Post on 05-Apr-2018
8/2/2019 Common Genetic Diseases-2548
1/52
Common Genet ic Diseases:
Case Approach
Chanin Lim w ongse, MD
Dept of Medicine,
Facul t y of Medicine Sir iraj Hospit al
8/2/2019 Common Genetic Diseases-2548
2/52
Case presentation - Diagnosis
Diagnosis of a genet ic disorder can be made based upon
- recognit ion of classic present at ion- pathognomonic feature- subdivision int o cat egory and dif ferent ial Dx- recognit ion of special inher it ance pat tern
- guess based on the most common
Brief overv iew of syndromes and t heir classic present at ions
Review of pathognomonic feature of comm on disorders
Sympt om category and different ial diagnosis
Review of inherit ance pat t ern
8/2/2019 Common Genetic Diseases-2548
3/52
Q: Which is the least likely to be hereditary ?
A. Coronary artery diseaseB. Canada-Cronkhite syndrome
C. Gluten enteropathy celiac diseaseD. Mixed hyperlipidemia
E. SLE
8/2/2019 Common Genetic Diseases-2548
4/52
Category of genetic disorders
Chromosomal aberrations
numerical : trisomy, monosomy, etcstructural : translocation, deletion, etccontiguous gene syndrome
Single gene disordersAD,AR,XD,XR,mitochondrial
Multifactorial diseases
Atypical inheritancebigenicimprinting disorders
8/2/2019 Common Genetic Diseases-2548
5/52
Q: The most likely mode of inheritance is (are)
A. Autosomal dominantB. Autosomal recessive
C. X-linked recessive
D. X-linked dominant
E. A or C
P
8/2/2019 Common Genetic Diseases-2548
6/52
Autosomal dominant inheritance
Affected = heterozygote
Affected in both males
and FemalesMultiple generations
Transmission throughboth sexes
50% recurrence risk
New mutationIncomplete penetrance
Gonadal mosaicism
8/2/2019 Common Genetic Diseases-2548
7/52
Autosomal dominant sex-limited inheritance
Affected = heterozygote
Affected in only males
or FemalesMultiple generations
Transmission throughboth sexes skipping
in one gender
50% recurrence risk inonly one gender
New mutation
Incomplete penetrance
Gonadal mosaicism
8/2/2019 Common Genetic Diseases-2548
8/52
Autosomal recessive inheritance
Affected = homozygote
Affected in both males
and FemalesSingle generations
25% recurrence risk insiblings
Pseudodominant
Consanguinity
8/2/2019 Common Genetic Diseases-2548
9/52
X-linked recessive inheritance
Affected = hemizygote
Affected in males and
rarely femalesMultiple generations
25% recurrence risk inoffsprings of female
carrier
8/2/2019 Common Genetic Diseases-2548
10/52
Mitochondrial (maternal) inheritance
Affected = homoplasmyor heteroplasmy
Affected in both sexes
Multiple generationsTransmitted onlythrough females
8/2/2019 Common Genetic Diseases-2548
11/52
Q: Mendelian forms of following disorders
are well known except
A. Diabetes mellitus type 2B. Senile dementia
C. Hyporeninemic hypertensionD. Distal IP osteoarthritis
E. Coronary heart disease
8/2/2019 Common Genetic Diseases-2548
12/52
Q: Which is incorrect ?
A. Marfan syndrome ascending aortitis
B. Turner syndrome aortic coarctation
C. DiGeorge syndrome interrupted Aoarch
D. Ehlers-Danlos syndrome aortic
dilatationE. Williams syndrome aortic stenosis
8/2/2019 Common Genetic Diseases-2548
13/52
Marfan syndrome- AD, new mutation 50%
Acut e chest pain, Aort icdissect ion, CHF, Aort ic
regurgit ation, Dilat ed aort icroot
Lens subluxation/ dislocation
Skeletal finding: t all st ature,
pectus, scoliosis, pes planus,dolichost enomelia, j oint laxi t y
Charact erist ic signs: thum b,w rist , arachnodact yly,onycho-um bilical, duralectasia, st riae at rophica
W/ U: echo, eye
Rx: beta blocker, Bentall
operation for root > 5.5 cmG:FBN1 15q P:Fibrillin 1
8/2/2019 Common Genetic Diseases-2548
14/52
Marfan syndrome
8/2/2019 Common Genetic Diseases-2548
15/52
Q: Treatment for Marfan syndrome include
all except
A. Avoidance of weight lifting
B. Bental operation for severe AR
C. Beta adrenergic blocker for Ao dilatation
D. Lens removal for subluxation
E. Hormonal treatment for excessive height
8/2/2019 Common Genetic Diseases-2548
16/52
Velocardiofacial syndrome
DiGeorge sequence
22q11 m icrodelet ion (cont iguous gene syndrome)
Sporadic or f amil ial Conot runcal heart defect + t hymus hypoplasia +
t ransient hypocalcemia + cleft palate
Long f ingers, abnorm al nose, smooth ph ilt rum
W/ U: FI SH w ith 22q11 probe
8/2/2019 Common Genetic Diseases-2548
17/52
Q:Adults with Down syndrome are prone
to all of the following except ?
