on the ventral side of the penis proximal to the tip of the glans penis
- Defect occurs between weeks 8-20
Hypospadias
- Both ovarian and testicular tissue in one or both gonads
- Internal and external differentiation is variable
- Ovotestis is the MC gonad found
Ovotesticular DSD
- Aromatase (CYP450-aromatase) deficiency
- Expressed in ovary and testis
- Tissue-specific promoters
- Elevated testosterone and androstenedione
- Masculinization of female genitalia
- Pubertal failure
Female 46,XX DSD
- Abnormalities of gonad development
- Cholesterol synthesis defects
- Testosterone synthesis defects
- Testosterone metabolism defects
- Androgen action defects
- Persistence of Mullerian ducts syndrome
- Congenital non-genetic 46,XY DSD
Male 46,XY DSD
more complicated
- Prenatal and postnatal growth retardation, microcephaly, moderate to severe mental retardation, and multiple major and minor malformations.
- Malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes.
- Clinical spectrum is wide and individuals have been described with normal development and only minor malformations.
Abnormal cholesterol synthesis in 46,XY DSD
“Smith-Lemli-Opitz syndrome”
• Impaired Leydig cell differentiation
• Defects in adrenal and testicular
steroidogenesis
• P450scc deficiency
• 3β hydroxysteroid dehydrogenase deficiency
• 17α hydroxylase deficiency
• 17β hydroxysteroid dehydrogenase deficiency (MC)
Testosterone synthesis defects in 46,XY DSD
• 46,XY with female external genitalia
• Testes and Wolffian derivatives present
• At puberty – absence of male differentiation – Deepening voice
– Clitoral enlargement – Hirsutism
– Male muscularity
– Breast development
17B-hydroxysteroid dehydrogenase deficiency
- Female genitalia
- Partial virilization at puberty
- Elevated testosterone:DHT ratio
5a-reductase deficiency
(testosterone metabolism defects)
(46,XY DSD)
• Deficient conversion of testosterone to DHT
– Deficient DHT to bind to androgen receptor
• Two isozymes
– Type 2: Expressed before and after birth
» Prostate, Wolffian derivatives, scrotum, liver
– Type 1: Expressed in non-genital tissues
• Mutation in female - genitalia normal; menarche delayed
• Mutation in male - testes extra-abdominal; usually inguinal – Hypospadic microphallus
– Blind vaginal pouch
5a-reductase deficiency
(testosterone metabolism defects)
(46,XY DSD)
• Steroid hormone receptor family
• Mediates growth and differentiation in AR responsive tissues
Lipid soluble ligand enters cell ->
Binds to receptor with HSP sequence and displaces HSP ->
Transported into nucleus ->
Binds to hormone response element
What receptor is described?
Androgen receptor
46,XY DSD
• Androgeninsensitivitysyndrome
– Complete and partial forms
– Mutations in the androgen receptor (Transcription factor)
Androgen insensitivity syndrome
46,XY DSD
- Defect in AMH synthesis
* Defect in AMH receptor
Persistence of Mullerian duct syndrome
46,XY DSD
• Maternal intake of endocrine disruptors
– Chemicals that disrupt the endocrine system
Congenital non-genetic 46,XY DSD
- Common cause of male hypogonadism seen in infertility work-up
- 47,XXY
- Variants: XXXY, XXXXY, XXYY, and XXY/mosaics
- Usually from maternal nondisjunction
- Testicular atrophy, eunuchoid body shape, tall, long extremities, gynecomastia (due to high E:T ratio), female hair distribution
- May present with developmental delay
- Increased risk for autoimmune disorders (e.g., diabetes)
- Presence of inactivated X chromosome (Barr body)
- Incr LH, Incr FSH, Decr testosterone, Decr sperm count
Klinefelter syndrome
- 46,XO
- Short stature (if untreated), ovarian dysgenesis (streaked ovary), shield chest, bicuspid aortic valve, coarctation of aorta, webbed neck or cystic hygroma, horseshoe kidney
- MC cause of 1º amenorrhea
- Menopause before menarche
- Can result from mitotic or meiotic error
Turner syndrome
Must have individuals with Turner syndrome karyotype to rule out presence of Y-chromosome because the presence of y-chromosome increases the risk (95%) of:
Gonadoblastoma
prophylactic removal of streaked ovaries
• “Male Turner” syndrome
• Autosomal dominant
• Mutations in PTPN11 gene (~ half of cases)
– Oncogene regulating RAS/MAPK signaling pathway
• Regulates cell proliferation, differentiation, migration, apoptosis.
