Genetic Disorders
Types of Inheritance
Mosaicism
Genetic Growth Disorders
Genetic Immunosupressed Syndromes
Disorders of *Sexual
Development
Bruton/X-linked
Agammaglobulinemia
- mutation / absent cytosolic tyrosine kinase messaging molecules
- aggammaglob = loss of B cells
--> no CD 19, 20 ,21
--> no GAM antibodies
- aggammaglob = loss of B cells
Genetic Blood Disorders
- follow these according to ethnicity
Southeast
Asian Populations
African Descent
- especially DR Congo
Sickle Cell Disease
SCD
α-Thalassemia
- hypochromic, microcytic
- part of "SALTI microphone"
click to edit
Notes:
- Alpha-thalassemia (causes --> hypochromic microcytic anemia) is seen in southeast Asian populations (Thailand here)
- adult Hb
--> 2 x alpha globin protein chains
--> 2 x beta globin protein chains - fetal Hb
--> 2 x alpha globin protein chains
--> 2 x gamma globin protein chains - gamma globin protein chains have a much higher affinity for oxygen, so in severe Alpha-thalassemia, there are defective alpha Hb, so the body compensates by making 4 gamma-Hb
--> these 4 gamma chains are too high in O2-affinity
--> they cannot drop off O2 to tissues and you get severe hypoxia and death
Clinical Case:
Abnormal Protein/ *Connective Tissue Disorders
- Marfans is the most common connective tissue disorder
*Marfan's Syndrome
- Marfans is the most common connective tissue disorder
- defect in the fibrillin-1 gene
- affects skeleton, eyes and CVS
Ehler Danlos Syndrome
Dystrophin Disorders
Duchene MD = worse form
-- > "walking up your legs like a RECESSIVE DUCHE!!"
Becker's MD = milder form of Duchenes
OI = Osteogenesis Imperfecta
- "blue sclera" precursor to osteoporosis
Case presentation:
Notes:
- Osteogenesis Imperfecta is a genetic inherited disorder with abnormal collagen production that affects the bones, sclera, ligaments and tendons
- it can cause early onset osteopenia and osteoporosis
- note that they may also present with hearing loss
- OI people will present fairly early, so any woman who present in early 20s with signs of blue sclera and osteoporosis, you must rule out COL1A1 gene mutation of collagen and Osteogenesis Imperfecta
Duchene's Muscular Dystrophy
- "walking up the legs" at age 4
Notes:
- Q: what is the probability that her son marked with a P will get the disease?
--> solution = 50% - note that in Duchene's MD there is normal development until about age 4, normal crawling and walking, etc.
- then the child starts to have proximal lg weakness, then distal and also upper extremity muscle weakness
- Duchenes MD is an X-linked recessive disorder
-->thus it mostly affects men and women are normally carriers, since they have one affect X and one normal - note that it matters whether the parent carrier is male or female
- "walking up your legs like a RECESSIVE DUCHE!!"
--> Duchenne's is x-linked recessivve
--> presents clinically with 4 year old boys walking up their own legs to get up
--> this is called Gowers sign
Case presentation:
Trisomy Genetic Disorders
- order of prevalence counts down
--> +21 --> +18 --> +13
Klinefelter's Syndrome
- see sexual development disorders
Meoitic *Non-Disjunction
- note that meotic nondisjunction causes all of the main chromosome and sexual genetic mutations
- trisomy 13 18 21
- Turner's Syndrome and Klinefelters syndrome
Chromosome Mutation Diseases
Trisomy 21 = *Down's Syndrome
- 47 XX / XY +21
- most common genetic intellectual disability cause
- less common = translocations
--> 46 XY t(14,21)
X-linked Androgen
Insensitive Receptors
- biological male = 46 X,Y
- largely female outer phenotype
Kallman Syndrome
- affects both males and females?