A. Premature myocardial infarctionB. Dementia of Alzheimer type
C. Acute leukemiaD. Hypothyroidism
E. Spinal cord injury
8/2/2019 Common Genetic Diseases-2548
18/52
Down syndrome
Shor t , flat facies, upslantpalpebral f issure, low set ear,epicanthus, large tongue,
sim ian crease, t oe 1-2 gap Adult issue: hypothyroidism,
C1-2 instabilit y, dement ia,DM, CHD
CHD: AV canal, VSD, TOF W/ U: chromosome, echo, TSH
Almost alw ays sporadict risomy 21 by maternalnondisjunction
Recurrent risk only int ranslocation Dow n comm onlyt (14;21) t (21;22) t (21;21)
Male infert ile, female possibly
fert i le
8/2/2019 Common Genetic Diseases-2548
19/52
Q: Growth hormonal supplement in Turner
syndrome should
A. Begin before pubertyB. Be given lifelong
C. Be used with estrogenD. Never be given
E. Always be attempted if pt is short
8/2/2019 Common Genetic Diseases-2548
20/52
Turner syndrome
Short , prepubert al, broad chest ,increased carrying angle, nevi,
pt osis, neck w ebbing, shor t 4 MCP Amenorrhea primary / secondary
Adult issue: in fert ili t y, HTN, CVArisk, DM, thyroidit is
W/ U: BP, chromosome Comm only 45,X 50% mat
nondisjuction
Less comm on: 46,Xi(Xq)
46,Xr( X) or mosaic abnormality Rx: HRT prevent osteoporosis,
grow th hormone in children
8/2/2019 Common Genetic Diseases-2548
21/52
Q: A female with hemophilia A is least
likely to be ?
A. A Turner syndrome ptB. A pt with chromosomal translocation
C. A product of carrier father and motherD. A product of carrier mother plus new
mutationE. A sex reversal pt
8/2/2019 Common Genetic Diseases-2548
22/52
Q:A male with 47,XXY should
A. Be mentally retardedB. Be infertile
C. Be an aggressive maleD. Have gynaecomastia
E. Have two Barr bodies in buccal smear
8/2/2019 Common Genetic Diseases-2548
23/52
Klinefelter syndrome
Normal t o sl ight ly high normalheight , gynecomast ia, smallf i rm t estes
Variable int elligence f romnormal in most t o borderl ine
Adult issue: hypogonadism,
chron ic st asis ulcer,mediast inal germ cell t umor
W/ U: chromosome
Ext ra X such as 47,XXY
48,XXYY etc. All sporadic 50%paternal nondisjuction
Rx: t estosterone I M
8/2/2019 Common Genetic Diseases-2548
24/52
Q: Which of the followings is not true
regarding treatment of Klinefelter syndrome
A. Assisted reproduction could be attempted
B. Hormone replacement can result in increased spermcount
C. Secondary sexual characterisitics can be enhanced
D. Lifelong hormonal treatment may not be necessary
E. Libido is improved with hormone implementation
8/2/2019 Common Genetic Diseases-2548
25/52
Neurocutaneous syndrome
8/2/2019 Common Genetic Diseases-2548
26/52
Q: Which of the following cutaneous disorders is
NOT likely to be associated with mental deficiency ?
