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Condition Hereditary breast-ovarian cancer syndrome Breast and ovarian cancer syndromes

Basic Mechanisms


Li Fraumeni

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 AD, STK11 gene hyperpigmented macules lips/mouth, GI hemartomatous polyps NPNCC-related tumors: colorectal, endometrial, ovarian, urinary tract; Rx: Colectomy, Cancer surveillance

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 childhood GI hamartomas/cancer, breast cancer, ovarian cancer

Peutz-Jeghers syndrome


Lynch syndrome

AD, MLH1 and MSH2 (mismatch repair, caretaker)

colon, endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, skin Breast cancer, thyroid cancer, endometrial cancers childhood GI hamartomas/cancer, breast cancer, ovarian cancer extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain) gardner syndrome: + osteomas and soft tissue tumors; turcot syndrome: +CNS tumors (medulloblastoma); short stature, hyper/hypopig mentation, pancytopenia, urogenital abnormalities


AD; PTEN gene (tumor hamartomatous polyps; suppressor) facial/buccal papules AD; TP53 tumor suppressor hamartomatous polyps; hyperpigmented macules adenomatous polyps; attenuated FAP: fewer polyps Rx: surgery/chemo, cancersurveillance, prophylactic surgery


Colon Cancer

many polyps

familial adenomatous polyposis (FAP)

AD; APC gene tumor suppressor (gatekeeper)

autosomal recessive

Fanconi's anemia

AR; chromosomal breakage disorder

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

Ataxia telangiectasia

AR; chromosome breakage disorder

lymphoma, leukemia

Von Hippel-Lindau disease MEN 1


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 AD; VHL gene tumor suppressor (gatekeeper) AD; MEN1 gene tumor suppressor retinoblatoma (bilateral = hereditable, unilateral = nonheritable) heritable: extraocular osteosarcomas, sarcomas, melanomas




AD; RB1 tumor suppressor

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 Condition Basic Mechanisms Clinical Features Other Dx DDx Galactosemia intoxication phenotypes AR; Galactose-1-phosphate cataract, hepatomegaly, E. coli uridyltransferase (GALT) sepsis. Rx: dietary intervention, enzyme lactose restriction AR; branched-chain alphalethargy - coma, seizures, maple ketoacid dehydrogenase syrup odor; Rx: dietary enzyme complex (BCKAD); intervention, BCAA restriction aminoacidopathy AR; organic acidemia X-linked recessive; urea cycle disorder AR, phenylalanine hydroxylase enzyme, aminoacidopathy AR, cystathionine beta synthase enzyme (CBS) 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 Urea Cycle disorder OTC deficiency galactosuria, FTT, vomiting/diarrhea, hepatomegaly, e coli sepsis poor feeding, maple syrup odor elevated BCAAs, enzyme analysis ketosis, no acidosis, no hyperammonemia

Maple Syrup Urine Disease

Methylmalonic acidemia Ornithine Transcarbamyl-ase deficiency (OTC)

severe ketoacidosis, hyperammonemia, neutropenia, vomiting hyperammonemia, respiratory expressed in females due alkalosis, protein avoidance, to lyonization FTT, vomiting musty body odor, hyperactivity, seizures newborn screen, plasma phenylalanine newborn screen; urine homocystine, plasma Aas, enzyme analysis, DNA analysis

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

nonintoxication phenotypes



Amino Acidopathy PKU MSUD homocystinuria

Organic Acidemia methylmalonic acidemia

ENERGY DEFICIENCY 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 mtDNA point mutations Clinical Features bilateral vision loss- young adult Other bilndness, neuropathy, myopathy cardiomyopathy, arrhythmia, encephalomyopathy, stroke like episodes, seizures, hearing loss, lactic acidosis, vomiting Facial dysmorphism: high forehead, large fontanels, hypotonia, seizures, poor feeding liver dysfunction Dx opthalmology exam, mtDNA analysis lactate, brain imaging, muscle biopsy, mtDNA analysis biochem testing including VLCFA levels, DNA analysis DDx



mtDNA pt mutation: m3243A>G MT-TL1 gene (tRNA) AR; peroxisomal disease (no peroxisomes are formed)

mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes

Fatty-acid oxidation peroxisom defect al

Zellweger syndrome

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

normal at birthy, vomiting, sudden infant death

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 Condition Glycogen 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 AR; acid alpha glucosidase cardiomegaly/HCM, macroglossia, (GAA) enzyme; glycogen muscle weakness. Rx: Enzyme storage and lysosome replacement therapy storage X-linked; alpha galactosidase enzyme, lysosomal storage disease corneal opacities, angiokeratomas, acroparesthesias. Rx: enzyme replacement therapy Dx clinical features, liver enzyme analysis and/orDNA analysis von gierke's symptomes + cardiomegaly DDx

Glycoge + lysosome

Pompe disease

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


Gaucher Lysosome

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 AR; hexoasminidase A infant, cherry red spot, enzyme; lysosomal storage progressive neurodegeneration disease 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 clinical features, enzyme analysis and/or DNA analysis

no cherry red spot

Tay Sachs

cherry red spot

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

blood enzyme activity and/or DNA analysis