*DiGeorge Syndrome
- hypoplastic thymus
- low set ears
- failure of the 3rd and 4th pharyngeal pouches
Genetics and *Pedigrees
- autosomal vs sex-linked
- recessive vs dominant
*Autosomal recessive Disorders
- CAN skip generations
--> but don't need to - affect M / F same
- most enzyme deficient disorders are Auto recessive
Bruton/X-linked
Agammaglobulinemia case 1
Clinical Case:
Notes:
- keys to Bruton/X-linked Agammaglobulinemia are that the patient has:
- recurrent infections
--> suggests there is a possible genetic immunosupression - absent cytosolic tyrosine kinase messaging molecules
- X-linked Agammaglobulinemia has B cells that don't mature and ever leave the bone marrow to go to the thymus
--> recall that B cells are CD19+ and CD20+
Bruton/X-linked
Agammaglobulinemia case 2
Clinical Case:
Notes:
- keys to Bruton/X-linked Agammaglobulinemia are that the patient has:
- recurrent infections
--> suggests there is a possible genetic immunosupression - absent cytosolic tyrosine kinase messaging molecules
- X-linked Agammaglobulinemia has B cells that don't mature and ever leave the bone marrow to go to the thymus
--> recall that B cells are CD19+ and CD20+
CF = Cystic Fibrosis example 2
Notes
- note that auto recess is always carrier probability x 1/2
Case example:
Notes:
- geneitc mosaicism = where there are multiple cell lines in someone
- these cell lines are either somatic or germ lines
--> you can differentiate between germline or somatic mosaicism when there are parents or offspring affected - if parents have no mutant phenotypes, but offspring do
--> this is germline mosaicism - if parents have mutant phenotypes, and no offspring do
--> this is somatic mosaicism since it is not passed on
Multifactorial Inheritance
- cases where there is a very complex inheritance pattern plus environmental factors in getting a disease
- examples:
- spina bifida
- diabetes
- cleft lip and pallate
- CAD and HTN
Multifactorial inheritance example
Clinical Case
Notes:
- showing here that spin bifida is a complex inheritance pattern
--> Multifactorial Inheritance
*Mitochondrial Genetic Disorders
- Blotchy red muscle fibers on Gomori trichrome stain
--> think mitochondrial disorders - ONLY passed by the mother
- there are also MANYmitochondria are also LARGE and ABNORMALLY SHAPED
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
Trisomy 21 = Down's Syndrome case 2
- Downs have a high incidence of umbilical hernia
- they can happen without Downs though --> Ella and Cecilia
- they spontaneously close in first few years
- if not closed by age 5 --> operate to close it
Notes:
- note that there are 3 causes of Down's Syndrome that all result in Trisomy of chromosome 21
- 95% of cases are meotic nondisjunctions = meaning one parent's chromosome 21 doesn't disjoin and you get a trisomy
- ~ 2% = unblanaced translocations
- < 2% = mosaicism
--> note that the last 2 are very rare, but can still lead to trisomy
Clinical Case
Trisomy 21 = Down's Syndrome case
- most common GI defect in Downs is duodenal atresia
= closure of the Gi tract at the duodenum - present with emesis and classic "double bubble" air in the GI
--> stomach and duodenum
Notes:
- note that on scan Trisomy 21 has increased nuchal transluciency
--> area down the back of the fetus
--> not sure what it is? - also on labs it has decrease Alpha fetoprotein = AFP
Clinical Case
Trisomy 21 = Down's Syndrome case 3
- Downs is normally trisomy caused by non-disjunction during meiosis
- smaller subset are caused by balanced robertsonian translation carriers
Balanced Robertsonian Translocations
and Acrocentric Chromosomes
Notes:
- note that
Clinical Case
Trisomy 21 = Down's Syndrome case 1
Notes:
- note that there are 3 causes of Down's Syndrome that all result in Trisomy of chromosome 21
- 95% of cases are meotic nondisjunctions = meaning one parent's chromosome 21 doesn't disjoin and you get a trisomy
- ~ 2% = unblanaced translocations
- < 2% = mosaicism
--> note that the last 2 are very rare, but can still lead to trisomy
Clinical Case
Sequalae to Down's Syndrome
- ASD in 80% of cases?
