genetic conditions for usmle

7/28/2019 Genetic conditions for USMLE

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Condition Basic Mechanisms Clinical Features Other Cancers

Hereditary breast-ovarian cancer syndromeAD; BRCA1 and

BRCA2

Breast cancer, ovarian cancer.

Rx: surgery/chemo, cancer

surveillance, prophylactic

sur er

BRCA1- prostate and colon; BRCA2-

laryngeal, colon, stomach, bile duct,

hematologic and melanoma

CowdenAD; PTEN gene (tumor

suppressor)

GI hemartomatous polyposis;Macrocephaly, Facial/buccal

papules

Breast cancer, thyroid cancer,

endometrial cancers

Li FraumeniAD; TP53 tumor

suppressor

soft tissue sarcoma,

osteosarcoma, bilateral breast

cancer, CNS tumors

very high cancer risk. Early onset.

leukemia, brain, adrenal cortical

cancer, melanoma, etc

Peutz-Jeghers syndrome AD, STK11 genehyperpigmented macules -

lips/mouth, GI hemartomatous

polyps

childhood GI hamartomas/cancer,

breast cancer, ovarian cancer

n o n -

p o l y p o s i s

Lynch syndrome

AD, MLH1 and MSH2

(mismatch repair,

caretaker)

NPNCC-related tumors:

colorectal, endometrial, ovarian,

urinary tract; Rx: Colectomy,

Cancer surveillance

colon, endometrium, ovary,

stomach, small intestine,

hepatobiliary tract, urinary tract,

brain, skin

CowdenAD; PTEN gene (tumor

suppressor)

hamartomatous polyps;

facial/buccal papules

Breast cancer, thyroid cancer,

endometrial cancers

Peutz-JeghersAD; TP53 tumor

suppressor

hamartomatous polyps;

hyperpigmented macules

childhood GI hamartomas/cancer,

breast cancer, ovarian cancer

familial adenomatous polyposis (FAP)

AD; APC gene tumor

suppressor

(gatekeeper)

adenomatous polyps;

attenuated FAP: fewer polyps

Rx: surgery/chemo,

cancersurveillance, prophylactic

surgery

extracolonic tumors (upper GI,

desmoid, osteoma, thyroid, brain)

gardner syndrome: + osteomas

and soft tissue tumors; turcot

syndrome: +CNS tumors

(medulloblastoma);

Fanconi's anemiaAR; chromosomal

breakage disorder

Radial hypoplasia (absent radii

and thumbs), pancytopenia Rx:

bone marrow transplant

leukemia, myelodysplasic

syndrome, solid tumors, liver

short stature,

hyper/hypopigmentation,

pancytopenia,

urogenital

abnormalities

Ataxia telangiectasia

AR; chromosome

breakage disorder

ataxia, telangiectasias, cancer

risk lymphoma, leukemia

Von Hippel-Lindau disease

AD; VHL gene tumor

suppressor

(gatekeeper)

Hemangioblastoma (cerebellum,

retina, spinal cord),

pheochromocytoma (HTN),

renal cell ca

MEN 1

AD; MEN1 gene tumor

suppressor

PPP (pituitary, parathyroid,

pancreas)

MEN 2

AD; RET gene, proto-

oncogene

thyroid-medullary cancer,

pheochromocytoma,

marfanoid habitus mucosal neuromas

O t h e r

Retinoblastoma

AD; RB1 tumor

suppressor

retinoblatoma (bilateral =

hereditable, unilateral =

nonheritable)

heritable: extraocular

osteosarcomas, sarcomas,

melanomas

B r e a s t a n d o v a r i a n c a n c e r

s y n d r o m e s

m a n y p o l y p s

C o l o n C a n c e r

a u t o s o m a l r e c e s s i v e

E n d o c r i n e

7/28/2019 Genetic conditions for USMLE

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Condition Basic Mechanisms Clinical Features Other Dx DDx

Galactosemia

AR; Galactose-1-phosphate

uridyltransferase (GALT)

enzyme

cataract, hepatomegaly, E. coli

sepsis. Rx: dietary intervention,

lactose restriction

galactosuria, FTT,

vomiting/diarrhea,

hepatomegaly, e coli sepsis

Maple Syrup UrineDisease

AR; branched-chain alpha-

ketoacid dehydrogenaseenzyme complex (BCKAD);

aminoacidopathy

lethargy - coma, seizures, maple

syrup odor; Rx: dietary

intervention, BCAA restriction

poor feeding, maple syrupodor

elevated BCAAs, enzymeanalysis

ketosis, no acidosis,no hyperammonemia

Methylmalonic

acidemiaAR; organic acidemia

severe ketoacidosis, seizures,

encephalopathy

severe ketoacidosis,

hyperammonemia,

neutro enia, vomitin

ketosis, acidosis,

hyperammonemia

Ornithine

Transcarbamyl-ase

deficiency (OTC)

