Genetic Disorders - Sheet1 (1) Flashcards
- Severe photosensitivity
- Hyperpigmentation in sun-exposed areas
- Increased risk for skin cancer
Etiology? Inheritance?
Xeroderma Pigmentosum
Defective Nucleotide Excision Repair
Autosomal recessive
- Colorectal cancer
- Endometrial cancer
- Ovarian cancer
- Skin cancers
Etiology? Inheritance?
Lynch Syndrome (HNPCC)
Defective Mismatch Repair (MLH1)
Autosomal dominant
- Immnodeficiency
- Gait instability & ataxia
- Cutaneous telangiectasias
Etiology?
Ataxia Telangiectasia
Defective repair of double-stranded DNA breaks
(ATM gene)
- Genetic susceptibility to
- breast
- ovarian
- pancreatic cancers
Etiology?
BRCA1 Mutation
Defective repair of double-stranded DNA breaks
- Young child with pancytopenia
- Dry bone marrow tap
- Short stature
- Absent thumb/radial defects
- Cafe-au-lait spots
- Increased risk for leukemia/tumors
Etiology?
Fanconi anemia
Defective repair of double-stranded DNA breaks
- Rapid onset macrocytic anemia within 1st year of life
- Short stature
- Craniofacial abnormalities
- Triphalangeal thumbs
Diamond Backfan Anemia
- Multiple fractures with minimal trauma
- Blue sclerae
- Dental abnormalities
- Hearing loss
Etiology? Inheritance?
Osteogenesis Imperfecta
Defective type I collagen
Autosomal dominant
- Hyperextensible skin
- Easy bruising
- Hypermobile joints & joint dislocation
Etiology?
Ehlers-Danlos Syndrome (Classical type)
Defect in type V collagen
- Many berry aneurysms
- Risk for aortic aneurysms
- Organ rupture
Etiology?
Ehlers-Danlos Syndrome (Vascular type)
Defect in type III collagen
- Brittle, kinky hair
- Growth retardation
- Hypotonia
Etiology? Inheritance?
Menkes Disease
Impaired copper absorption
(ATP7A mutation) leads to decreased lysyl oxidase activity (collagen cross-linking)
X-linked recessive
- Tall with long extremities & arachnodactyly
- Pectus carinatum/excavatum
- Hypermobile joints
- Medial necrosis of aorta (risk for aneurysms)
- Aortic regurgitation
- Floppy mitral valve
- Subluxation of lens
Etiology? Inheritance?
Marfan Syndrome
Defective fibrillin (FBN1 gene)
Autosomal dominant
- Fibrous dysplasia of several bones
- Precocious puberty
- Unilateral hyperpigmented cutaneous macules with ragged edges
- Other endocrinopathies
Etiology?
McCune-Albright Syndrome
Activating mutation in G-protein signaling (exhibits mosaicism)
- Hyperphagia
- Obesity
- Intellectual disability
- Hypogonadism
- Hypotonia
Etiology?
Prader-Willi Syndrome
Paternal mutation, maternal imprinting
- Inappropriate laughter
- Seizures
- Ataxia
- Severe intellectual disability
Etiology?
Angelman Syndrome
Maternal mutation, paternal imprinting
- Child with bowed legs & soft bones
- Resistant to vitamin D supplementation
Etiology? Inheritance?
Hypophosphatemic rickets
Phosphate wasting at proximal tubule
X-linked dominant
- Autism & intellectual disability
- Long face with large jaw
- Large everted ears
- Macroorchidism
- Mitral valve prolapse
Etiology? Inheritance?
Fragile X Syndrome
CGG repeat expansion in FMR1 gene (hypermethylation)
X-linked dominant
- Retinopathy & lens dislocation
- Sensorineural deafness
- Glomerulonephritis
Etiology? Inheritance?