- acute lymphoblastic leukemia = ALL
- most common Cardiac defect in Down's is common AV valve
Trisomy 13 = *Pateaus Syndrome
- 47 XX / XY +13
- 3rd most common trisomy with live borth = very rare
--> behind Downs and Edwards
Trisomy 18 = *Edwards Syndrome
- 47 XX / XY +13
- 2nd most common trisomy with live birth
--> behind Downs and Edwards
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
Trisomy 18 = Edward's Syndrome
Notes:
- remember the EDWARD mnemonic for trisomy 18
E = ELONGATED occiput
D = DIGITS 2 and 5 extend over the other
W = / V --> VSD = ventricular septal defect Cardiac problem
A = APNEA = cause of death usually
R = ROCKER-bottom feet
D = disability and dysplastic ears = low set
Clinical Case
Turner's vs. Klinefelter's
Key similarities:
- ATROPHIC hypogonads
--> in Klines they are atrophic and also cryptoorchidism = gabernaculum doesn't pull them down (remain in the abdomen)
--> in Turners they have ATROPHIC ovaries = "streaked ovaries" with fibrous scarring
Key differences:
- note that Klines are taller and have more musckuloSkeletal problems like scoliosis
- Turner's are short and fat
--> thus they have cardiac problems - 10% Turner's have coarctation of the aorta
--> present with lower extremity hypoxia
*Turner's Syndrome
- 45, X_
- SOMATIC mosaicism 45,X / 46 XX
Infertility of Turner's Syndrome
- degeneration of the ovaries
--> don't produce enough estrogen and progesterone to support a pregnancy plus no oocytes that are mature to be fertilized - CAN give birth ONLY with IVF and estrogen and progesterone supplements for endometrial growth
Clinical Cases
Turner's Syndrome case 3
- example shows Turner's, even though there is a missing X chromosome
- it comes from meotic non-disjunction
Notes:
-
Clinical Case
Turner's Syndrome example
- example shows Turner's is SOMATIC mosaicism, NOT germline
Notes:
- note that 2 types of mosaicism are germline and somatic
- any case where there is mosaicism in the phenotype of someone, that is somatic mosaicism
--> even though it is a sexual genetic condition - germline mosaicism ONLY affects the germline in someone and whether they pass it on to their offspring
Clinical Case
Turner's Syndrome case 2
- example shows Turner's Syndrome and risk for aortic coarctation --> infant preductal vs adult postductal
Notes:
- note that Turner's Syndrome hasrisk for aortic coarctation
--> infant preductal vs adult postductal - infant ductus arteriosis
- adult = ligamnetum arteriosum
- need to be able to recognize Aortic coarctation and aortic dissections based on the symptoms present
- note also that for coarctations, you differentiate pre or post ductal based on infant vs adult
--> here it is a child so post ductal
--> note on pic to the left, the preductal has a patent ductus arteriosus so there is blood getting to the low extremities - this example shows an important presentation for Turner's syndrome
- 10% of Turners have aortic coarctation and present with hypoxia to the lower exttremities
-> look out for this
Clinical Case
Turner's Syndrome case 4
- example shows Turner's common presentations
- coarctation of aorta --> femoral pulses weak
- bilateral swelling of the fett and hands
- posterior neck mass = cystic hygroma
Notes:
- classic presentations here for Turners Syndrome
- coarctation of aorta --> femoral pulses weak
- bilateral swelling of the fett and hands
--> this is due to lymphedmea
--> very common in Turners in early years of life and slowly regresses - posterior neck mass = cystic hygroma
--> this is a mix of cysts and connective tissue
Clinical Case
Turner's Syndrome case 5
- example shows Turner's most common cardiac defect is bicuspid aortic valve
- think that Turner's has 2 wide nipples, 2 wide neck side and 2 aortic valves = bicuspid valve
Notes:
-
Clinical Case
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
X-linked Androgen
Insensitive Receptors case 1
- biological male = 46 X,Y
Case presentation:
Notes:
- Androgen insensitivity x-linked syndrome is similar in many ways to Turner's syndrome, though very different