X-linked recessive; urea

cycle disorder

Coma, seizures,

hyperammonemia; Rx:

hemodialysis

hyperammonemia, respiratory

alkalosis, protein avoidance,

FTT, vomiting

expressed in females due

to lyonization

hyperammonemia,

no ketosis, no

acidosis

PKU

AR, phenylalanine

hydroxylase enzyme,

aminoacidopathy

MR, blue eyes/fair skin,

eczematous rash. Rx: dietary

phenylalanine restriction

musty body odor,

hyperactivity, seizures

newborn screen, plasma

phenylalanine

homocystinuriaAR, cystathionine beta

synthase enzyme (CBS)

ectopic lentis,

thromboembolism, MR/DD,

marfanoid. Rx: dietary protein

restriction

newborn screen; urine

homocystine, plasma Aas,

enzyme analysis, DNA

anal sis

Amino Acidopathy Organic Acidemia Urea Cycle disorder

PKU methylmalonic acidemia OTC deficiency

MSUD

homocystinuria


Leber Hereditary

Optic Neuropathy

(LHON)

mtDNA point mutations bilateral vision loss- young adultbilndness, neuropathy,

myopathy

opthalmology exam,

mtDNA analysis

MELAS

mtDNA pt mutation:

m3243A>G MT-TL1 gene

(tRNA)

mitochondrial

encephalomyopathy, lactic

acidosis, stroke-like episodes

cardiomyopathy, arrhythmia,encephalomyopathy, stroke

like episodes, seizures,

hearing loss, lactic acidosis,

vomiting

lactate, brain imaging,

muscle biopsy, mtDNA

analysis

p e r o x i s o m

a l

Zellweger syndrome

AR; peroxisomal disease

(no peroxisomes are

formed)

hypotonia, facial dysmorphism,

elevated VLCFA

Facial dysmorphism: high

forehead, large fontanels,

hypotonia, seizures, poor

feeding liver dysfunction

biochem testing including

VLCFA levels, DNA

analysis

F a t

t y - a c i d o x i d a t i o n

d e f e c t Medium-Chain Acyl-

Coenzyme A (MCAD)

deficiency

AR; MCAD enzyme, fatty

acid oxidation defect

hypoketotic hypoglycemia,

myopathy, cardiomyopathy. Rx:

avoid fasting, frequent feedings,

carbs

normal at birthy, vomiting,

sudden infant death

newborn screen, plasma

acylcarnitines, enzyme

and/or DNA analysis


G l y c o g e n

von Gierke's disease

(GSD I)

AR; glucose 6-phosphatase;

glycogen storage disease

hypoglycemia, massive

hepatomegaly, lactic acidosis; Rx:

avoid fasting, frequent feedings,

carbs

growth failure, hypoglycemic

seizures

clinical features, liver

enzyme analysis

and/orDNA analysis

G

l y c o g e +

l y

s o s o m e

Pompe disease

AR; acid alpha glucosidase

(GAA) enzyme; glycogen

storage and lysosome

storage

cardiomegaly/HCM, macroglossia,

muscle weakness. Rx: Enzyme

replacement therapy

cardiomegaly, macroglossia,

hypotonia, poor feeding,

failure to thrive, elevated

creatinine kinase

blood enzyme activity

and/or DNA analysis

von gierke's

symptomes +

cardiomegaly

Fabry

X-linked; alpha

galactosidase enzyme,

lysosomal storage disease

corneal opacities,

angiokeratomas,

acroparesthesias. Rx: enzyme

replacement therapy

cardiomyopathy, transient

ischemic attacks, stroke,

neuropathy, angiokeratoma,

proteinuria, kidney failure,

irritable bowel s ndrome

clinical features. Male:

enzyme analysis and/or

DNA analysis. Females:

DNA analysis

Gaucher

AR; glucosylceramidase

enzyme, lysosomal storage

disease

anemia, hepatosplenomegaly, no

cherry red spot

absence of primary CNS

disease, bone disease/pain,

lipid-laden macrophages with

wrinkled paper inclusions

clinical features, enzyme

analysis and/or DNA

analysis

no cherry red spot

Tay Sachs

AR; hexoasminidase A

enzyme; lysosomal storage

disease

infant, cherry red spot,

progressive neurodegeneration

hypotonia, loss of motor skills,

hyperacusis neurodeneration:

seizures, spasticity; normal

sized liver and spleen

clinical features, enzyme

analysis and/or DNA

analysis

cherry red spot

Hurler syndrome,

Mucopolysaccharidos

es type I (MPS I)

AR, [all MPS =AR except

Hunter (MPS II) is X-linked];

lysosomal storage disease.

coarse features, MR,

hepatosplenomegaly. Rx: ERT,

bone marrow transplant

macrocep a y, cornea

opacities, enlarged tongue,

valvular heart disease,

hearing loss, joint stiffness,

dwarfism, Urine: dermatan

blood enzyme activity

and/or DNA analysis

i n t o x i c a t i o n p h e n

o t y p e s

n o n i n t o x i c a t i o n

p h e n o t y p e s

INTOXICATION

General characteristics of intoxication pathways: normal delivery, symptom-free before crash. Poor feeds, weak suck, weight loss, vomit, weak cry,

hypertonia/hypotonia/seizures/coma

ENERGY DEFICIENCY

L y s o s o m e

prenatal abnormalities (absent corpus callosum), no symptom-free interval, flaccid birth, poor respiratory effort, several hypotonia, dysmorphology, usually craniofacial, true

seizures from birth

m i t o c h o n

d r i a l

STORAGE DISEASE

Glycogen storage: metabolic symptoms - hypoglycemia, hepatomegaly and no splenomegaly

Lysosome storage: hepatosplenomegaly, CNS, bone, skin. Symptoms are progressive

genetic conditions for usmle

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