Alport Syndrome
Defect in type IV collagen
X-linked dominant
- Recurrent pulmonary infections
- Chronic bronchitis & bronchiectasis
- Malabsorption with steatorrhea
- Biliary cirrhosis & liver disease
- Meconium ileus in newborns
- Infertility in men, subfertility in women
- Nasal polyps
- Clubbing of nails
Etiology? Inheritance?
Cystic fibrosis
CFTR Phe508 deletion
Autosomal recessive
- Adolescent onset of proximal muscle weakness
- Calf pseudohypertrophy
- Positive Gower sign
Etiology? Inheritance?
Becker Muscular Dystrophy
Mutation in dystrophin gene (not frameshift)
X-linked recessive
- Early onset proximal muscle weakness
- Calf pseudohyertrophy
- Positive Gower sign
- Dilated cardiomyopathy
Etiology? Inheritance?
Duchenne Muscular Dystrophy
Frameshift mutation in dystrophin gene
X-linked recessive
- Delayed muscle relaxation after contraction
- Muscle wasting
- Cataracts
- Testicular atrophy
- Frontal balding (toupee)
- Arrhythmias
Etiology? Inheritance?
Myotonic dystrophy
CTG repeat expansion in DMPK gene
Autosomal dominant
- Sudden, jerky movements of limbs
- Snake-like writhing of fingers
- Agression
- Depression
- Dementia
Etiology? Inheritance?
Huntington Disease
CAG repeat expansion (deacetylation)
Autosomal dominant
- Muscle weakness
- Loss of deep tendon reflexes, vibratory sense, proprioception
- Staggering gait with frequent falls
- Nystagmus
- Dysarthria
- Pes cavus
- Hammer toes
- Diabetes mellitus
- Hypertrophic cardiomyopathy
- Kyphoscoliosis
Etiology? Inheritance?
Friedreich Ataxia
GAA repeat expansion frataxin gene
Autosomal recessive
- Intellectual disability
- Flat facies
- Prominent epicanthal folds
- Single palmar crease
- Gap between 1st & 2nd toes
- Duodenal atresia
- Hirschsprung disease
- Atrioventricular septal defect
- Brushfield spots in eyes
- Early onset Alzheimer disease
- Increased risk of ALL & AML
Etiology?
Down syndrome
Trisomy 21
- Intellectual disability
- Prominent occiput
- Rocker-bottom feet
- Clenched fists with overlapping fingers
- Low-set ears
- Micrognathia
- Congenital heart disease
- Death usually by age 1
Etiology?
Edwards Syndrome
Trisomy 18
- Intellectual disability
- Rocker-bottom feet
- Microphthalmia
- Microcephaly
- Cleft lip/palate
- Holoprosencephaly
- Polydactyly
- Cutis aplasia
- Congenital heart disease
- Death usually by age 1
Etiology?
Patau Syndrome
Trisomy 13
- Microcephaly
- Epicanthal folds
- Intellectual disability
- High pitched crying/meowing
- Cardiac VSD
Etiology?
Cri-du-chat Syndrome
Microdeletion of chromosome 5 short arm
- Intellectual disability
- Hypercalcemia
- Well-developed verbal skills
- Extreme friendliness with strangers
- Distinctive elfin facies
- Cardiovascular problems
Etiology?
Williams Syndrome
Microdeletion of chromosome 7
- Thymic aplasia & immunodeficiency
- Hypocalcemia
- Cardiac defects
- Facial & palatal abnormalities
Etiology?
DiGeorge Syndrome
22q11 deletion (impaired development of 3rd & 4th branchial pouches)
- Cleft palate
- Abnormal facies
- Cardiac defects
Etiology?
Velocardiofacial Syndrome
22q11 deletion (impaired development of 3rd & 4th branchial pouches)
- Port-wine stain of face
- Ipsilateral leptomeingeal angioma
- Seizures & epilepsy
- Intellectual disability
- Episcleral hemangioma
- Early-onset glaucoma
Etiology?