--> both are X-linked (Turner's is X chromosome monosomy)
--> both have phenotype of female
--> both Turner's and Androgen insensitive receptors (x-linked) present with primary ammenorrhea (menarche late = at or after age 16) - phenotype = female, but karyotype os 46 -XY
--> normal male levels of testosterone, but androgen receptors are insensitive to testosterone and thus male secondary sexual characteristics can't develop
--> primary male sexual reproductive organs present = testicles (usually located in the lower abdomen / inguinal area)
--> default mullerian duct --> no penis, female external genitalia with no uterus - excess circulating testosterone that cannot activate androgen receptors
--> testosterone converted into estradiol
--> breast formation and other female phenotypical characteristics
*Klinefelter's Syndrome
- biological male = 47, XXY
- also mosacism + 48 XXXY
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
Klinefelter's Syndrome
- 47, XXY
- also mosacism + 48 XXXY
Clinical Case
Notes:
- note the main presentation of Klinefelter's Syndrome is hypoorchidea, dysfunctional Leydig cells which then causes gynecomastea due to higher levels of FSH and LH
- some have intellectual disabilites and some do not
- note that these patients usually don't present until puberty
- note that 47 XXY is the most common karyotype, bute there is also mosaicism
--> mosaicism = 46 XX / 47 XXY
--> 48 XXXY - the more chromosomes the more severe the condition
*Fragile X Syndrome
- most common cause of mental retardation
- FMR1 gene = fragile x mental Retardation gene
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
*Fragile X Syndrome
- most common cause of mental retardation
Notes:
- fragile X syndrome is the most common cause of mental retardation
- classic clinical features are:
- mental retardation
- large prominant forehead
- large ears and long face
- macroorchidism
--> orchi referring to testicles
Clinical case:
- F = face is long
- R = repeats in FMR gene CGG (=chin and GIANT GONADS)
- A = autism and ADHD
- G = Giant gonads (testes)
- I = intelectual disability (most common cause)
- L = large hands and feet
- E = ears are long
- X = Xtensible joints and X linked dominant
--> reason why most common
- X = Xtensible joints and X linked dominant
Notes:
- Cryptorchidism = failure of the gabernaculum to drop the testes into the scrotum
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
Mitochondrial disorder
- blotchy red muscle fibres on stain
Clinical Case
X-linked recessive Disorders
- CAN skip generations
--> mostly ONLY affected males - women are usually carriers
- mother to son transmission
- male --> male transition impossible
*X-linked recessive disorders
- G6PD deficiency (HMP Shunt)
- WAS = Wiskott-Aldrich Syndrome
--> WASp mutation
--> WATER triad
*Genetic terms
Presentation of Turner's Syndrome
"AMENNOREA ...WIDE neck, WIDE breasts, SHORT stature, SHORT ovary life"
- "SHORT ovary life" = ovaries degenerate
--> causes the amennorea
Downs's Cardiac defects
- endocardial cushion defects
- most common Cardiac defect in Down's is common AV valve
--> between both chambers of the heart
- C = cardiac A/V complete and septal defects (ASD most common)
- H = hypotonic / hypoplastic midface
- E = epicanthic folds
- F = flattened nose
- S = Short stature and simean crease
- B = brachycephaly (short skull)
- U = upslanting palpable fissures
- G = GAP 21 = gap in 1st /2nd toe
- M = mental retardation
- A = atresia (duodenal/anal) and APP gene on chromosome 21 = early AD
- P = protruding tongue
Presenting Signs and Symptoms of Down's Syndrome
XLINE FELTER
- X = extra X chromosome
- L = little testes (cryptoorchidism)
- IN = INfertile and INtelectual disability
- Elevated X 2 = FSH and LH
- F = facial hair loss
- E = estrogen high / gynecomastea
- L = long limbs
- T = tall and slim
- Elevated X 2 = FSH and LH
- R = rage/aggressive
It takes many TURNS to become
Horse track B CHAMPS
- B = bicuspid aortic valve
--> hard to TURN OPEN the aortic valve - C = cystic hygroma/webbed neck
--> hard to TURN your NECK - H = Horseshoe kidney
