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Deposition Disorders
Deposition Disorders/Amyloidosis/Mucinoses
| Question | Answer |
|---|---|
| What is the ultrastructure of amyloid protein? | fibrillar beta-pleated sheet |
| What are the 3 major forms of primary cutaneous amyloidosis? | 1) macular 2) lichen 3) nodular |
| What is biphasic amyloidosis? | the patient has features of both macular and lichen amyloidosis |
| What diagnostic test can be performed in patient's without cutaneous lesions in whom you suspect primary systemic amyloidosis? | abdominal fat aspiration |
| What are the three most commonly used stains for amyloid? | Congo Red, Crystal violet, and Thioflavin T |
| What color is the birefringence of amyloid with Congo Red? | Apple-Green |
| What color does amyloid stain with Thioflavin T? | bright yellow-green fluorescent |
| (Apo) serum AA protein is associated with which forms of amyloidosis? | secondary systemic, periodic fever syndromes |
| AL protein is associated with which forms of amyloidosis? | primary systemic (plasma cell dyscrasia >> MM) and primary cutaneous nodular |
| B2-microglobulin is associated with which form of amyloidosis? | chronic hemodialysis |
| Corneodesmin in the protein precursor of amyloidosis in which clinical syndrome? | hypotrichosis simplex of the scalp |
| Calcitonin is the precursory protein of amyloidosis in which clinical disease? | medullary carcinoma of the thyroid |
| Immunoglobulin light chains are the protein precursor for which clinical syndromes? | primary systemic amyloidosis and nodular amyloidosis |
| What is the pathogenesis of nodular amyloidosis? | local Ig production by local plasma cells |
| Transthyretin is the protein precursor of amyloid in which clinical syndromes? | familial amyloid polyneuropathy and senile systemic amyloidosis |
| Keratin is the protein precursor of amyloid in which forms of amyloidosis? | primary cutaneous - macular and lichen |
| Which types of amyloid lose their affinity for Congo Red after exposure to potassium permanganate? | AA (not AL) |
| What components make up amyloid? | -fibril beta-pleated sheet protein -amyloid P (glycoprotein) -glycosaminoglycans -ApoE lipoprotein |
| What are the clinical features of macular amyloidosis? | -hyperpigmented rippled pattern, usually on the upper back or extensor surfaces |
| What are the clinical features of lichen amyloidosis? | pruritic discrete hyperpigmented, scaly papules that coalesce into rippled plaques, usually on the lower legs |
| What is the most common form of primary cutaneous amyloidosis? | lichen |
| Are bullous amyloid lesions more common in systemic or cutaneous? | systemic |
| What autoimmune diseases have been associated with macular and/or lichen amyloid? | scleroderma, SLE, DM, primary biliary cirrhosis |
| What percent of patients with nodular amyloidosis progress to systemic involvement? | 7% (previous studies indicated about 50%); 40% of patients have paraproteinemia at the time of diagnosis |
| What are the anti-keratin antibodies that are used to detect amyloid in macular/lichen amyloidosis? | LP34, MNF116, RCK102 |
| What are the histologic features of nodular amyloid? | the dermis, subcutis, and blood vessels are all filled with amyloid |
| What is the main clinical Ddx for macular amyloid? | PIH, notalgia paresthetica, TV, EDP |
| What is the main clinical Ddx for lichen amyloid? | LSC, hypertrophic LP, prurigo nodules, papular mucinosis |
| What is the main clinical Ddx for nodular amyloidosis? | lymphoma cutis, cutaneous lymphoid hyperplasia |
| What is secondary systemic amyloidosis? | clinically inapparent amyloid deposits that are seen incidentally on biopsy of other lesions - IDN, DF,SK, trichoep, pilomatricoma, BCC, Bowens, porokeratosis |
| What is the underlying cause of primary systemic amyloidosis? | plasma cell dyscrasia with deposition of Ig light chain (lambda) |
| What type of light chains (kappa or lamda) are usually found in primary systemic amyloidosis? | lambda |
| What are the mucocutaneous features of primary systemic amyloidosis? | -soft, rubbery, infiltrative swellings of the mucosa (sometimes hemorrhagic) -macroglossia -pinched purpura (esp around eyes) -xerostomia -waxy, translucent, purpuric papules or plaques on the skin |
| What percent of patients with primary systemic amyloidosis have skin findings? | 25% |
| What are the skin findings in primary systemic amyloidosis? | -pinched purpura (from infiltration of the blood vessels) -waxy, translucent, purpuric papules and plaques (esp head and neck -smooth, red, waxy infiltration of the palms of the hands |