Sturge-Weber Syndrome (Encephalotrigeminal angiomatosis)
Abnormal development of neural crest derviatives
(GNAQ gene mutation)
- Hamartomas in CNS & skin
- Angiofibromas
- Mitral regurgitation
- Ash-leaf spots
- Cardiac rhabdomyomas
- Intellectual disability
- Renal angiomyolipoma
- Seizures Shagreen patches
- Subependymal giant cell astrocytomas
- Ungual fibromas
Etiology? Inheritance?
Tuberous sclerosis
TSC1/2 mutation
Autosomal dominant
- Hyperpigmented cutaneous macules with smooth edges
- Cutaneous neurofibromas
- Optic gliomas
- Pheochromocytomas
- Lisch nodules (pigmented iris hamartomas)
Etiology? Inheritance?
Neurofibromatosis type I (von Recklinghausen disease)
NF1 tumor suppressor mutation
Autosomal dominant
- Bilateral acoustic schwannomas
- Juvenile cataracts
- Meningiomas
- Ependymomas
Etiology? Inheritance?
Neurofibromastosis type II
NF2 tumor suppressor mutation
Autosomal dominant
- Hemangioblastomas in retina, brain stem, cerebellum, & spine
- Angiomatosis (skin, mucosa, organs)
- Renal cell carcinomas
- Pheochromocytomas
Etiology? Inheritance?
Von Hippel-Lindau Disease
VHL gene deletion
Autosomal dominant
- Hemolytic anemia in response to
- infection
- fava beans
- sulfonamides
- primaquine
- anti-TB drugs
Etiology? Inheritance?
G6PD Deficiency
Defect in glucose-6-phosphate dehydrogenase
X-linked recessive
- Normocytic anemia
- Increased reticulocyte counts
- Splenomegaly
- Normal haptoglobin
- Spherocytes on blood smear
- Frequent gallstones
Etiology? Inheritance?
Hereditary Spherocytosis
Ankyrin/band3/spectrin defect
Autosomal dominant
- Pituitary tumor
- Pancreatic endocrine tumor
- Parathyroid hyperplasia
Etiology? Inheritance?
MEN 1 Syndrome
MEN1 gene mutation (menin)
Autosomal dominant
- Parathyroid hyperplasia
- Pheochromocytoma
- Medullary thyroid carcinoma
Etiology? Inheritance?
MEN 2A Syndrome
RET gene mutation
Autosomal dominant
- Pheochromocytoma
- Medullary thyroid carcinoma
- Mucosal neuromas
- Marfanoid habitus
Etiology? Inheritance?
MEN 2B Syndrome
RET gene mutation
Autosomal dominant
- Thousands of colonic polyps starting after puberty
Etiology? Inheritance?
Familial adenomatous polyposis (FAP)
APC gene mutation
Autosomal dominant
- Thousands of colonic polyps starting after puberty
- Osseous & soft tissue tumors
- Congenital hypertrophy of retinal pigment epithelium
- Impacted, supernumerary teeth
Gardner Syndrome
- Thousands of colonic polyps
- Medulloblastomas
- Gliomas
Turcot Syndrome
- Hamartomas in GI tract
- Hyperpigmented mouth, lips, hands, & genitalia
- Increased risk of:
- breast cancers
- colorectal cancers
- stomach cancers
- small bowel cancers
- pancreatic cancers
Inheritance?
Peutz-Jeghers Syndrome
Autosomal dominant
- Children (< 5yrs old) with hamartomatous polyps in colon, stomach, & small bowel
- Increased risk of colorectal cancer
Inheritance?
Juvenile polyposis syndrome
Autosomal dominant
- Mild jaundice that occurs with stress, illness, or fasting
- Increased unconjugated bilirubin
- No hemolysis
Etiology? Inheritance?
Gilbert Syndrome
Decreased UDP-glucuronosyltransferase
Autosomal Recessive
- Jaundice
- Kernicerus
- Increased unconjugated bilirubin
- No hemolysis
Etiology? Inheritance?