--> your Kidneys TURN to join each other - A = Aortic Coarctation
--> your Aorta takes a SHARP TURN inward - M = monosomy X
--> your other X TURNS into an O - P = Primary Amennoria
--> you never make the TURN towards puberty - S = Streak Ovaries
--> your Ovaries TURN into streaks
*Friedreich Ataxia
- Friedreich is a FRATAXIC Frat brother who is a "GAA head"
- has a big heart
--> presents in childhood with kyphoscoliosis - "Friedreich is a GAA head"
--> Friedreich Ataxia is auto recessive with GAA repeats
--> young athelete in GAA = die from hypertrophic cardiomypathy
*Autosomal dominant disorders
ABCDEFGH for autosomal recessive
- A = Albinism
- B = Beta thalasemia
- C = CF /
- D = Dubin Johnson Syndrome (liver enzyme)
- E = Emphysema (alpha antitrypsin)
- F = Friedrich Ataxia (Fratastic GAA player/kyphoscoliosis)
- G = Galactosemia / Glycogen storage diseases
- Hemochromatosis / Homocystinuria
"A Very DOMINANT Heriditary HUMAN family"
*Achondroplasia
(Dwarfism)
- normal trunk of the body with shorter limbs and extremities
- autosomal dominant
--> BUT 80% are actually sporadic mutations and only 20% are hereditary - mutation in the FGTR gene = fibroblast growth factor receptor
- "Tiaran Lannister is A CON MAN and the Hounds funny GFR" = "CON MAN" = achondroplasia
--> Peter Dinklage has achondroplasia - for achondroplasia think of "Hounds funny GFR and her NEEDLE"
--> "GFR " = funny little GIRLFRIEND
--> "stick them with the POINTY END"
--> Terian = point mutation in FGFR
--> MARFANS in contrast has the "TGFR = transforming" mutation for fibrillin-1 for estin scaffolding
*Neurocutaneous genetic disorders
--> neuro and skin signs together
- Neurofibromatosis
--> types 1 and 2 - VHL = Von-Hippel-Lindau Syndrome
- Tuberus sclerosis
- Sterge-Weber syndrome
*VHL = Von Hippel-Lindau Disease
- mutation in VHL
- "the VON HARP" - VONT trap dominant kid plays the HARP
*NFM = Neurofibromatosis
- type 1 and 2
Neurofibromatosis (type 1)
- "CAFE SPOT" --> eyes, arm pits, fibro back and BOWed Tibias
Clinical Cases
Clinical Case
Notes:
- note that
Clinical Case
Case
Clinical Presentation
Notes:
- note that Neurofibromatosis is a single gene autosomal dominant disorder
- there are 2 types of NF
- it has a mutation in the NF-1 gene = neurofibromatosis gene
- remember that Neurofibromatosis has Cafe Au Lait spots on their skin, which also gives prime = 17 - CAFE SPOT = all the possible symptoms of NF:
- C = cafe au lait spots
- A = axillary freckling (this is much more in NF 1 vs. NF2)
- F = fibromas (dermal often)
- E = eye Lisch Nodules (hamartomas around the iris of the eye)
S = scoliosis and skeletal bowing - P = pseudoarthrosis
- OT = Optic tumors (meningiomas, gliomas, astrocytomas, etc.)
- prime 17 = NF comes from mutation of NF-1 gene on chromosome 17
Neurofibromatosis (type 2)
*Homocystinuria
- see metabolism map
- high homocysteine in urine
- recall HOBO peter patrick
--> living in the Cystern
--> has MARFANS syndrome
--> with HOMOCY + OCCULAR problems - recall HOBO peter patrick PYRIDIMINE and the Methionine VB12 THF folate cycle
--> can't convert homocysteine --> cysteine and disrupts the whole methionine pathway
--> can't make sulfur containing AA's
--> needed for collagen 1 in MARFANs
HOMOCYsteine
- H = high homocysteine in urine
- O = occular problems
- M = marfans (kyphosis and CVS with it)
- O = osteoporosis
- C = CVS problems
- Y = kYphosis (from the marfans)
*CF = cystic fibrosis
- mutation in CFTR Cl- ion protein channel
--> most CFTR can't fold and get degraded before reaching the surface - CF in eccrine sweat glands
--> in resp pumps the cl- out of sweat ducts and back into the cells
--> again the ENaC get inhibited
--> high salt in sweat - CF in lungs and pancreaas
--> in resp pumps the cl- out
--> CFTR inhibits the Na+ ENaC also
--> get dry mucus in lungs = viscous
Clinical Cases
Clinical Case
Notes:
- note that
Clinical Case
Note:
- for autosomal recessive someone with NO disease present and heterozygous auto recessive parents
--> 2/3 chance of being a carrier
--> 1/3 chance of passing 1 mutated allele on