| What other organ systemics can be involved in primary systemic amyloidosis? | -renal (proteinuria, edema) -heart (restrictive cardiomyopathy, CHF) -autonomic and sensory neuropathies (carpal tunnel) -liver (hepatosplenomegaly) |
| What biopsy sites can pick up 80-90% of cases of primary systemic amyloidosis? | abdominal fat aspirates and rectal biopsies |
| What are the histologic findings in primary systemic amyloidosis? | amyloid deposition in the deep dermis, subcutis, around the sweat glands and blood vessels |
| What is the clinical ddx the waxy papules/nodules seen in primary systemic amyloidosis? | -papular mucinosis -nodular amyloid -lipoid proteinosis -adnexal tumors |
| What is the main therapy for primary systemic amyloidosis? | melphalan and systemic steroids and/or stem cell transplant |
| What is the pathogenesis behind secondary systemic amyloidosis? | severe, chronic inflammation caused by autoimmune disease or infection |
| What are some of the most common causes of secondary systemic amyloidosis? | -TB -leprosy -RA -AS -SLE -DM |
| What type of amyloid is found in secondary systemic amyloidosis? | AA protein |
| What are the cutaneous manifestations of secondary systemic amyloidosis? | -usually none -amyloid can often be seen incidentally on skin biopsies |
| What organ systems are typically affected by secondary systemic amyloidosis? | -kidneys -liver -adrenals -heart |
| What are the symptoms of hemodialysis associated amyloidosis? | MSK- carpal tunnel, bone cysts, destructive joint disease (caused by deposition in synovial membrane) |
| What is the type of amyloid found in hemodialysis associated amyloidosis? | beta-2 microglobulin |
| What autoinflammatory syndromes are often associated with secondary systemic amyloidosis? | Muckle-Wells syndrome and Familial Mediterranean Fever |
| What is the protein precursor of the amyloid seen in Familial amyloidosis, Finnish type? | gelsolin - causes corneal lattice dystrophy, cranial neuropathies, and skin fragility |
| What are the clinical features of familial amyloid polyneuropathy? | peripheral sensorimotor and autonomic neuropathy, paresthesias, carpal tunnel, postural hypotension, erectile dysfunction, GI disturbance |
| Multiple endocrine neoplasia type IIA is also known as? | Sipple syndrome |
| What is the triad of findings in MEN2A (Sipple syndrome)? | -medullary carcinoma of the thyroid -pheochromocytoma -hyperparathyroidism |
| What cutaneous findings of amyloidosis are seen in MEN2A? | macular and/or lichen amyloid (usually on the back) secondary to elevations of calcitonin that lead to amyloid deposition |
| What specific mutation is associated with the cutaneous amyloidosis seen in MEN2A? | mutation in codon 634 of the RET proto-oncogene |
| What is hypotrichosis simplex of the scalp? | AD disorder where patients have normal hair at birth and then lose scalp hair by 3rd decade (all other hair remains) -mutation in corneodesmosin that leads to truncated proteins in the hair follicle and deposits of amorphous amyloid |
| What is X-linked Reticulate Pigmentary Disorder? | X-linked disease in which female have streaks of hyperpigmentation and males have reticulated mottled hyperpigmentation -biopsy of adults show keratin-derived amyloid -males only- recurrent respiratory tract infections, corneal dystrophy, and photophobi |
| What alters the protein beta 2 micro globulin in patients with renal failure? | Uremia |
| What is the source of AA protein seen in secondary systemic amyloidosis? | Acute phase reactant made by the liver |
| What findings on the tongue are seen in primary systemic amyloidosis? | Macroglossia with indentations from the teeth on lateral aspects of the tongue |
| What is the shoulder pad sign. | Enlarged deltoid muscle seen in primary systemic amyloidosis |
| What is mucin? | Glycosaminoglycan component of the extracellular matrix made by fibroblasts |
| What are the mucin stains? | Alcian blue, colloidal iron, toluidine blue, PAS negative |
| Which cytokines are thought to increase mucin deposition in the skin ? | IL1, TNFalpha, TGFbeta |
| Sclerromyxedema is also known as? | Papular mucinosis |
| Scleromyxedema is associated with what systemic disorder? | IgG paraproteinemia lambda type |
| What percent of patients with scleromyxedema progress to multiple myeloma? | 10 percent |
| What is 'dermato-neuro' syndrome? | Potentially life-threatening encephalopathy seen in older men with scleromyxedema with sudden onset of worsening skin lesions, flu-like symptoms, fever, seizures, and eventually coma |
