abnormalities in dermal connective tissue erik austin, d.o., m.p.h
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ABNORMALITIES INDERMAL CONNECTIVE TISSUE
Erik Austin, D.O., M.P.H.
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Elastosis perforans serpiginosa – Serpiginous arrangement of confluent, keratotic papules on the arms, face/neck, legs
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Keratotic papules of EPSTypical site affected = neck
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Elastosis perforans serpiginosaEPS MC in young adults with a M:F ratio of 4:1 Runs a variable course of 6 mos to 5 years
with spontaneous resolution Associated with: Down Syndrome, Ehlers-
Danlos, osteogenesis imperfecta, Marfan’s, Rothmund-Thomson, acrogeria, systemic sclerosis
Tx = LN2, Penicillamine
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Annular plaques of EPS
Atrophic scars often form
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EPS
Hyperelastic epidermis that clutches the increased dermal elastic fibers like a claw
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EPS
Transepidermal elimination of neutrophils and elastic fibers from the dermis through a channel in the epidermis
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Reactive perforating collagenosis (RPC)Keratotic papules on upper extremity, face or buttocks
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Reactive perforating collagenosisRPC Rare, familial, non-pruritic skin disorder Lesions begin in 2nd decade Involution occurs after 6-8 weeks, with new
crops appearing for years May be a reaction to trauma Acquired form may be assoc. w/systemic dz TX = treat underlying disease
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Pseudoxanthoma elasticum (PXE)
Yellow papules, calcified plaques, sagging skin; chicken skin
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Pseudoxanthoma elasticumPXE Inherited disorder of the skin, eyes, and
cardiovascular system Has recessive and dominant inheritance Exaggerated nasolabial folds is
characteristic Involvement of the cardiovascular system
occurs with a propensity to hemorrhage
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Mucosal lesions
Retinal change = Angioid streaks; in up to 85%
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Pseudoxanthoma elasticumPXE Mitral valve prolapse, 71% of 14 pts Young pt w/hypertension = r/o PXE Histo: mid-dermis w/elastic fibers that are
swollen and granular - “raveled wool” No distinctive therapy Limit dietary calcium and phosphorus
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Histopathology of PXE
A. calcium deposits on elastic fibers in advanced PXE
B. irregularly clumped elastic fibers, Verhoeff van Giesson
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Perforating calcific elastosis
Acquired, localized disorder Frequently found in obese, multiparous,
middle-aged women Yellowish, lax, well circumscribed,
reticulated or cobblestones plaques occur in the periumbilical region with keratotic papules
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Perforating calcific elastosis
Shares features with PXE, without systemic features
Trauma of pregnancy, obesity or surgery promote elastic fiber degeneration
No effective therapy
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Ehlers-Danlos syndromes
A group of genetically distinct disorders characterized by excessive stretchability and fragility of the skin
Tendency toward easy scar formation, calcification of the skin to produce, pseudotumors, and hyperextensibility of the joints
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Clinical features of Ehlers-Danlos syndrome
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Two types of growths seen with EDS Molluscum pseudotumor = a soft fleshy
nodule seen in areas of trauma Spheroids = hard subcutaneous nodules that
become calcified, ?Result of fat necrosis
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Types I, II, III and one subtype each of types of IV, VII and possibly VIII = AD
One subtype of IV, VI, VII, and X = AR Type V = X-linked inheritance Treatment is supportive Avoidance of trauma
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Marfan syndrome
AD Skeletal, cardiovascular, and ocular
involvement Important abnormalities include: tallness,
loose-joints, a dolichocephalic skull, high arched palate, arachnodactyly, pigeon breast, pes planus, poor muscular tone, large deformed ears
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Ascending aortic aneurysm and mitral valve prolapse are commonly seen
Ectopic lentis and striae Gene defect = chromosome 15 Abnormal elastic tissue in fibrillin 1 and
fibrillin 2
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Cutis Laxa – loose, hanging skin – usually entire integument is involved
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Cutis laxa (generalized elastosis)
AD = primarily cutaneous, good prognosis AR = significant internal involvement, die young X-linked recessive = occipital horn syndrome Nonfamilial forms have been described May be associated with an underlying disease or
inflammatory skin process Mid-dermal elastosis is an acquired, nonfamilial