Crigler-Najjar Syndrome
Absent UDP-glucuronosyltransferase
Autosomal Recessive
- Black liver
- Elevated conjugated bilirubin
- No biliary tract obstruction
Etiology? Inheritance?
Dubin-Johnson Syndrome
Defective liver excretion of bilirubin
Autosomal Recessive
- Elevated conjugated bilirubin
- No biliary tract obstruction
- Liver is not black
Etiology? Inheritance?
Rotor Syndrome
Defective liver excretion of bilirubin
Autosomal Recessive
- Liver disease
- Dysarthria, dystonia
- Tremor, parkinsonism
- Psychiatric disease
- Kayser-Fleischer rings in cornea
- Hemolytic anemia
- Fanconi Syndrome
- Decreased serum ceruloplasmin
Etiology? Inheritance?
Wilson Disease
ATP7B gene mutation
Autosomal Recessive
- Cirrhosis
- Diabetes mellitus
- Skin hyperpigmentation
- Cardiomyopathy
- Hypogonadism
- Arthropathy (pseudogout)
Etiology? Inheritance?
Hemochromatosis
HFE gene mutation (C282Y)
Autosomal Recessive
- Respiratory distress
- Right heart failure
- Atherosclerosis, fibrosis, & plexiform lesions in pulmonary artery
Etiology?
Heritable Pulmonary Arterial Hypertension
Mutation in BMPR2 gene/ endothelin
- Hypokalemia
- Metabolic alkalosis
- Hypercalciuria
- Increased plasma renin & aldosterone
Etiology? Inheritance?
Bartter Syndrome
Defect in NKCC transporter in ascending limb of loop of Henle
Autosomal Recessive
- Hypokalemia
- Metabolic alkalosis
- Hypocalciuria
- Hypomagnesemia
- Increased plasma renin & aldosterone
Etiology? Inheritance?
Gitelman Syndrome
Defect in NaCl transporter in DCT
Autosomal Recessive
- HTN
- Hypokalemia
- Metabolic alkalosis
- Decreased renin & aldosterone
- Normal levels of cortisone
Etiology? Inheritance?
Liddle Syndrome
Activation of ENaC
Autosomal Dominant
- Wilms tumor
- Aniridia
- Genitourinary malformations
- Mental retardation
Etiology?
WAGR complex
WT1 deletion
- Wilms tumor
- Early-onset nephrotic syndrome
- Male pseudohermaphroditism
Etiology?
Denys-Drash
WT1 mutation
- Wilms tumor
- Macroglossia
- Organomegaly
- Hemihyperplasia
Etiology?
Beckwith-Wiedemann
WT2 mutation
- Cysts & abnormal connective tissue in the kidney at birth
- Can be unilateral or bilateral
Etiology?
Multicystic Dysplastic Kidney
Congenital malformation (non-inherited)
- HTN with increased renin
- Hematuria
- Enlarged kidneys with cysts in cortex & medulla
- Berry aneurysms
- Hepatic cysts
- Mitral valve prolapse
Etiology? Inheritance?
Autosomal Dominant PKD
APKD1 or APKD2 gene mutation
- Renal failure & HTN in infant
- Enlarged kidneys with cysts in cortex & medulla
- Potter sequence
- Hepatic fibrosis & cysts
Inheritance?
Autosomal Recessive PKD
- Shrunken kidneys & renal failure
- Cysts in medullary collecting ducts
Inheritance?
Medullary cystic kidney disease
Autosomal dominant
- Recurrent epistaxis
- Easy bruising
- Petechiae & purpura
- Increased bleeding time
- Increased PTT, normal PT
- No aggregation with ristocetin assay
Etiology? Inheritance?
Von Willebrand Disease
vWF deficiency
Autosomal dominant
- DVT at early age
- Cerebral vein thromboses
- Recurrent pregnancy loss
Etiology?
Factor V Leiden
Mutant factor V resistant to degradation
