Genetic Syndromes Flashcards
McCune Albright Syndrome
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
Prader Willi Syndrome
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
Angelman Syndrome
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
Hypophosphatemic Rickets (Vitamin D resistant Rickets)
X linked dominant
Increased phosphate wasting at PCT, results in rickets like presentation
Mitochondrial Myopathies
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
Myoclonic epilepsy with ragged red fibers (MERRF)
Same as mitochondrial myopathies + myoclonic epilepsy!
Polycystic Kidney Disease (PKD)
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)
Familial Adenomatous Polyposis
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.”
Familial Hypercholesterolemia
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).
Hereditary Hemorrhagic Telangiectasia
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.
Hereditary spherocytosis
AD
Spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia; MCHC, RDW. Treatment: splenectomy.
Huntington disease
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.”
Li-Fraumeni syndrome
AD
Abnormalities in TP53 multiple malignancies at an early age. Also known as SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland).
Marfan syndrome
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.
Multiple endocrine neoplasias (MEN)
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.
Neuro bromatosis type 1 (von Recklinghausen disease)
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.”
Neuro bromatosis type 2
AD
Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas. NF2 gene on chromosome 22; type 2 = 22.
Tuberous sclerosis
AD
Neurocutaneous disorder with multi-organ system involvement, characterized by numerous benign hamartomas. Incomplete penetrance, variable expression.
von Hippel-Lindau disease
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.
MEN1
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)
MEN2A
AD
2Ps
Parathyroid hyperplasia Pheochromocytoma
Medullary thyroid carcinoma (secretes
calcitonin)
Associated with marfanoid habitus; mutation in
RET gene (codes for receptor tyrosine kinase)
MEN2B
AD 1P Pheochromocytoma Medullary thyroid carcinoma (secretes calcitonin) Oral/intestinal ganglioneuromatosis (mucosal neuromas) Associated with marfanoid habitus; mutation in RET gene
Albinism
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.
ARPKD
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.
Cystic Fibrosis
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).
Von Gierke Disease Type I
AR
Deficient Enzyme: Glucose-6-phosphatase
Severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, triglycerides, increased uric acid, and hepatomegaly
Pompe disease (type II)
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)
Cori disease (type III)
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
McArdle disease (type V)
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
Fabry Disease
XR
Deficient Enzyme: α-galactosidase A
Accumulated Substances: Ceramide, trihexoside
Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease.
Gaucher Disease
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.
Riemann Pick Disease
AR
Deficient Enzyme: Sphingomyelinase
Accumulated Substance: Sphingomyelin
Progressive neurodegeneration, hepatosplenomegaly, foam cells (lipid-laden macrophages) B , “cherry-red” spot on macula C .a
Tay Sachs Disease
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).
Krabbe disease
AR
Deficient Enzyme: Galactocerebrosidase
Accumulated Substance: Galactocerebroside, psychosine
Peripheral neuropathy, developmental delay, optic atrophy, globoid cells.
Metachromatic leukodystrophy
AR
Deficient Enzyme: Arylsulfatase A
Accumulated Substance: Cerebroside sulfate
Central and peripheral demyelination with ataxia, dementia.
Hurler syndrome
AR
Deficient Enzyme:α-l-iduronidase
Accumulated Substance: Heparan sulfate, derma tan sulfate
Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly.
Hunter Syndrome
XR
Deficient Enzyme:Iduronate sulfatase
Accumulated Substance: Heparan sulfate, derma tan sulfate
Mild Hurler + aggressive behavior, no corneal clouding.
Hemochromatosis
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
Kartagener syndrome (1° ciliary dyskinesia)
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).
Phenylketonuria
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.
Homocystinuria
AR
Fndings: increased homocysteine in urine, intellectual
disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke and MI).
Sickle Cell Anemia
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).
Aplastic crisis (due to parvovirus B19). Autosplenectomy (Howell-Jolly bodies)
risk of infection by encapsulated
organisms.
Splenic infarct/sequestration crisis.
Salmonella osteomyelitis.
Painful crises (vaso-occlusive): dactylitis
(painful swelling of hands/feet), acute chest
syndrome, avascular necrosis, stroke.
Renal papillary necrosis ( Po2 in papilla) and
microhematuria (medullary infarcts).
α-thalassemia
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.
β-thalassemia
AR
Point mutations in splice sites and promoter sequences β-globin synthesis.
Prevalent in Mediterranean populations.
Wilson Disease
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).
Bruton agammaglobulinemia
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
Wiskott Aldrich Syndrome
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
G6PD Deficiency
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.
Ocular Albinism
X linked Recessive
Lesch Nyhan Syndrome
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.
Duchenne Muscular Dystrophy
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
Becker Muscular Dystrophy
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.
Hemophilia A and B
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).
Hemophilia C
AR
Macrohemorrhage in hemophilia—hemarthroses (bleeding into joints, such as knee), easy bruising, bleeding after trauma or surgery (e.g., dental procedures).
Ornithine Transcarbmylase Deficiency
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).
Friedriech ataxia
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
Fragile X
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.
Myotonic Dystrophy
AD CTG repeat
expansion in the DMPK gene abnormal expression of myotonin protein kinase myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia
Down Syndrome
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
Edwards Syndrome
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.
Patau Syndrome
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
Cri du chat Syndrome
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)
Williams Syndrome
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.
DiGeorge and Velocardiofacial Syndrome
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.