• Critical in development of heart, blood cells, bones and other tissues
Noonan syndrome
- Delayed puberty
- Down-slanting or wide-set eyes
- Hearing loss (varies)
- Low-set or abnormally shaped ears
- Mild mental retardation(~25% of cases)
- Pulmonary stenosis***
- Ptosis
- Short stature
- Small penis
- Undescended testicles
- Pectus excavatum
- Short, webbed neck
- Fertility problems but fertile**
Noonan syndrome
List the essential amino acids.
“PVT TIM HALL”
Phenylalanine Valine Threonine Tryptophan Isoleucine Methionine Histidine Arginine Leucine Lysine
Findings: intellectual disability, growth retardation, seizures, fair skin/hair, eczema, musty/mousey body odor*
Dx?
What enzyme is deficient?
Which AA becomes essential?
What test is used to view PHE levels?
Phenylketonuria (type I)
Due to decreased phenylalanine hydroxylase.
Tyrosine becomes essential.
Guthrie test – bacterial inhibition assay
(Now more likely to see Mass Tandem Spec in hospitals)
- Insufficient BH4 (tetrahydrobiopterin cofactor) which leads to BH2 deficiency
- Due to deficiency of dihydropteridine reductase
- Major clinical finding: abnormal response to diet
- Progressive deterioration
- May respond to BH4 treatments
Dx?
Type II Hyperphenylalaninemia
“Malignant PKU”
- Due to deficiency of dihydropteridine synthetase
- 1-3% of all hyperphenylalaninemia
- Progressive neuro deterioration
- May respond to BH4 tx
Type III Hyperphenylalaninemia
- Lack of proper dietary therapy during pregnancy
- Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects
Maternal PKU
- Autosomal recessive
- Deficiency of homogentisate oxidase
- In degradative pathway of tyrosine to fumarate
- Arthritis
- Dark colored cartilage
- Urine turns black on standing
Alkaptonuria
- Autosomal recessive
- Unable to synthesize melanin
- Hair, skin, eyes affected
- Associated ocular defects
- Photophobia
Albinism
- Autosomal recessive
- Failure to thrive
- Benign, transient defect in TYR metabolism
- Defect in p-hydroxyphenylpyruvic acid oxidase
- (+) Guthrie test
Neonatal tyrosinemia
Defect in tyrosine aminotransferase
Hepatorenal tyrosinemia
Renal obstruction
Liver failure
Dx?
Tyrosinemia type II
Defect in fumarylacetoacetate hydrolase
Oculocutaneous tyrosinemia
Photophobia
Conjunctivitis
Dx?
Tyrosinemia type I
Albinism subtype.
Tyrosinase (–)
Albinism type IA
Albinism subtype.
Tyrosinase (+)
General reduction in pigmentation
Albinism type IB
Albinism subtype (MC).
Tyrosinase (+)
In pigmented nevi
Hair yellow or light colored
Albinism type II
Findings: Increased homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus (tall, long limbs), lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke/MI)
Dx?
Deficiency of what enzyme?
Homocystinuria
Deficient enzyme: cystathionine synthase
Methionine and cysteine – sulfur groups*
(See p. 108 in FA)
- Defect in alpha ketoacid dehydrogenase
- Blocked degradation of branched chain amino acids (elevated leucine, isoleucine, valine)
- Seizures
- Mental retardation
Maple syrup urine disease
- Absence of galactose-1-phosphate uridyltransferase
- Autosomal recessive
- Damage caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye)
- Sx: failure to thrive, jaundice, hepatomegaly, infantile cataracts*** (due to increased osmotic pressure), intellectual disability
Dx?
Classic galactosemia
- Hereditary deficiency of galactokinase
- Autosomal recessive, relatively mild
- Sx: galactose appears in blood and urine, infantile cataracts*
- May present as failure to track objects or to develop a social smile
Galactokinase deficiency (non-classical galactosemia)
TQ
What is the biggest risk factor for breast cancer?
Name some other risk factors..
#1: Increasing age • Family history • Mutations in BRCA1 and BRCA2 • Early menarche • Nulliparity • Late menopause • Estrogen use • Dietary factors
Features assoc w/ incr risk of breast and ovarian cancers?
BCRA1 & 2 mutation
TP53 mutation
PTEN mutation
HNPCC
What is “family clustering” of cancer?
