Genetic Syndromes

Question 1

McCune Albright Syndrome

Answer 1

Mutation in G protein Signaling
Unilateral Cafe au lait spots, polyostotic fibrous dysplasia, precocious puberty, multiple endocrine abnormalities.
Lethal if occurs before fertilization but SURVIVABLE IN PATIENTS WITH MOSAICISM

Question 2

Prader Willi Syndrome

Answer 2

Chromosome 15
Maternal Imprinting: Gene from momma is normally silent
Paternal Deletion
Hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia
25% of cases due to material uniparental disomy

Question 3

Angelman Syndrome

Answer 3

Paternal Imprinting: gene from papa is normally silent
Maternal deletion
Inappropriate laughter (happy puppet), seizures, ataxia, severe intellectual disability
5% if cases due to paternal uniparental disomy

Question 4

Hypophosphatemic Rickets (Vitamin D resistant Rickets)

Answer 4

X linked dominant

Increased phosphate wasting at PCT, results in rickets like presentation

Question 5

Mitochondrial Myopathies

Answer 5

Mitochondrial inheritance
Presentation and severity may vary due to heteroplasmy
Secondary to failure of oxidative phosphorylation
Myopathy, lactic acidosis, CNS disease, proximal muscle weakness, dysphagia, ophthalmoplegia, short stature, hearing loss.
Pathonogmonic: RAGGED RED FIBERS

Question 6

Myoclonic epilepsy with ragged red fibers (MERRF)

Answer 6

Same as mitochondrial myopathies + myoclonic epilepsy!

Question 7

Polycystic Kidney Disease (PKD)

Answer 7

Autosomal Dominant (ADPKD)
Bilateral massive enlargement of kidneys due to multiple large cysts. 85% of cases due to mutations of PKD1 on chromosome 16 (16 letters in polycystic kidney)
remainder due to mutations in PKD2 (chromosome 4)

Question 8

Familial Adenomatous Polyposis

Answer 8

Autosomal Dominant
Colon becomes covered with adenomatous polyps after puberty. 100% of affected progresses to colon cancer unless colon is resected. Mutations on chromosome 5q (APC gene); 5 letters in “polyp.”

Question 9

Familial Hypercholesterolemia

Answer 9

Autosomal Dominant
Elevated LDL due to defective or absent LDL receptor. Leads to severe atherosclerotic disease early in life, corneal arcus, tendon xanthomas (classically in the Achilles tendon).

Question 10

Hereditary Hemorrhagic Telangiectasia

Answer 10

Autosomal Dominant
Inherited disorder of blood vessels. Findings: branching skin lesions (telangiectasias), recurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs), GI bleeding, hematuria. Also known as Osler-Weber-Rendu syndrome.

Question 11

Hereditary spherocytosis

Answer 11

AD

Spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia; MCHC, RDW. Treatment: splenectomy.

Question 12

Huntington disease

Answer 12

AD
Findings: depression, progressive dementia, choreiform movements, and caudate atrophy. dopamine, GABA, ACh in the brain. Gene on chromosome 4; trinucleotide repeat disorder: (CAG)n. Demonstrates anticipation: repeats age of onset. “Hunting 4 food.”

Question 13

Li-Fraumeni syndrome

Answer 13

AD
Abnormalities in TP53 multiple malignancies at an early age. Also known as SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland).

Question 14

Marfan syndrome

Answer 14

AD
FBN1 gene mutation on chromosome 15 defective–>fibrin (scaffold for elastin) connective tissue disorder affecting skeleton, heart, and eyes. Findings: tall with long extremities, pectus excavatum, hypermobile joints, and long, tapering ngers and toes (arachnodactyly); cystic medial necrosis of aorta aortic incompetence and dissecting aortic aneurysms; oppy mitral valve. Subluxation of lenses, typically upward and temporally.

Question 15

Multiple endocrine neoplasias (MEN)

Answer 15

AD (SEE 3 OTHER CARDS FOR EACH TYPE)
Several distinct syndromes (1, 2A, 2B) characterized by familial tumors of endocrine glands, including those of the pancreas, parathyroid, pituitary, thyroid, and adrenal medulla. MEN 1 is associated with MEN1 gene, MEN 2A and 2B are associated with RET gene.

Question 16

Neuro bromatosis type 1 (von Recklinghausen disease)

Answer 16

AD
Neurocutaneous disorder characterized by café-au-lait spots, cutaneous neuro bromas, optic gliomas, pheochromocytomas, Lisch nodules (pigmented iris hamartomas). Autosomal dominant, 100% penetrance, variable expression. Caused by mutations in the NF1 gene on chromosome 17; 17 letters in “von Recklinghausen.”

