Exam 3 Genetic Diseases Flashcards
Neurofibromatosis.
a. ) Genetic mechanism of inheritance
b. ) Types, pathogeneses and clinicopathologic correlation
a. ) Disease characterized by skin growths and tumors
b. ) AD with 100% penetrance and variable expressivity (some with only café-au-lait macules). One of the highest known mutation rates, ~ 50% of cases are result of new mutation
- Type 1: mutation of NF1 gene (tumor suppressor protein = neurofibromin on c/s 17) leads to inability to inactivate p21 GTP-Ras (oncoprotein). Clinical presentation = axillary/inguinal freckling, café-au-late macules, Lisch nodules (benign growths on iris), neurofibromas* (benign peripheral nerve tumors), bone lesions and optical gliomas. If severe, malignant tumors occur from plexiform neurofibromas, such as malignant peripheral nerve sheat tumors, pheochromocytoma, Wilms tumor, rhabdomyosarcoma, leukemia). Diagnostic criteria: 2 or more of symptoms above (with >2 of the fibromas or Lisch nodules).
- Type 2: mutation in NF2 gene (c/s 22, tumor suppressor protein = merlin/schwannomin) leads to sporadic tumors. Clinical features = bilateral vestibular schwannomas^ (acoustic neuromas) affecting branch of 8th CN – pts often present with tinnitus, hearing loss, balance issues. Also can cause low-grade CNS tumors, meningiomas, ependymomas and gliomas. CALMs, cutaneous neurofibromas and juvenile cataracts can also be seen.
* cell of origin = Schwann cell, but contain multiple cell types from peripheral nerve, not just Schwann cells. Resection is therefore difficult. Histologically: spindle cells.
^ Histologically: Antoni A: fibrotic dense tissue interspersed with Antoni B: myxoid less dense CT with Verocay body, which consists of an anuclear area palisaded by cells
Pompe dz
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a) Mode of inheritance: AR
b) Enzyme deficiency: lysosomal glucosidase (aka acid maltase) – (c/s 17)
c) Accumulating metabolite: glycogen
d) Key clinical manifestation: glycogen storage dz
- Infantile onset, floppy baby, failure to thrive, macroglossia, EKG changes, progressive cardiomyopathy, cardiomegaly, neonates die from cardiorespiratory failure by age 12-24 months.
e) Histological feature(s):
- accumulation of glycogen in all organs, depending on preparation of microscopic material, may appear as white empty spaces or pink if PAS stained
Marfan syndrome.
a. ) What is it?
b. ) Genetic mechanism of inheritance
c. ) Pathogenesis
d. ) Clinicopathologic correlation
e. ) Diagnostic criteria
a. ) CT defect d/t mutation in fibrillin-1 gene with defects involving eyes, skeletal muscle and CV system primarily.
b. ) AD (c/s 15)
c. ) Fibrillin-1 is the glycoprotein constituent of microfibrils in elastic fibers of CT. Mutation leads to stiffening of aortic wall, increased TGF-beta1 activity, inflammation, MMP upregulation, elastolysis and cell disarray.
d. ) Ectopia lentis (displaced lens = nearsightedness), pectus carinatum/excavatum, arachnodactyly (spider fingers), joint hypermobility, arm span>height, MV prolapse (parachute valve), aortic valve incompetence, dissection (d/t cystic media degeneration), CHF.
e. ) Diagnostic criteria: 4 features skeletal, ocular, CV, genetic findings
Name the lysosomal storage diseases
- Tay Sachs
- Gaucher dz
- Niemann-Pick
- Mucopolysaccharidoses (Type I: Hurler, Type II: Hunter)
Name the glycogen storage diseases
- Type I: Von Gierke’s
- Type II: Pompe’s
- Type III: Cori dz (not responsible for on this exam)
- Type IV: Andersen dz (not responsible for on this exam)
- Type V: McArdle dz
Patau syndrome
a. ) Karyotype
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) 47 (+13) or 46 (mosaicism w/13)
b. ) Non-dysjunction = full copy or Robertsonian translocation
c. ) Most children die within first year of life, microcephaly, mental retardation, microphthalmia (or cyclopsia), polydactyly, rocker bottom feet, cardiac defects, umbilical hernia, renal defects, cleft lip
Klinefelter syndrome
a. ) Karyotype
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) 47, XXY
b. ) Non-dysjunction on maternal or paternal end
c. ) Tall stature, slightly feminized physique, mildly impaired IQ, tendency to lose chest hair, female-type pubic hair pattern, frontal baldness absent, poor beard growth, gynecomastia, osteoporosis, hypogonadism, increase risk for breast CA d/t hyperestrogenism, most are infertile
Alkaptonuria.
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a. ) Mode of inheritance: AR
b. ) Enzyme deficiency: deficiency in homogentisic acid oxidase
c. ) Accumulating metabolite: homogentisate – in collagen (CT), tendons, cartilage
d. ) Key clinical manifestation: blue/black pigmentation in ears nose, black urine (alkalized, oxidized), degenerative arthropathy (severe osteoarthritis) early age
e. ) Histological feature(s): yellow-brown (ochronotic) pigment in CT
Huntington dz
a. ) Mode/mechanism of inheritance
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) AD
b. ) Pathogenesis:
- TNR-expansion (CAG in exon of HD gene encoding for huntingtin protein on c/s 4): = 36 TNRs = may or may not HD, >=40 = HD, >=60 = onset of HD prior to age 21
- Exhibits amplification
c. ) Progressive neurodegenerative disorder (caudate nuclei atrophy) manifesting in motor, cognitive and psychiatric changes with mean age of onset between 35 and 44 years of age. Survival is typically bw 15-18 years.
