Genetic conditions for USMLE

Condition

Breast and ovarian cancer syndromes

Hereditary breast-ovarian cancer syndrome

Cowden

many polyps autosomal recessive Other

Endocrine

Colon Cancer

nonpolyposis

Li Fraumeni

Basic Mechanisms

Clinical Features Breast cancer, ovarian cancer. AD; BRCA1 and Rx: surgery/chemo, cancer BRCA2 surveillance, prophylactic surgery GI hemartomatous polyposis; AD; PTEN gene (tumor Macrocephaly, Facial/buccal suppressor) papules soft tissue sarcoma, AD; TP53 tumor osteosarcoma, bilateral breast suppressor cancer, CNS tumors

Other Cancers BRCA1- prostate and colon; BRCA2laryngeal, colon, stomach, bile duct, hematologic and melanoma Breast cancer, thyroid cancer, endometrial cancers very high cancer risk. Early onset. leukemia, brain, adrenal cortical cancer, melanoma, etc

Peutz-Jeghers syndrome

AD, STK11 gene

hyperpigmented macules lips/mouth, GI hemartomatous polyps

childhood GI hamartomas/cancer, breast cancer, ovarian cancer

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

Cowden

AD; PTEN gene (tumor hamartomatous polyps; suppressor) facial/buccal papules

Peutz-Jeghers

AD; TP53 tumor suppressor

hamartomatous polyps; hyperpigmented macules

childhood GI hamartomas/cancer, breast cancer, ovarian cancer

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);

AR; chromosomal breakage disorder

Radial hypoplasia (absent radii leukemia, myelodysplasic and thumbs), pancytopenia Rx: syndrome, solid tumors, liver bone marrow transplant

AR; chromosome breakage disorder

ataxia, telangiectasias, cancer risk

familial adenomatous polyposis (FAP)

Fanconi's anemia

Ataxia telangiectasia

Breast cancer, thyroid cancer, endometrial cancers

lymphoma, leukemia

MEN 2

Hemangioblastoma (cerebellum, retina, spinal cord), pheochromocytoma (HTN), renal cell ca PPP (pituitary, parathyroid, pancreas) thyroid-medullary cancer, AD; RET gene, proto- pheochromocytoma, oncogene marfanoid habitus mucosal neuromas

Retinoblastoma

AD; RB1 tumor suppressor

Von Hippel-Lindau disease MEN 1

AD; VHL gene tumor suppressor (gatekeeper) AD; MEN1 gene tumor suppressor

retinoblatoma (bilateral = hereditable, unilateral = nonheritable)

heritable: extraocular osteosarcomas, sarcomas, melanomas

short stature, hyper/hypopig mentation, pancytopenia, urogenital abnormalities

INTOXICATION

nonintoxication phenotypes

intoxication phenotypes

General characteristics of intoxication pathways: normal delivery, symptom-free before crash. Poor feeds, weak suck, weight loss, vomit, weak cry, hypertonia/hypotonia/seizures/coma Condition Basic Mechanisms Clinical Features Other Dx DDx Galactosemia

AR; Galactose-1-phosphate cataract, hepatomegaly, E. coli uridyltransferase (GALT) sepsis. Rx: dietary intervention, enzyme lactose restriction

galactosuria, FTT, vomiting/diarrhea, hepatomegaly, e coli sepsis

Maple Syrup Urine Disease

AR; branched-chain alphalethargy - coma, seizures, maple ketoacid dehydrogenase syrup odor; Rx: dietary enzyme complex (BCKAD); intervention, BCAA restriction aminoacidopathy

poor feeding, maple syrup odor

Methylmalonic acidemia

AR; organic acidemia

Ornithine Transcarbamyl-ase deficiency (OTC)

X-linked recessive; urea cycle disorder

PKU

AR, phenylalanine hydroxylase enzyme, aminoacidopathy

homocystinuria

AR, cystathionine beta synthase enzyme (CBS)

Amino Acidopathy PKU MSUD homocystinuria

Organic Acidemia methylmalonic acidemia

severe ketoacidosis, seizures, encephalopathy Coma, seizures, hyperammonemia; Rx: hemodialysis MR, blue eyes/fair skin, eczematous rash. Rx: dietary phenylalanine restriction ectopic lentis, thromboembolism, MR/DD, marfanoid. Rx: dietary protein restriction

elevated BCAAs, enzyme analysis

severe ketoacidosis, hyperammonemia, neutropenia, vomiting hyperammonemia, respiratory expressed in females due alkalosis, protein avoidance, to lyonization FTT, vomiting musty body odor, hyperactivity, seizures

ketosis, no acidosis, no hyperammonemia

ketosis, acidosis, hyperammonemia hyperammonemia, no ketosis, no acidosis

newborn screen, plasma phenylalanine newborn screen; urine homocystine, plasma Aas, enzyme analysis, DNA analysis