Question 17

Neuro bromatosis type 2

Answer 17

AD
Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas. NF2 gene on chromosome 22; type 2 = 22.

Question 18

Tuberous sclerosis

Answer 18

AD
Neurocutaneous disorder with multi-organ system involvement, characterized by numerous benign hamartomas. Incomplete penetrance, variable expression.

Question 19

von Hippel-Lindau disease

Answer 19

AD
Disorder characterized by development of numerous tumors, both benign and malignant. Associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p). Von Hippel-Lindau = 3 words for chromosome 3.

Question 20

MEN1

Answer 20

AD
3 Ps
Parathyroid tumors
Pituitary tumors (prolactin or GH) Pancreatic endocrine tumors—Zollinger-
Ellison syndrome, insulinomas, VIPomas,
glucagonomas (rare)
Associated with mutation of MEN1 gene
(menin, a tumor suppressor)

Question 21

MEN2A

Answer 21

AD
2Ps
Parathyroid hyperplasia Pheochromocytoma
Medullary thyroid carcinoma (secretes
calcitonin)
Associated with marfanoid habitus; mutation in
RET gene (codes for receptor tyrosine kinase)

Question 22

MEN2B

Answer 22

AD
1P
Pheochromocytoma
Medullary thyroid carcinoma (secretes
calcitonin)
Oral/intestinal ganglioneuromatosis (mucosal
neuromas)
Associated with marfanoid habitus; mutation in
RET gene

Question 23

Albinism

Answer 23

AR
Normal melanocyte number with melanin production due to tyrosinase activity or defective tyrosine transport. Can also be caused by failure of neural crest cell migration during development. risk of skin cancer.

Question 24

ARPKD

Answer 24

AR–> Sorry no tricks here
Formerly infantile polycystic kidney disease. Presents in infancy. Associated with congenital hepatic fibrosis. Signi cant oliguric renal failure in utero can lead to Potter sequence. Concerns beyond neonatal period include systemic hypertension, progressive renal insufciency, and portal hypertension from congenital hepatic fibrosis.

Question 25

Cystic Fibrosis

Answer 25

AR See FA pg 84 for labs and genetics just sx here: Recurrent pulmonary infections (e.g., Pseudomonas), chronic bronchitis and bronchiectasis reticulonodular pattern on CXR, pancreatic insuficiency, malabsorption with steatorrhea, and nasal polyps. Meconium ileus in newborns. Infertility in males (absence of vas deferens), and subfertility in females (amenorrhea, abnormally thick cervical mucus). Fat-soluble vitamin de ciencies (A, D, E, K).

Question 26

Von Gierke Disease Type I

Answer 26

AR Deficient Enzyme: Glucose-6-phosphatase Severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, triglycerides, increased uric acid, and hepatomegaly

Question 27

Pompe disease (type II)

Answer 27

AR Deficient Enzyme: Lysosomal α-1,4-glucosidase (acid maltase) Cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, and systemic ndings leading to early death Lysosomal α-1,4-glucosidase (acid maltase)

Question 28

Cori disease (type III)

Answer 28

AR Deficient Enzyme: Debranching enzyme ( α - 1 , 6 - g l u c o s i d a s e) Milder form of type I with normal blood lactate levels

Question 29

McArdle disease (type V)

Answer 29

AR Deficient Enzyme: Skeletal muscle glycogen phosphorylase (myophosphorylase) Increased glycogen in muscle, but muscle cannot break it down painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities

Question 30

Fabry Disease

Answer 30

XR Deficient Enzyme: α-galactosidase A Accumulated Substances: Ceramide, trihexoside Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease.

Question 31

Gaucher Disease

Answer 31

AR Deficient Enzyme: Glucocerebrosidase Accumulated Substance: Glucocerebroside Most common. Hepatosplenomegaly, pancytopenia, osteoporosis, aseptic necrosis of femur, bone crises, Gaucher cells A (lipid-laden macrophages resembling crumpled tissue paper); treatment is recombinant glucocerebrosidase.

Question 32

Riemann Pick Disease

Answer 32

AR Deficient Enzyme: Sphingomyelinase Accumulated Substance: Sphingomyelin Progressive neurodegeneration, hepatosplenomegaly, foam cells (lipid-laden macrophages) B , “cherry-red” spot on macula C .a

Question 33

Tay Sachs Disease

Answer 33

AR Deficient Enzyme: Hexosaminidase A Accumulated Substance: GM2 ganglioside Progressive neurodegeneration, developmental delay, “cherry-red” spot on macula C , lysosomes with onion skin, no hepatosplenomegaly (vs. Niemann-Pick).