| What is the triad of histologic features seen in scleromyxedema? | 1) diffuse deposit of mucin in the upper and mid reticular dermis 2) increased collagen deposition 3) marked proliferation of irregularly arranged fibroblasts |
| What are the cutaneous features of scleromyxedema? | -2-3mm firm, waxy, closely spaced papules in a symmetrical distribution, usually on the head, neck, upper trunk and hands. -surrounding skin is sclerodermoid -glabella shows deep furrowing and can lead to leonine facies -erythema, edema, discoloration |
| What is the doughnut sign ? | A central depression surrounded by elevated rim on the PIP joints in scleromyxedema |
| What is the ddx of leonine facies? | -scleromyxedema -systemic amyloidosis -lipoid proteinosis -lepromatous leprosy -leishmania -CTCL -leukemia cutis -sarcoidosis -MRH |
| What is the treatment of scleromyxedema? | Melphalan, dexamethasone, thalidomide |
| What systemic manifestations can be seen in scleromyxedema? | Muscle weakness, neuropathy, restrictive lung disease, renal disease, CHF/cardiomyopathy |
| What are the 4 subtypes of lichen myxedematosus? | 1) discrete papular 2) acral persistent papular mucinosis 3) cutaneous mucinosis of infancy 4) pure modular form |
| What are the clinical features if lichen myxedematousus? | Small, firm, waxy papules and plaques limited to a few sites- mostly upper and lower limbs and trunk |
| Is lichen myxedematousus associated with plasma cell dyscrasia? | No |
| What are the clinical features of discrete papular lichen myxedematosus? | 2-5mm papules symmetrically distributed on the trunk and extremities; the face is spared; never progresses to sclermyxedema |
| What are the clinical features of acral persistent papular mucinosis? | Multiple skin colored papules that develop on the dorsal hands only; usually in women |
| What are the clinical features of cutaneous mucinosis of infancy? | Firm, opalescent papules on the neck, upper arms, and trunk; usually does not spontaneously resolve |
| How is localized lichen myxedematosus associated with HIV infection? | Firm, discrete mutinous papules have been described in HIV men with hypergammaglobulinemia |
| What 'toxic syndromes' have been associated with lichen myxedematosus? | Toxic oil syndrome and L-tryptophan associated eosinophilia myalgia syndrome (constitutional sx, peripheral eosinophilia, sclerodermoid appearance and mutinous papules) - resolves after the offending agent is removed |
| What are the histologic features of lichen myxedematosus? | Mucin accumulation in the upper and mid dermis with variable fibroblast proliferation; no fibrosis |
| What are the 3 types of scleredema? | 1) post-strep infection (spontaneously resolves) 2) associated with monoclonal gammopathy 3) associated with diabetes |
| What are the features of type I scleredema (associated with strep infection)? | -primarily middle-aged women -preceded by strep infection -sudden onset of hardening of the cervicofacial skin with extension to the trunk and proximal upper limbs -resolves over a few months |
| What are the features of type III scleredema (diabetes-associated)? | -usually middle-aged men with insulin-dependent diabetes -subtle onset of induration of the posterior neck and back -peau d' orange appearance of skin -waxy distal extremities -more likely than others to have systemic involvement |
| What systemic involvement can be seen with scleredema? | serositis, dysarthria, dysphagia, myositis, cardiac problems, ocular disease |
| What are the histologic features of scleredema? | large, thick collagen bundles in the reticular dermis that are separated by clear spaces filled with mucin -no increase in the number of fibroblasts |
| Does control of hyperglycemia have any effect on the skin disease in scleredema? | no |
| Pretibial myxedema is highly associated with which other manifestation of Grave's disease? | exophthalmos (25% of patients with eye involvement will also have pretibial myxedema) |
| What is the pathogenesis behind pretibial myxedema? | unknown- possibly some other serum factor (other than TSH) stimulates fibroblasts in the legs to produce mucin |
| What are the clinical features of pretibial myxedema? | skin-colored to purple/brown yellowish, waxy indurated nodules or plaques -classically have peau d' orange appearance -located on anterolateral aspect of lower legs -can progress to elephantiasis appearance -rarely affects other areas |
| What is a potential neural complication of pretibial myxedema? | mucin around the peroneal nerves can cause foot drop |