CF = Cystic Fibrosis example
- shows if someone with NO disease present and heterozygous auto recessive parents
--> 2/3 chance of being a carrier
--> 1/3 chance of passing 1 mutated allele on
Notes
- note that since he has a sibling with CF, and her parents have no disease
--> skipped generation
--> auto recessive
--> means her parents are heterozygous - draw a punnett square
--> 4 choices, but patient doesn't have the disease so only 3 - of these 3 2 of them are carriers
--> 2/3 chance of being a carrier - note that crucial step now is to multiply by 2 since if you assume she has 2/3 of being a carrier, she now has to actually pass one of those one
Case example:
Marfan Presentation:
- flat feet
- pectis carinatumm / pectis excavatum
- arachnodactyly
- high arm to height ratio
- tall and thin
longer legs than torso
affects skeleton, eyes and CVS
--> scoliosis / kyphosis
--> blurred vision
--> heart problems
Clinical Cases
Clinical Case
Notes:
- note that
Clinical Case
Marfans syndrome and CVS complications
- 2 most common CVS problems in Marfans
NOtes
- 75% of Marfans have aortic aneurisms
--> lead to aortic dissection = most common cause of death - mitral valve prolapse
--> mitral valve regurgitation
Case presentation:
*Fibrillin in Marfans
-
MARFANS :
- M = MVP
- A = AR (A regurge), AR (ARachnodactyly)
--> (ARACHNO - dactyly = "spider fingers" vs plain Dactyly = sausage fingers) - R = retinal detachment
--> (lens cords have fibrillin/elastin) - F = fibrillin-1 (ligaments and blood vessels)
- A = AN = aoritc ANeurism
- N = Negative Nitroprusside
--> (differentiates HOMOCYsteinuria whihc has marfan in it) - S = subluxated lens (=ectopia lentus)
Subluxation = ectopia lentus of the lens
- the lens is displaced in the eye, but still in the capsule (floating)
*Heteroplasmy
- HETERO = 2 differen cell lines = mito disorders are varient in families
- PLASMA = plamsa DNA = mito DNA
Pathophys - Achondroplasia
- Abnormal Endochondrial Bone growth in Achondroplasia
- normal membranous bone growth
--> facial bones + clavicle
--> they have a large head and large clavicle
Clinical Cases
Clinical Case
Notes:
- note that
Clinical Case
*Achondroplasia
(cases)
-
Clinical Case:
Notes:
- to the left is Peter Dinklage, who has achondroplasia and FGFR1 gene mutation
- achondroplasia = means "without cartilage growth"
- achondroplasia is not the only type of condition causing dwarfism (or little people), but it does make up 80% of the cases of dawrfism
- interesting that 90% of achondroplasia actually comes from de novo genetic defects in the germline FGFR1 gene
--> only 10% are inherited from parents with mutated FGFR1 gene
--> this is even surprising since achondroplasia is also autosomal dominant - note that even though most achondroplasia cases are de novo spontaneous genetic mutations, if you have the condition you are highly likely to pass it on to your children
--> homozygous achondroplasia is usually not compatable with life past the first month of life - brachydactyly
--> brachy- = short; brady- = slow - -dactyly = referring to digits (fingers and toes)
- midface hypoplasia
--> the scrunching up of the midline of the face in achondroplasia- rhizomelia = shortened proximal limbs
--> both upper and lower limbs
- rhizomelia = shortened proximal limbs
- "trident hands"
--> space between the 3rd and 4th digits in achondroplasia - Frontal bossing is a medical term used to describe a
--> prominent, protruding forehead that’s also often associated with a heavy brow ridge
--> think of Tyron Lannistor as the BOSS --> frontal bossing - patients with achondroplasia have increased risk of spinal stenosis
"the VON HARP"
- VONT trap dominant kid plays the HARP
--> can't stand because of RP (renal and adrenal problems) - dominant kid = autosomal dominant
- H = hemangioblastoma
- A = angiomatosis
- R = renal cell carcinoma (RCC bilateral)
- P = pheochromocytosis
--> RCC and pheochromocytosis are the VON trap kids RP reanal and adrenal problems
Hemangioblastoma
- A haemangioblastoma is a rare, slow growing brain tumour.