-No evidence of Mendelian inheritance
-May be a weaker predisposition
-Non-genetic influences
• Environment
• Socioeconomic factors
• Diet
TQ
What are the most common genes known to cause breast and ovarian cancer?
What is their gene function, expression, and mechanism of inheritance?
BRCA1 (chr 17) and 2 (chr 13) are tumor suppressor genes:
- Control cell division (G1/S)
- DNA repair
- Apoptosis
Expressed in most tissues (G1-S) and activates p21 CDK inhibitor
- Recognizable motifs (ring-finer and BRCT domain + tandem repeats)
- Breast ca 50-85% (early age)
- Second primary breast ca
- Ovarian cancer (15-45%)
- Incr risk for prostate and colon cancer
What is the mutation?
BRCA1
- Breast Cancer
- Ovarian cancer
- Male breast cancer
- Risk of prostate, laryngeal, and pancreatic cancers
What is the mutation?
BRCA2
AD
- cancer predisposition syndrome
- variety of cancers within the same family
- risk of multiple primary cancers
What is the mutation?
Ex: Breast + osteosarcoma + brain tumor + leukemia
Li-Fraumeni Syndrome
TP53 (chr 17)
90% lifetime cancer risk for women
- Multiple hamartoma syn w/ high risk of benign and malignant tumors of the breast, **thyroid, and endometrium, GI
- Macrocephaly
- Trichilemmomas
- Papillomatous papules by LATE 20s!
- Hyperkeratosis
What is the mutation?
Cowden syndrome
PTEN (chr 10)
Usually problem in tissues that are rapidly turning over (will have GF around PIP3 sensitive)
- multiple colon primary tumors
- endometrial ca
- ovarian ca
What is mutated?
HNPCC (Lynch syndrome II)
Mismatch repair gene mut
MSH6 MSH2 EPCAM PMS2 MLH1
How does micro-satellite instability lead to ineffective repair?
Mutations in repair enzymes
Ex: HNPCC
- Early onset BC (<50) yo
- Early onset BC + ovarian
- Bilateral dz
- Jewish
- Male breast cancer
What is the mutation?
BRCA 1 OR 2
AD
Same mutation but some individuals may not develop cancer…age of onset and type of cancer also varies…
Penetrance! (Breast and ovary)
T/F The longer you live w/ a BRAC mutation, the greater your risk of developing breast cancer.
TRUE
Which population is esp assoc with BRAC1 or 2 mutations?
- Ashkenazi Jews (1 in 100)
- Stabilization of mutation within a population (founder mutations traced back to 600 yrs ago)
3 BRCA 1 and 2 mutations account for most breast ca in Jews…
What is the three mutation test?
- Focuses on the 3 specific mutations (certain deletions)
- False negatives
If family member of BRCA + individual is tested for a family-specific mutation, and it is absent…are they still at risk?
YES just like general population….(1:500 to 1:1000)
TP53--> Incr p21 (CDK inhib) Incr GADD45 (DNA repair)-->BAX-->Apoptosis
Is p53 an oncogene or tumor suppressor gene?
Mode of inheritance for LiFraumeni?
- Tumor suppressor gene
- AD
Role of PTEN in the cell?
Is it an oncogene or tumor suppressor gene?
Inheritance pattern in Cowden’s syn?
- Dephosphorylate PIP3 to PIP2 to control growth…mutated=no dephos, upreg of oncogenes
- Tumor suppressor gene
- AD
- HNPCC
- Di-nucleotide repeats (CA12, 14, 16)
- Additions/deletions
- Defective mismatch repair
Microsatellite instabilty
GADD45 is assoc w/ what check point in the cell cycle?
G1/G2–>apoptosis via BAX
BAX=apoptosis pathway
BAX is part of which gene family?
How does it work?
BCL2 gene BAX controls mito apoptosis
p53–>BAX–>cyclophilin D–>membrane distruption–>apoptosis
AND
antagonize BCL2
(BCL2=survive, BAX=apoptosis)
Microsatellite instability:
Mononucleotide repeat G8 (loss or gain–>G6 or G7)
What does this affect?
Decr apoptosis ability by mutation BAX…
- A10 repeat (mononucleotide)
- Frameshift in HNPCC pts via insertions or deletions
What signaling pathway is the mutated gene involved in?
TGFBR2 gene
LAP cleavage–>R1–>R2–>signaling via SMADS*
TGFB=Multifunctional cytokine–>
SMAD–>apoptosis, prolif, or diff