| What are the histologic features of pretibial myxedema? | large quantities of mucin in the upper reticular dermis with a grenz zone of normal collagen and large stellate fibroblasts |
| What are treatment options for pretibial myxedema? | topical or intralesional steroids, compression stockings -may clear spontaneously |
| What is generalized myxedema? | manifestation of severe hypothyroidism with massive amounts of mucin deposition |
| What are the physical features of generalized myxedema? | -dull facial expression -puffy eyelids, hands, nose -pale, cool, waxy, dry sin -absence of sweating leads to dryness -brittle hair and nails -alopecia -purpura |
| What are the clinical features of reticular erythematous mucinosis? | pink to red macules and papules that merge into a reticulated and annular pattern, usually on the chest or midback -may be pruritic -photoexacerbated -not associated with any systemic disease -more common in women |
| What syndrome is REM histologically indistinguishable from? | tumid LE |
| What is the treatment for REM? | antimalarials and sun protection |
| What are the histologic features of REM? | -interstitial deposits of small amounts of mucin in the upper dermis -perivascular and sometimes perifollicular lymphs -no interface |
| What are the two types of follicular mucinosis? | 1) acute to subacute eruption that occurs in children and young adults and resolve spontaneously 2) form associated with MF in older adults |
| What are the clinical features of the juvenile form of follicular mucinosis? | acute to subacute eruption in children and young adults with one or several pink plaques or grouped follicular papules on the face and scalp with alopecia |
| What are the clinical features of MF-associated follicular mucinosis? | more generalized grouped follicular papules and larger, more numerous plaques -has a more chronic course -usually in older adults with MF (a secondary finding) |
| What are the histologic features of follicular mucinosis? | mucin accumulates in the follicular epithelium and disrupts the keratinocytes; infiltrate of lymphocytes, histiocytes, and eos |
| What are the features of urticaria-like follicular mucinosis? | -occurs mostly in middle-aged men -pruritic urticarial papules or plaques on the head and neck with a "seborrheic" background -no alopecia -red macules persist for weeks after the eruption is gone -no associated systemic disease -usually resolves |
| What is a mucinous nevus? | benign hamartoma -unilateral, linear, nevoid plaque that may be found associated with an epidermal nevu -CD34 positive fibroblasts with diffuse deposit of mucin in the upper dermis with absent collagen or elastic fibers |
| What are the features of Carney complex? | -cutaneous myxomas -cardiac myxomas -numerous lentigines -multiple blue nevi -endocrine overactivity |
| Where on the body are cutaneous myxomas typically found? | trunk, head, neck, genitalia |
| What are the histologic features of cutaneous myxoma? | well-defined, lobulated lesion with mucinous matrix within the dermis and subcutis and variably shaped fibroblasts and a few collagen fibers (cutaneous focal mucinosis is a reactive process that is more ill-defined) |
| What is the proposed pathogenesis of focal cutaneous mucinosis? | "muciparous" reaction of connective tissue to a nonspecific stimulus |
| What cytokine do urate crystals stimulate? | IL-1 which recruits neutrophils |
| Where are the most common locations for gouty tophi? | skin overlying the joints and the helix of the ear |
| How do gout crystals appear under polarized light? | negatively birefringent |
| What are the histologic features of gout? | amorphous pink material in the dermis and subcutis with needle-like clefts, surrounded by histiocytes and multi-nucleated giant cells |
| What fixative should be used for specimens when gout is suspected? | ethanol-based fixative, like Carnoy's fluid |
| What two stains are used to stain gout? | 20% silver nitrate (stains black) and De Galantha (stains brown to black) |
| Pseudogout crystals are composed of what? | calcium pyrophosphate dihydrate |
| How do pseudogout crystals appear under microscopy? | rhomboid, weakly positively birefringent |
| What common joint disease to most patients with pseudogout have? | osteoarthritis |
| What is the most common location for psedogout attacks? | knee |
| Urbach-Wiethe disease is also known as ? | lipoid proteinosis |
| What is the pathogenesis behind lipoid proteinosis? | loss of function mutation in ECM1 gene (AR mutation) |