Question 34

Krabbe disease

Answer 34

AR Deficient Enzyme: Galactocerebrosidase Accumulated Substance: Galactocerebroside, psychosine Peripheral neuropathy, developmental delay, optic atrophy, globoid cells.

Question 35

Metachromatic leukodystrophy

Answer 35

AR Deficient Enzyme: Arylsulfatase A Accumulated Substance: Cerebroside sulfate Central and peripheral demyelination with ataxia, dementia.

Question 36

Hurler syndrome

Answer 36

AR Deficient Enzyme:α-l-iduronidase Accumulated Substance: Heparan sulfate, derma tan sulfate Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly.

Question 37

Hunter Syndrome

Answer 37

XR Deficient Enzyme:Iduronate sulfatase Accumulated Substance: Heparan sulfate, derma tan sulfate Mild Hurler + aggressive behavior, no corneal clouding.

Question 38

Hemochromatosis

Answer 38

AR Primary hemochromatosis due to C282Y or H63D mutation on HFE gene. Associated with HLA-A3. Hemosiderosis is the deposition of hemosiderin (iron), which stains blue A ; hemochromatosis is the disease caused by this iron deposition. Classic triad of micronodular Cirrhosis, Diabetes mellitus, and skin pigmentation “bronze” diabetes. Results in HF, testicular atrophy, and risk of HCC

Question 39

Kartagener syndrome (1° ciliary dyskinesia)

Answer 39

AR immotile cilia due to a dynein arm defect. Results in male and female infertility due to immotile sperm and dysfunctional fallopian tube cilia, respectively; risk of ectopic pregnancy. Can cause bronchiectasis, recurrent sinusitis, and situs inversus (e.g., dextrocardia on CXR).

Question 40

Phenylketonuria

Answer 40

AR Due to decreased Phe Hydroxylase or decreased tetrahydrobioptrin cofactor (malignant PKU). excess phenylketones in urine. Findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor.

Question 41

Homocystinuria

Answer 41

AR Fndings: increased homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke and MI).

Question 42

Sickle Cell Anemia

Answer 42

AR HbS point mutation causes a single amino acid replacement in β chain (substitution of glutamic acid with valine). “Crew cut” on skull x-ray due to marrow expansion from erythropoiesis (also seen in thalassemias). ƒ Aplastic crisis (due to parvovirus B19). ƒ Autosplenectomy (Howell-Jolly bodies) risk of infection by encapsulated organisms. ƒ Splenic infarct/sequestration crisis. ƒ Salmonella osteomyelitis. ƒ Painful crises (vaso-occlusive): dactylitis (painful swelling of hands/feet), acute chest syndrome, avascular necrosis, stroke. ƒ Renal papillary necrosis ( Po2 in papilla) and microhematuria (medullary infarcts).

Question 43

α-thalassemia

Answer 43

AR Decreased alpha globin production cis deletion prevalent in Asian populations; trans deletion prevalent in African populations. 4 allele deletion: No α-globin. Excess γ-globin forms γ4 (Hb Barts). Incompatible with life (causes hydrops fetalis). 3 allele deletion: HbH disease. Very little α-globin. Excess β-globin forms β4 (HbH). 1–2 allele deletion: less clinically severe anemia.

Question 44

β-thalassemia

Answer 44

AR Point mutations in splice sites and promoter sequences β-globin synthesis. Prevalent in Mediterranean populations.

Question 45

Wilson Disease

Answer 45

AR Inadequate hepatic copper excretion and failure of copper to enter circulation as ceruloplasmin. Leads to copper accumulation, especially in liver, brain, cornea, kidneys (Fanconi syndrome), and joints. Autosomal recessive inheritance (chromosome 13). Copper is normally excreted into bile by hepatocyte copper transporting ATPase (ATP7B gene).

Question 46

Bruton agammaglobulinemia

Answer 46

X linked recessive Defect in BTK a tyrosine kinase gene--> no B cell maturation. Recurrent bacterial and enteroviral infection after 6 months. Decreased Ig and absent lymph nodes