- Early = subtle coordination changes, minor chorea, difficulty in mental planning, often depressed/irritable mood
- Following = chorea prominent, difficulty with voluntary activity, dysphagia, dysarthria
- Late = motor disability is severe, often totally dependent, mute and incontinent
Von Gierke
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a) Mode of inheritance: AR
b) Enzyme deficiency: G-6-Phosphatase
c) Accumulating metabolite: glycogen
d) Key clinical manifestation: glycogen storage dz – hepatorenal
- hepatomegaly, renomegaly, convulsions, hyperlipidemia (xanthomas) and hyperuricemia (gout)
e) Histological feature(s):
- accumulation of glycogen in liver, kidney and depending on preparation of microscopic material, may appear as white empty spaces or pink if PAS stained
Mucopolysaccharidoses
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a. ) Mode of inheritance: MPSI (Hurler) is AR, MPSII (Hunter) is XR
b. ) Enzyme deficiency:
- MPS I (Hurler): alpha-L-iduronidase
- MPS II (Hunter): L-iduronosulfate sulfatase
c. ) Accumulating metabolite: MPS (GAGs) such as heparan sulfate, dermatan sulfate, keratan sulfate etc.
d. ) Key clinical manifestation: lysosomal storage disease
- Hurler (very severe): gargoyle children, progressive mental retardation, cardiac abnormalities, hepatosplenomegaly, skeletal deformities, brain lesions, subendothelial arterial deposits (fast progression of CAD that usually causes death by age 6-10), corneal clouding
- Hunter (mild): no corneal clouding, presence of physical deformity, mild mental retardation
e. ) Histological feature(s)
- RES and SM accumulation of MPS shows cleared cytoplasm in liver, spleen, BM, LNs, BVs and heart
Gaucher dz
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a. ) Mode of inheritance: AR
b. ) Enzyme deficiency: glucocerebrosidase (c/s 1)
c. ) Accumulating metabolite: glucocerebroside
d. ) Key clinical manifestation: lysosomal storage disease (most common)
- Type I (most common): non-neuronopathic, hepatosplenomegaly, lymphadenopathy, skeletal problems including excruciating bone pain and fractures d/t osteonecrosis, anemia, thrombocytopenia
- Types II (most severe, rare) and II (rare): neuronopathic; Parkinsonian manifestations, hydrocephalus, cardiac valve issues, neurologic degeneration, hydrops fetalis
- High incidence in Ashkenazi Jew population
e. ) Histological feature(s):
- Huge macrophages (non-foamy as non lipid) in spleen, liver and bone marrow with wrinkled tissue paper appearance that is eosinophilic under H&E
Niemann-Pick dz
a. ) Mode of inheritance
b. ) Enzyme deficiency
c. ) Accumulating metabolite
d. ) Key clinical manifestation
e. ) Histological feature(s)
a. ) Mode of inheritance: AR
b. ) Enzyme deficiency:
- Type A and B: sphingomyelinase (c/s 11 – Dad’s imprinted, Mom’s has missense mutation)
- Type C: no enzyme defect, deficiency in cholesterol transport (NPC1 or NPCS2 gene mutation, more commonly NPC1)
c. ) Accumulating metabolite:
- Type A and B: sphingomyelin
- Type C: GM1/2 gangliosides + cholesterol
d. ) Key clinical manifestation: lysosomal storage disease
- Type A (severe): infantile death usually within 3 years, neurologic signs (shrunken gyri/widened sulci with ballooning of neurons), cherry red spot, hepatosplenomegaly, lymphadenopathy
- Type B: survive into adulthood, hepatosplenomegaly, no CNS involvement
- Type C: hydrops fetalis, stillbirth, neonatal hepatitis, hepatosplenomegaly (improves into adulthood) progressively worsening neurological damage into adulthood presents as ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor deterioration
- High incidence in Ashkenazi Jew population
e. ) Histological feature(s):
- EM: foamy/vacuolated cytoplasm with concentric lamellated myelin figures known as zebra bodies
Tay-Sachs dz
a) Mode of inheritance
b) Enzyme deficiency
c) Accumulating metabolite
d) Key clinical manifestation
e) Histological feature(s)
a. ) Mode of inheritance: AR
b. ) Enzyme deficiency: hexosaminidase A (c/s 15)
c. ) Accumulating metabolite: GM2 ganglioside
d. ) Key clinical manifestation: lysosomal storage disease
- Normal at birth – retardation, blind, uncoordinated, limp, enlarged brain and head, death prior to age 4, cherry red spot on macula.
- High incidence in Ashkenazi Jew population.
e. ) Histological feature(s):
- Light microscopy: swollen/ballooned neurons with pale granular material
- EM: membranous concentric bodies
Turner syndrome
a. ) Karyotype
b. ) Pathogenesis
c. ) Key clinical manifestation
a. ) 45 XO or mosaicism
b. ) Absence of X or Y from sperm
c. ) Most are miscarried (fetal hydrops), prenatally: cystic hygroma (failure of lymphatics to form and drain properly); birth: webbed neck, puffy hands and feet, low set rotated ears, poor suck, failure to thrive; bicuspid valve, VSD, coarctation of aorta, low posterior hairline, cubitus valgus, short 4th metacarpals, widely spaced nipples, short stature, triangle-shaped face, streaked ovaries (stroma, no follicles), failure of feminization (secondary sex characteristics), failure to menstruate. IQ normal.
**If any girl presents to office with short stature and failure to thrive, think Turner