- It starts in the cells lining the blood vessels in the brain and
--> sometimes in the spinal cord
Angiomatosis
- Angiomatosis is a non-neoplastic condition
- nests of proliferating capillaries arranged in a lobular pattern
- displacing adjacent muscle and fat
- consists of many angiomas
Patau MNeumonics
- pataeu syndrome = PUBERTY time
Edwards Scissor Hand = EDWARDS Syndrome = Trisomy 18
"EDWARD Scissor Hand president slogan = Make America Kids Again"
- E = elongate skull of his BUSH
- D = Digits overlapping
--> his Scissor hands - W = VSD
--> V in his scissor hands
Lets GET DOWN!!! Night Club for Downs people
- Duodenal Atresia Tree = Bouncer of the club
- Club closes at midnight = AD early in downs
--> APC = amyloid precursor protein
--> APC is on chromosome 21
Calvine KLINE FELTER FASHION SHOW
- MRS LADY BUG = fashion queen was there
--> abnormal leydig function
--> high FSH and LH
--> high estrogen - school bus watching = mental retardation
PUBERTY PADDLE PATEAU HALL MONITOR BABY who wear his HOLOPROSENCEPHALY HALO for being so perfect and ROCKS back and forth on his ROCKER BOTTOM FEET and POLYCYSTIC KIDNEYS
- PUBERTY PATEAU the HALL MONITOR with PADDLES
PUBERTY PATEAU PADDLE HALL MONITOR notices some BROKEN CLEFT PLATES and VASEs with DEFECTS in them because TRISOMY 13 ran them over with his TRYSOMY
- HALL MONITOR PADDLE PATEAU hits him in his MICROENCEPHALY small head
- PUBERTY HALL MONITOR PADDLE PATEAU then paddles POLLY DACTYLY who is TEXTING when she should have been studying her RETARDED TAR BOOK
*Diagnosis of Downs
- Quad blood screening test for Downs syndrome
- AFP
- hCG
- Estriol (estrogen from babies liver)
- Inhibin A
*Quad screening test for Downs
- Quad blood screening test for Downs syndrome
Low markers for Downs:
- LOW AFP
- LOW Estriol (estrogen from babies liver)
Raised = placenta compensation markers for Downs:
- hCG
- Inhibin A
- Lisch nodules
--> iris hammartomas
Fibromas
Skeletal bowing
Chromosome 15
- prader willi and angelman syndrome
- Marfan's syndrome
*Prader Willi Syndrome
and Angelman Syndrome
- imprinting of chromosome 15
--> either loss of the imprinting from one parent or loss of entire imprinting gene caused by uniparental disomy
*Prader Willi Syndrome
- imprinting of chromosome 15
- inherited alleles ONLY from MOM
- either microdeletion from father
- or complete loss of father gene from uniparental disomy from mom
*Angelman Syndrome
- imprinting of chromosome 15
- "DADDYs little ANGEL..."