Question 47

Wiskott Aldrich Syndrome

Answer 47

``` X Linked recessive Mutation in the WAS gene T cells unable to reorganize actin skeleton. Thrombocytopenia purpura (fewer and smaller platelets, eczema, recurrent infections. Risk of autoimmune disease and malignancy. Decreased to normal IgG and IgM Increased IgE and IgA ```

Question 48

G6PD Deficiency

Answer 48

X linked Recessive Defect in G6PD--> reduced glutathione, increased RBC susceptibility to oxidant stress. Back pain, hemoglobinuria a few days after oxidant stress. Labs: blood smear shows RBCs with Heinz bodies and bite cells.

Question 49

Ocular Albinism

Answer 49

X linked Recessive

Question 50

Lesch Nyhan Syndrome

Answer 50

X linked Recessive Defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP. Results in excess uric acid production and de novo purine synthesis. X-linked recessive. Findings: intellectual disability, self-mutilation, aggression, hyperuricemia, gout, dystonia.

Question 51

Duchenne Muscular Dystrophy

Answer 51

X linked recessive Due to Frameshift at the dystrophin gene Inhibited Muscle regeneration Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudo hypertrophy of calf. Gower Maneuver. Western Blot is Diagnostic

Question 52

Becker Muscular Dystrophy

Answer 52

X linked recessive due to non- frameshift insertions in dystrophin gene (partially functional instead of truncated). Less severe than Duchenne. Onset in adolescence or early adulthood.

Question 53

Hemophilia A and B

Answer 53

XR for both A: Factor VIII Deficiency B: Factor IX deficiency Macrohemorrhage in hemophilia—hemarthroses (bleeding into joints, such as knee), easy bruising, bleeding after trauma or surgery (e.g., dental procedures).

Question 54

Hemophilia C

Answer 54

AR Macrohemorrhage in hemophilia—hemarthroses (bleeding into joints, such as knee), easy bruising, bleeding after trauma or surgery (e.g., dental procedures).

Question 55

Ornithine Transcarbmylase Deficiency

Answer 55

XR Most common urea cycle disorder.. (other urea cycle enzyme de ciencies, which are autosomal recessive). Interferes with the body’s ability to eliminate ammonia. Often evident in the rst few days of life, but may present later. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway). Findings: orotic acid in blood and urine, BUN, symptoms of hyperammonemia. No megaloblastic anemia (vs. orotic aciduria).

Question 56

Friedriech ataxia

Answer 56

AR GAA repeat on chromosome 9 that encodes frataxin (iron binding protein) Impaired mitochondrial functioning Degeneration of multiple tracts muscle weakness and loss of DTRs, vibratory sense, proprioception. Staggering gait, frequent falling, nystagmus, dysarthria, pes cavus, hammer toes, diabetes mellitus, hypertrophic cardiomyopathy (cause of death). Presents in childhood with kyphoscoliosis

Question 57

Fragile X

Answer 57

X linked. CGG repeat efect affecting the methylation and expression of the FMR1 gene. The 2nd most common cause of genetic intellectual disability (after Down syndrome). Findings: post-pubertal macroorchidism (enlarged testes), long face with a large jaw, large everted ears, autism, mitral valve prolapse.

Question 58

Myotonic Dystrophy

Answer 58

AD CTG repeat expansion in the DMPK gene abnormal expression of myotonin protein kinase myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia

Question 59

Down Syndrome

Answer 59

Trisomy 21: most common viable chromosome disorder Intellectual disability, at facies, prominent epicanthal folds, single palmar crease, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (atrial septal defect [ASD]), Brush eld spots. Associated with early-onset Alzheimer disease (chromosome 21 codes for amyloid precursor protein) and risk of ALL and AML

Question 60

Edwards Syndrome

Answer 60

Trisomy 18 Findings: severe intellectual disability, rocker- bottom feet, micrognathia (small jaw), low-set Ears, clenched hands with overlapping ngers, prominent occiput, congenital heart disease. Death usually occurs within 1 year of birth.

Question 61

Patau Syndrome

Answer 61

Trisomy 13 Findings: severe intellectual disability, rocker- bottom feet, microphthalmia, microcephaly, cleft liP/Palate, holoProsencephaly, Polydactyly, congenital heart disease, cutis aplasia. Death usually occurs within 1 year of birth

Question 62

Cri du chat Syndrome

Answer 62

Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p−). Findings: microcephaly, moderate to severe intellectual disability, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VSD)

Question 63

Williams Syndrome

Answer 63

Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene). Findings: distinctive “el n” facies, intellectual disability, hypercalcemia ( sensitivity to vitamin D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems.

Question 64

DiGeorge and Velocardiofacial Syndrome

Answer 64

Micro deletion at chromosome 22q11 Due to aberrant development of 3rd and 4th brachial pouches Cleft palate, Abnormal facies, Thymic aplasia T-cell de ciency, Cardiac defects, and Hypocalcemia 2° to parathyroid aplasia. DiGeorge syndrome—thymic, parathyroid, and cardiac defects. Velocardiofacial syndrome—palate, facial, and cardiac defects.