condition affecting primarily young women, cause unknown
Tx = disappointing; surgery is unsuccessful
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Cutis laxa (generalized elastosis)
Premature aging, severe pulmonary emphysema, and fragmentation of dermal elastic fibers
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Blepharochalasis
Lax eyelid skin due to swelling of lids Uncommon AD Lack of elastic fibers, and abundant IgA
deposits have been demonstrated Ascher Syndrome = progressive
enlargement of the upper lip and blepharochalasis / treatment is surgical
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Anetoderma (macular atrophy)
A group of disorders characterized by looseness of the skin due to loss of elastic tissue
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Anetoderma (macular atrophy)
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Anetoderma – macular atrophy and atrophic plaques – buttonhole sign. Typical location: trunk, arms, shoulders, thighs
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Anetoderma: decreased elastic fibers in the papillary and reticular dermis
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Striae rubra, striae alba: depressed lines or bands
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Striae distensae
Can occur secondary to pregnancy or after sudden weight gain or muscle mass
Associated with Cushing’s syndrome and Prolonged application of topical steroids Overtime striae become less noticeable Tx = topical tretinoin; vascular lasers
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Linear focal elastosis(elastotic striae) Asymptomatic, palpable, striaelike yellow
line of the middle and lower back Distinguished from striae in that there is no
depression
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Acrodermatitis chronica atrophicans Acquired diffuse thinning of the skin Reddish appearance on extensor surfaces Progresses to smooth , soft, atrophic skin Results from infection with Borrelia
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Osteogenesis imperfecta
Affects: bones, joints, eyes, ears, and skin types I-IV, I and IV = AD II and III = AD/AR 50% are type I type II is lethal within 1st week of life Brittle bones, fractures occur early in life,
sometimes in utero Loose-jointedness and dislocations
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Osteogenesis imperfecta
Blue sclera Deafness Thin skin; atrophic scars EPS has associated
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Osteogenesis imperfecta
Defect is abnormal collagen synthesis, resulting in type I collagen of abnormal structure
Major causes of death = respiratory failure and head trauma
Type I and IV have a normal life span TX = Pamidronate
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Homocystinuria
Inborn error in the metabolism if methionine
Homocystine in the urine and CT abnormalities
cystathionine synthetase deficient Genu valgum, kyphoscoliosis, pigeon
breast, frequent fractures
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Homocystinuria
Facial skin has a characteristic flush Other skin is blotchy red Hair is fine, sparse and blonde Teeth are irregularly aligned Downward dislocations of lens TX = hydroxocobalamin and
cyanocobalamin – variable results
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ERRORS IN METABOLISM
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SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis Involves mesenchymal tissue, the tongue,
heart, gastrointestinal, and skin Cutaneous manifestations in 40% Amyloid fibril proteins are composed of AL Derived from immunoglobulin light chains 90% will have fragment in urine and serum
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SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis Waxy, firm, flat-topped or spherical papules Coalesce to form nodules and plaques Eyes, nose, mouth, and mucocutaneous
junctions are commonly involved Purpuric lesions and ecchymosis (15%) Results from amyloid infiltration of vessels
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SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis Glossitis with macroglossia (20%) May cause dysphagia Bullous disease is rare and scarring Subepidermal: DDx PCT and EBA
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SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis Systemic findings: peripheral neuropathies,
arthropathy, GI bleeding, cardiac disease Prognosis is poor, median survival 13 mos,
5 mos in myeloma associated cases Treatment is difficult = melphalen,
prednisone, hematopoietic stem cell transplantation
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primary systemic amyloidosis
Macroglossia with dental impression of the tongue
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primary systemic amyloidosis
Periorbital ecchymosis, “raccoon sign”
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primary systemic amyloidosis
Numerous waxy and translucent papules
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Secondary systemic amyloidosis
Amyloid involvement of adrenals, liver spleen, and kidney as a result of some chronic disease (TB, leprosy, etc.)