A. Multiple lentigenes over the whole body
B. Multiple caf-au-lait spots
C. Multiple unilateral facial hemangioma
D. Multiple nasolabial angiofibroma
E. Multiple linear verrucous multistaged
pigmentary abnormality along Blaschkos line
8/2/2019 Common Genetic Diseases-2548
27/52
Neurofibromatosis I - AD
Caf au lait macule, NF, opt icglioma
Diff Dx: fami lial CAL Variant : NF-Noonan, Watson
Risk of malignancy: PNST 14% ,j uvenile MMoL
Adult issue: HTN, renal a st enosis,pheochromocytoma, CVA
W/ U: None
Rx: symptomat ic, surgery rarely
G:NF1 17q P:Neurofibromin
8/2/2019 Common Genetic Diseases-2548
28/52
Neurofibromatosis II- AD
Hearing impairment, tinnitus,
weakness
Small amount of Caf-au-laitmacules, subcutaneous nodules,posterior subcapsular cataract,retinal hamartoma
CNS tumor: schwannoma,meningioma, ependymoma, glioma
Two subtype : Wishart early severe,
Gardner late mild to moderate W/U: MRI whole brain-spine,
hearing
Rx: surgery
G:NF2 22q P:MERLIN
8/2/2019 Common Genetic Diseases-2548
29/52
Sturge Weber syndrome
Almost alw ays sporadic
Port w ine stain uni lat eral
Nevus flammeus Cerebral gyral calcif icat ion
Adult issues: epilepsy
W/ U: CT brain
Rx: ant i-epilept ic drug
8/2/2019 Common Genetic Diseases-2548
30/52
Tuberous sclerosis
Hamartomata in manyorgans: tuber
MR, seizures
Periungual fibroma
Glioma in brain/fundus
Angiofibroma on face
Angiomyolipoma in kidneys W/U: U/S, CT, echo
Rx: anti-epileptic
G1: TSC1 9q P1: Hamartin
G2: TSC2 16p P2: Tuberin
8/2/2019 Common Genetic Diseases-2548
31/52
Klippel Trenaunay Weber syndrome
Uni lateral AVM
Hemihypert rophy of affectedside
No malignancy r isk Sporadic in most cases
No CNS sympt om
8/2/2019 Common Genetic Diseases-2548
32/52
Li-Fraumeni syndrome - AD
Mult iple t umors esp: brain,sarcoma, breast , leukemia
Tw o hit t heory (Knudson) Tumor suppressor gene
mutation
1st hit = germ line mut at ion
2nd hit = somat ic mut at ion
Bilateral Breast, 40Bilateral Breast, 40
Leukemia, 33Leukemia, 33
Brain tumor, 32Brain tumor, 32
Breast, 40Breast, 40
OsteosarcomaOsteosarcoma, 42, 42
Breast, 35Breast, 35
Soft tissueSoft tissue
sarcoma, 7sarcoma, 7Leukemia, 6Leukemia, 6
G:TP53 17p P:p53
Cl f C h d d
8/2/2019 Common Genetic Diseases-2548
33/52
Cluster of Cancer in hereditary cancer syndromes
FAP: colon, duodenum , ampul la of Vater, st omach
HNPCC: colon, ur inary, endometrial, GI t ract , brain
HBOC: breast , ovarian, male breast , prostate, pancreas
VHL: cerebellar hemangioblastoma, renal cell CA,pheochromocytoma, paraganglioma
Turcot : brain, colon
Muir Torre: acanthom a, colon PJS: colon, pancreas, sex cord
LFS: brain, sarcoma, leukemia, adrenal cell CA, breast
Fami lial melanoma: melanoma, pancreas
Q: A 16 h f d t h
8/2/2019 Common Genetic Diseases-2548
34/52
Q:A 16 yo woman who was found to have
numerous colonic polyposis should
A. Have her polypectomy attempted
B. Have her brain imaged
C. Have her chromosome studied
D. Have her fundi examined
E. Have her mammogram performed
Q: Indicated testing fo HNPCC famil
8/2/2019 Common Genetic Diseases-2548
35/52
Q: Indicated testing for HNPCC family
members include all except
A. Urine cytology annually
B. Sigmoidoscopy biannually
C. Pelvic exam with endometrial aspirateannually
D. Sputum cytology annually
E. PSA annually
8/2/2019 Common Genetic Diseases-2548
36/52
Familial adenomatous polyposis- AD
Adenomatous polyposis
Sit e: colon t o rect um, sparse
elsewhere Risk of malignancy : 100%
CHRPE pat hognomonic
Sympt om: t umor
W/ U: GI FT, biopsy Rx: t otal colectomy w ith
colostomy, proctocolectomyw it h ileoanal anastomosis or
ileal pouch ileorect alanastomosis, COX2 inhibi t or(celecoxib preferred)
8/2/2019 Common Genetic Diseases-2548
37/52
Gardner syndrome- AD
Desmoid tumor of rectussheath
Adenomatous polyposis Sit e: colon t o rect um, sparseelsewhere
Risk of malignancy : 100%