Urea Cycle disorder OTC deficiency

ENERGY DEFICIENCY

Fatty-acid oxidation peroxisom defect al

mitochondrial

prenatal abnormalities (absent corpus callosum), no symptom-free interval, flaccid birth, poor respiratory effort, several hypotonia, dysmorphology, usually craniofacial, true seizures from birth Condition Leber Hereditary Optic Neuropathy (LHON)

Basic Mechanisms

Clinical Features

Other

Dx

mtDNA point mutations

bilateral vision loss- young adult

bilndness, neuropathy, myopathy

opthalmology exam, mtDNA analysis

MELAS

mtDNA pt mutation: m3243A>G MT-TL1 gene (tRNA)

mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes

Zellweger syndrome

AR; peroxisomal disease (no peroxisomes are formed)

hypotonia, facial dysmorphism, elevated VLCFA

Medium-Chain AcylAR; MCAD enzyme, fatty Coenzyme A (MCAD) acid oxidation defect deficiency

hypoketotic hypoglycemia, myopathy, cardiomyopathy. Rx: avoid fasting, frequent feedings, carbs

cardiomyopathy, arrhythmia, encephalomyopathy, stroke like episodes, seizures, hearing loss, lactic acidosis, vomiting Facial dysmorphism: high forehead, large fontanels, hypotonia, seizures, poor feeding liver dysfunction

normal at birthy, vomiting, sudden infant death

DDx

lactate, brain imaging, muscle biopsy, mtDNA analysis biochem testing including VLCFA levels, DNA analysis

newborn screen, plasma acylcarnitines, enzyme and/or DNA analysis

STORAGE DISEASE Glycogen storage: metabolic symptoms - hypoglycemia, hepatomegaly and no splenomegaly Lysosome storage: hepatosplenomegaly, CNS, bone, skin. Symptoms are progressive

Lysosome

Glycoge + lysosome

Glycogen

Condition von Gierke's disease (GSD I)

Basic Mechanisms

Clinical Features Other hypoglycemia, massive AR; glucose 6-phosphatase; hepatomegaly, lactic acidosis; Rx: growth failure, hypoglycemic glycogen storage disease avoid fasting, frequent feedings, seizures carbs

Dx

Pompe disease

AR; acid alpha glucosidase cardiomegaly/HCM, macroglossia, (GAA) enzyme; glycogen muscle weakness. Rx: Enzyme storage and lysosome replacement therapy storage

Fabry

X-linked; alpha galactosidase enzyme, lysosomal storage disease

Gaucher

absence of primary CNS AR; glucosylceramidase clinical features, enzyme anemia, hepatosplenomegaly, no disease, bone disease/pain, enzyme, lysosomal storage analysis and/or DNA lipid-laden macrophages with cherry red spot disease analysis wrinkled paper inclusions

Tay Sachs

AR; hexoasminidase A infant, cherry red spot, enzyme; lysosomal storage progressive neurodegeneration disease

corneal opacities, angiokeratomas, acroparesthesias. Rx: enzyme replacement therapy

Hurler syndrome, AR, [all MPS =AR except coarse features, MR, Mucopolysaccharidos Hunter (MPS II) is X-linked]; hepatosplenomegaly. Rx: ERT, es type I (MPS I) lysosomal storage disease. bone marrow transplant

cardiomegaly, macroglossia, blood enzyme activity hypotonia, poor feeding, and/or DNA analysis failure to thrive, elevated creatinine kinase cardiomyopathy, transient ischemic attacks, stroke, neuropathy, angiokeratoma, proteinuria, kidney failure, irritable bowel syndrome

hypotonia, loss of motor skills, hyperacusis neurodeneration: seizures, spasticity; normal sized liver and spleen macrocephaly, corneal opacities, enlarged tongue, valvular heart disease, hearing loss, joint stiffness, dwarfism, Urine: dermatan sulfate and heparin sulfate

DDx

clinical features, liver enzyme analysis and/orDNA analysis von gierke's symptomes + cardiomegaly

clinical features. Male: enzyme analysis and/or DNA analysis. Females: DNA analysis

clinical features, enzyme analysis and/or DNA analysis

blood enzyme activity and/or DNA analysis

no cherry red spot

cherry red spot