--> inherited alleles ONLY from DAD - either microdeletion from mother
- or complete loss of mother gene from uniparental disomy from dad
- see metabolism map
*Genetics and Inheritance patterns
- pleiotropy = "ploidy of phenotropes"
--> multiple phenotypes from one gene
--> ex: homocysteinuria (HOMOCY symptoms) = all very different systems and proteins but from the same gene
*pleiotropy = "ploidy of phenotropes"
- multiple phenotypes from one gene
--> ex: homocysteinuria (HOMOCY symptoms) = all very different systems and proteins but from the same gene
*Linkage disequilibrium
- the frequency of 2 separate genes/alleles on the same chromosome coming together in the same HAPLOID gamete cell is
--> GREATER than expected
Example:
- always take the frequency of the two alleles
--> p = 0.2 and q = 0.3
--> multiply them = 0.2 x 0.3 = 0.06 - expected frequency of the 2 seaparate genes together = 0.06
--> but in this example the ACTUAL frequency of them together = 0.02
--> much higher than the 0.06 expected
--> thus LINKAGE DISEQUILLIBRIUM
Clinical Cases
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Notes:
- note that
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
*FHH = Familial Hypocalciuric Hypercalcemia
- mutation in CaSRs = calcium sensing receptors
- CaSRs = G protein receptors
*WAS = Wiskott-Aldrich Syndrome
- WASp mutation
- WA-TER triad
--> thrombocytopenia
--> Eczema
--> recurrent infections (immunodeficient)
Clinical Cases
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Notes:
- note that
Meiosis 1 vs 2 Non-disjunction
- Meiosis 1 = disjunction of HOMOLOGOUS chromosomes
--> homologous = different chromosomes - Meiosis 2 = disjunction of SISTER chromatids
--> sister chromatid = copy of the SAME chromosome
Clinical Cases
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Notes:
- note that
CURIOUS GEORGE PHAROH MONKEYS WHO are using their 3 and 4 PHAROH FORKS to try and CATCH 22 the HYPOCALCEMIA COW who stole their THYMIC TURKEY LEG on the PLATE and BROKE their TETANIS TITANIC TOY
Clinical Cases
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Notes:
- note that
DiGeorge Hypothymus Syndrome case 2
Case example:
Notes:
- note that DiGeorge Syndrome here presented with the classic low set ears and cleft palate
- note that DiGeorge has hypocalcemia and hypothymus
--> they present with abnormal muscle movements and seizures due to this
DiGeorge Syndrome
- T cell deficiency
- absent / hypoplastic thymus
- normal B cells
DiGeorge is the CATCH 22 --> CATCH all 3 kinds of bugs!
C = conotruncal cardiac defects (tetralogy of Fallot)
A = abnormal facies
T = T cell deficiency / thymus absent or hypoplastic
C = Cleft palate (or other craniofacial deformities)
H = hypoparathyroidism / hypocalcemia
--> think thymus is absent and also the parathyroid
--> causes hypocalcemia (no PTH)
3 = CD3 counts are lower due to low T cells (CD3+)
--> more prone to all infections (bacteria, fungal, viral)
Genetic deletion on chromosome 21 in DiGeorge Syndrome:
- DiGeorge syndrome is caused by a heterozygous deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2 (22q11.2).
- note the chromosome nomenclature goes:
--> chromosome (#)(p/q = short/long arm)(region on chromosome)(band)(sub-band)
Notes:
- DiGeorge Syndrome is a T cell deficiency genetic disorder due to an absent or hypoplastic thymus
- T cell deficiency in DiG Syndrome comes from a gene deletion on chromosome
- recall that CD = cluster of differentiation re the specific antigens for the different lymphocytes
- B cells (humoral immunity / antibodies)
- CD20+ are B lymphocyte antigens (these are the ones affected in HIV)
--> think of the tv station "WB 20" --> B cells have CD20+ antigens - CD3+ are T lymphocyte antigens (these are the ones affected in DiGeorge Syndrome)
--> think "tylenol 3s = T3s" --> T cells have CD3+ antigens
Pathophys of Di George
- micro deletion of chrom 22.11
- failure of the neural crests cells to migrate to the 3rd and 4th pharyngeal pouches
--> 3/4 puches make the thymus and parathyroid gland
--> this causes the thymus and t cell dysfunction and hypocaclemia from the paraT loss - note the thyroid is separate and descends from the glossus foreman cecum canal
*Mitochondrial myopathy
- red ragged fibres onmuscle biopsy
*Polygenic Inheritance
- "POLY GENES" determine 1 thing
- "AA 8EIGHTS Ball Diseases"
--> AA = Androgenic Alopecia (most common form of male balding and also done by polygenic)
--> Ball = WB 20 chromosome
*Androgenic Alopecia
- "POLY GENES" determine 1 thing
- "AA 8EIGHTS Ball Diseases"
- AA = Androgenic Alopecia (most common form of male balding and also done by polygenic)
--> Ball = WB 20 chromosome for AA
--> also X and Y chromosomes
--> reason why you have variable expressivity with males vs females
*Lysosomal Storage Diseases
- failure to thrive
- see other notes
*Inclusion cell = I cell Lysosomal storag disease
- Lysosomal Storage Diseases
- failure to thrive
Clinical Cases
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Clinical Case
Notes:
- note that
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