Sympt om: t umor W/ U: GI FT, biopsy
Rx: t otal colectomy w ithcolostomy, proctocolectomy
w it h ileoanal anastomosis orileal pouch ileorect alanastomosis, COX2 inhibi t or(celecoxib preferred)
Q: A female with Peutz Jeghers syndrome
8/2/2019 Common Genetic Diseases-2548
38/52
Q:A female with Peutz-Jeghers syndrome
could have all of the followings except
A. Chronic abdominal painB. Rectal polyp
C. Iron deficiency anemiaD. Pancreatic carcinoma
E. Retinal hyperpigment abnormality
8/2/2019 Common Genetic Diseases-2548
39/52
Peutz-Jegher syndrome
Hyperm elanosis at oral/ acral
Hamartomatous polyposis
Site: t hroughout GI t ract , mostat int est ines
Risk of malignancy : low t omoderate: colon, pancreas,
breast , sex cord t umor Symptom: I DA, colics
W/ U: GI FT, biopsy
Rx: surgery if obstruct ion
occurs
G:STK11 19p
P:serine/threonine kinase
8/2/2019 Common Genetic Diseases-2548
40/52
Spinobulbar muscular dystrophy
SBMA or Kennedy disease
CAG expansion in androgen
receptor gene Prox imal w eakness,gynecomast ia, hypogonadism
XR inherit ance
DNA test available Rx: t estosterone if necessary
8/2/2019 Common Genetic Diseases-2548
41/52
Osler-Weber-Rendu disease- AD
HHT
2 genes: endoglin and act ivin -
l ike grow th factor AD
AVM in organs: livermult iplenodules, hemoptysis
W/ U: CT w cont rast or MRA,liver CT
h h
8/2/2019 Common Genetic Diseases-2548
42/52
Dystrophinopathy
3 subt ypes
Duchenne early severe, veryhigh CK, lif e span less t han 30
Becker early or late, mild CKelevat ion, near norm al spanupto 40-50 yrs.
Cardiomyopathy only
Balf pseudohypert rophy isseen is bot h Becker and
Duchenne subtypes DNA test ing available,
prenatal diagnosis possible
Wil di
8/2/2019 Common Genetic Diseases-2548
43/52
Wilson disease
KF r ing, low ceruloplasmin,high urine copper > 200 ug/ D
Liver hepat it is or
cholestasis, low ALP CNS- parkinsonism, dement ia
Others: hemolyt ic anemia
Rx: zinc SO4 as 1st line, use D-penicil lamine only w hen lifet hreatening such asimpending liver failure, severeneurologic disease
Asymptomatic memberw orkup: eye,ceruloplasmin,24 hr ur ine Cu
G:CuATPase 13pP:Copper ATPase
S t t
8/2/2019 Common Genetic Diseases-2548
44/52
Symptom category
Hematologic abnormalityanemiathrombosis
bleeding (systemic) Neurologic abnormality
myopathyneuropathyencephalopathydementiaabnormal movementseizures
Urinary abnormalit y
hematuria Oncologic abnorm alit y
Skin abnormality
Skeletal abnormalityshort staturetal l st ature
CVS abnormalityCHFchest painsudden deathmalignant HTN
Respiratory abnormalityhemoptysislung lesion on CXRpneumothorax
GI abnormalit ybleedingpolyposisj aundice/ cirrhosis
Sk l t l b lit
8/2/2019 Common Genetic Diseases-2548
45/52
Skeletal abnormality
Short st atureproport ionate or notassociated f indings
Diff Dx: famil ial short stature,familail delayed m aturat ion,bone dysplasia, endocrine esphypothyroidism, primordial
short st ature, specif icsyndrome
W/ U: dysmorphic exam, boneage, specif ic t est ing,
chromosome if mult ipleanomalies or DNA if suspect aspecif ic syndrome
Tall st atureGigantismSotos syndrome
MarfanAndrogen insensit ivit yKlinefelter
Maj or point
MR ? -> Sotosfemale XY ? -> AI SMarfanoid ?Advanced bone age ->
Sotos W/ U: chromosome, specific
t est for each syndrome
CVS b lit
8/2/2019 Common Genetic Diseases-2548
46/52
CVS abnormality
Sudden deathWPW AD t ypeBrugada AD; SCN5A
LQT syndrome AD; KVLQT1
Malignant HTNpheochromocytoma
MEN I and I Ivon Hippel-Lindau s.Neurofibromatosis t ype 1
CHF cardiomyopathyX-linked Dyst rophinopathyHOCM :myosin heavy chain
and many other genes
Chest painMI homocyst inur ia,
thrombophil iadissect ion - Marfan
Respiratory GI & Hematologic abnormality
8/2/2019 Common Genetic Diseases-2548
47/52
Respiratory, GI & Hematologic abnormality
GI abnormalit ybleeding- HHT
polyposis- Familialadenomatous polyposis,Peutz-Jeghers S., Turcot S.