| What is the function of ECM1 protein? | secretory glycoprotein that acts as a negative regulator of endochondral bone formation and promotes angiogenesis; also found in the BMZ |
| What is often the first clinical sign of lipoid proteinosis? | weak cry or hoarseness due to infiltration of the laryngeal mucosa |
| What is the first stage of lipoid proteinosis? | vesicles and hemorrhagic crusts on the face, extremities, in the mouth; associated with trauma |
| What is the second stage of lipoid proteinosis? | increase in hyalin deposits in the dermis thta leads to diffusely thickened, waxy, yellow skin with papules, plaques, and nodules on the face (esp eyelid margin), axillae, scrotum -verrucous lesions -alopecia of the eyebrows and eyelashes |
| What are the extracutaneous manifestations of lipoid proteinosis? | -diffuse infiltration of the tongue and frenulum -recurrent parotitis -hyperplasia and aplasia of the teeth -usually lose teeth at an early age -seizures and abnormal behavior |
| What is the pathognomonic radiographic sign in lipoid proteinosis? | bilateral, intracranial, sickle-shaped calcification within the temporal lobes |
| What are the histologic features of lipoid proteinosis? | -deposition of amorphous pink hyalin material around the blood vessels of noncollagen protein (neutral mucopolysacc) -older lesions have bundles of pink hyalin deposits diffusely, oriented perpendicular to the epidermis |
| What are the 4 types of colloid milium? | 1) adult 2) juvenile 3) pigmented 4) nodular colloid degeneration |
| What are the clinical features of colloid milum? | multiple dome-shaped,translucent to yellow or yellow-brown papules on areas of chronic sun exposure |
| What is the cause of pigmented colloid milium? | combination of excessive sun exposure plus application of topical hydroquinone |
| What are the eye lesions in lipoid proteinosis called? | moniliform blepharosis |
| What kind of changes occur in the tongue in lipoid proteinosis? | diffuse thickening of the tongue and frenulum which makes tongue movement difficult |
| Does treatment of the thyroid disorder improve pretibial myxedema? | no |
| Does treatment of the paraproteinemia in scleromyxedema improve the skin findings? | no |
| Nucleoside triphosphate pyrophosphohydrolase is responsible for making what crystals? | CPPD crystals in pseudogout |
| What is the classic radiographic finding in gout? | rat bite of the bone |
| What drugs inhibit microtubules? | -colchicine -griseofulvin -vinblastine -podophyllin |
| What are the main glycosaminoglycans? | dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate |
| What is the enzyme defect in Hurler syndrome? | alpha-L-iduronidase |
| What is inheritance pattern for all of the mucopolysaccharidoses (except for Hunter's syndrome)? | AR |
| Which MPS does not have corneal clouding? | Hunter's |
| Which MPS exhibit vacuolated lymphocytes? | Hurler, Hurler-Scheie, and Scheie |
| What is the enzyme defect in Hunter syndrome? | Iduronate-2-sulfatase |
| What is the inheritance pattern of Hunter syndrome? | XLR |
| What are the clinical features of Hunter syndrome? | -distinctive pebbling of the skin (usually over the scapulae) -retinal degeneration -coarse facies -CV disease -joint stiffness -no corneal clouding -HSM |
| What is the MPS associated with extensive dermal melanocytosis? | Hurler |
| What screening tests are done for the mucopolysaccharidoses? | urine tests for the glycosaminoglycans and peripheral smears to examine the WBCs |
| What do skin biopsy specimens from patients with MPS exhibit? | vacuolated cells within sweat glands and hair follicles with pale keratinocytes and mucin deposition |
| Which MPS syndromes exhibit granulated neutrophils? | Morquio, Maroteaux-Lamy, Sly |
| What is the enzyme defect in Maroteaux-Lamy? | arylsulfatase B |
| What is the enzyme defect in Sly syndrome? | B-glucuronidase |
| What is the enzyme defect in Morquio A? | N-acetylgalactosamine-6-sulfatase |
| What is the enzyme defect in Morquio B? | Beta-galactosidase |
| What two mucopolysaccharidoses have granulated lymphocytes? | Hunter and Sanfilippo |
| What are the typical constellation of findings for the mucopolysaccharidoses? | -coarse facies -MR -HSM -skeletal abnormalities (dysostosis multiplex) -joint stiffness -CV disease -corneal clouding |
| What is the typical skeletal abnormality in patients with mucopolysaccharidoses? | dysostosis multiplex |
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criddel
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