Common Genetic Diseases-2548

8/2/2019 Common Genetic Diseases-2548

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Common Genet ic Diseases:

Case Approach

Chanin Lim w ongse, MD

Dept of Medicine,

Facul t y of Medicine Sir iraj Hospit al


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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


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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


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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


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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


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Autosomal dominant inheritance

Affected = heterozygote

Affected in both males

and FemalesMultiple generations

Transmission throughboth sexes

50% recurrence risk

New mutationIncomplete penetrance

Gonadal mosaicism


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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


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Autosomal recessive inheritance

Affected = homozygote

Affected in both males

and FemalesSingle generations

25% recurrence risk insiblings

Pseudodominant

Consanguinity


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X-linked recessive inheritance

Affected = hemizygote

Affected in males and

rarely femalesMultiple generations

25% recurrence risk inoffsprings of female

carrier


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Mitochondrial (maternal) inheritance

Affected = homoplasmyor heteroplasmy

Affected in both sexes

Multiple generationsTransmitted onlythrough females


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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


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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


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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


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Marfan syndrome


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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Neurocutaneous syndrome


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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


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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


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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


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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


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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


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Klippel Trenaunay Weber syndrome

Uni lateral AVM

Hemihypert rophy of affectedside

No malignancy r isk Sporadic in most cases

No CNS sympt om


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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


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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


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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


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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


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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)


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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)

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Common Genetic Diseases-2548