j aundice/ cirr hosis Wi lson disease, hereditaryhemochromatosis
Hematologic abnormalityanemia thalassemiableeding- hemophilia,
von Wil lebrand disease
HemoptysisAVM- Osler Weber Rendu orhereditary hemorrhagic
telangiectasia (HHT)
Lung lesion on CXRAVM- Osler Weber Rendu or
hereditary hemorrhagictelangiectasia (HHT)
Spontaneous pneumothoraxMarfan, t uberous sclerosis
Myopathy
8/2/2019 Common Genetic Diseases-2548
48/52
Myopathy
Muscular dyst rophyelevated CK, muscle w ast ing, biopsy show ed
necrosis+ regenerat ion
AD- facioscapulohumeral dyst rophyAD- oculopharyngeal muscular dyst rophy
XR- Duchenne and Becker subt ype of dyst rophinopathyXR- Emery-Dreyfuss dyst rophyAR- Limb girdle muscular dyst rophy
Peripheral Neuropathy
8/2/2019 Common Genetic Diseases-2548
49/52
Peripheral Neuropathy
Heredit ary sensorim otor neuropathy (Charcot -Marie-Toothdisease)
AD non-progressiveabsent reflexesclaw hand and pes cavus deform it y champagne bot t le leg
consist ent NCV Porphyria acute intermit t ent porphyria AI P
AD interm it t entpure motor
respiratory failuredark colored urineelevated plasma porphobilinogen
Q: Which of the following is true regarding
8/2/2019 Common Genetic Diseases-2548
50/52
Q g g g
a male with symmetric polyneuropathy ?A. Pure motor neuropathy is halmark of acute intermittent
porphyria (AD)
B. Pure motor neuropathy is hallmark of familial amyloidneuropathy (AD)
C. Pure sensory neuropathy is hallmark of metachromatic
leukodystrophy (AR)D. Pure sensory neuropathy is hallmark of Charcot-Marie-
Tooth disease (AD)
E. Mixed sensorimotor neuropathy is hallmark of spinalmuscular atrophy (AR)
Motor neuron disease Spinal neuropathy
8/2/2019 Common Genetic Diseases-2548
51/52
Motor neuron disease Spinal neuropathy
Spinal muscular at rophy - ARusually infant ile onset
absent reflexnormal or m inimally elevated CKgroup at rophy on biopsyconsist ent EMG/ NCV
DNA test available Spinobulbar muscular at rophy (Kennedy disease)- XR
orofacial fasciculat iongynecomast ia, hypogonadism
DNA test for CAG expansion in androgen receptoravailable
Pathognomonic features
8/2/2019 Common Genetic Diseases-2548
52/52
Pathognomonic features
KF ring Wilson disease
Ort hodeoxia HHT
Osteoma of mandible Gardner syndrome (FAP) CHRPE- FAP
Oral hamart oma MEN 2B
Ectopia lent is Marfan or Homocyst inur ia Chorea Hunt ington disease
Prim ary lact ic acidemia mit ochondrial diseases
Winged scapula - FSHD
Myotonia Myotonic dyst rophy (adult )
Myotonia congenit a (children)