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)
-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)
-pinched purpura (esp around eyes)
-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
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
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
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
-leukemia cutis
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
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
-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
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
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
-skeletal abnormalities (dysostosis multiplex)
-joint stiffness
-CV disease
-corneal clouding
What is the typical skeletal abnormality in patients with mucopolysaccharidoses? dysostosis multiplex