Skin is not involved Amyloid fibrils are designated AA, protein
component is unrelated to immunoglobulin Treat the underlying condition
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CUTANEOUS AMYLOIDOSISprimary cutaneous amyloidosis Divided into macular and lichen amyloid Asian , Hispanic, and Middle Eastern Amyloid deposition contains keratin Histologic picture is similar for both Differ only in size of amyloid deposits Absence of amyloid deposits around blood
vessels excludes systemic involvement
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Macular Amyloidosis: pruritic, brown macules with a rippled pattern
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Lichen amyloidosis Pruritic, keratotic,
hyperigmented plaques on the legs
Tx = high potency corticosteroids, oral retinoids, cyclophosphamide, dermabrasion and occlusion
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Nodular amyloidosis
Extremities, trunk, genitals and face with localized nodules
Lesions contain numerous plasma cells, amyloid is immunoglobulin-derived AL
TX = physical removal or destruction
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Secondary cutaneous amyloidosis
Following PUVA therapy and in benign and malignant cutaneous neoplasms, deposits of amyloid may be found
Most frequently associated neoplasms are NMSC and SKs
In all cases, this is keratin-derived amyloid
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Familial syndromes associated with amyloidosis (heredofamilial amyloidosis)
Muckle-Wells syndrome MEN IIA Most present with neurologic disease and
are now designated familial amyloidotic polyneuropathy
Four types identified FAP I through IV AD inherited
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PORPHYRIAS
Porphyrinogens are the building blocks of hemoproteins
Produced primarily in the liver, bone marrow and erythrocytes
Each form is associated with a deficiency in the metabolic pathway of heme synthesis
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Absorption of UV radiation in the Soret band (400-410 nm) by the increased porphyrins leads to photosensitivity
Activated porphyrins form reactive oxygen species that causes tissue damage
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Current grouping of the porphyrias is based on the primary site of increased porphyrin production Erythropoietic forms
Congenital erythropoietic porphyria (CEP)
Erythropoietic protoporphyria (EPP)
Erythropoietic coproporphyria ECP
Hepatic forms Acute intermittent
porphyria (AIP) ALA dehydrogenase
deficiency Hereditary
coproporphyria (HCP) Variegate porphyria
(VP) Porphyria cutanea
tarda
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Porphyria cutanea tarda
Most common porphyria Photosensitivity leads to bullae, which leads
to ulcers, scarring, milia and dyspigmentation
Hypertrichosis, fragility and skin thickening
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Alcoholism is common; Hep C in 94% Associated with DM, LE, HIV, and
estrogen therapy
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Multiple erosions with hemorrhagic crusts, as well as an intact blister on the lateral fourth finger
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PCT in chronic renal failure
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PCT
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Deficiency = uroporphyrinogen decarboxylase
Most common = sporadic nonfamilial form, (80%), abnormal enzyme activity
Presents in midlife Familial type = AD; deficiency in liver and
RBCs Nonfamilial = acquired toxic; associated
with exposure to hepatotoxins
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Diagnosis = suspected on clinical grounds Coral red fluorescence of urine 24 hour urine Uroporphyrins to coproporphyrins 3:1 to 5:1 DIF shows IgG and C3 at the DEJ, and in the
vessel walls in a linear pattern
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Histologic features of PCT
Subepidermal blister with minimal dermal inflammatory infiltrate. Festooning of dermal papillae.
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treatment
Remove environmental exposures Sunscreens Phlebotomy / uroporphyrinogen
decarboxylase is inhibited by iron 500 ml at 2 week intervals, hemoglobin 10 g/dL Several months, 6-10 phlebotomies
Antimalarials / full doses may produce severe hepatotoxic reaction
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Remission may last for years Iron chelation May respond to transplant in renal failure May improve with treatment if assoc. with
Hep C
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pseudoporphyria
Skin and Histo similar to PCT Normal urine and serum porphyrins No hypertrichosis, dyspigmentation or
cutaneous sclerosis Commonly caused by NSAIDs, naproxen,
sunbed use, hemodialysis
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treatment
Sun protection Discontinue inciting medication
May resolve over several months
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Hepatoerythropoietic porphyria
Very rare form / AR Deficiency of uroporphyrinogen
decarboxylase, 10% of normal in both the liver and erythrocytes
Dark urine at birth Vesicles, scarring, hypertrichosis,
pigmentation, red fluorescence of teeth
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Abnormal urinary porphyrins as in PCT Elevated erythrocyte protoporphyrins Increased coproporphyrins
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Hepatoerythropoietic porphyria
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Acute intermittent porphyria
Second most common form Characterized by periodic attacks of
abdominal colic, gastrointestinal disturbances, paralyses, and psychiatric disorders
No skin lesions are seen AD / deficiency in porphobilinogen
deaminase Only 10 % develop disease, all are at risk for
primary liver cancer
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Severe abdominal colic +/- NVDC Elevated urinary porphobilinogen Increased dALA in plasma and urine No specific treatment Avoid precipitating factors Glucose loading
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Hematin infusions Pain management Oral contraceptives may prevent attacks in
women with premenstrual symptoms
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Hereditary coproporphyriaHCP Rare, AD Deficiency of coproporphyrinogen oxidase One third are photosensitive Prone to GI attacks Fecal coproporphyrin is always increased Urinary coproporphyrin, ALA, and PBG are
only increased during attacks
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Variegate porphyriaVP AD Decreased activity of protoporphyrinogen
oxidase Majority of relatives have silent VP Characterized by skin lesions of PCT and
the GI and neurologic disease of AIP
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Suspect VP when finding indicate both PCT and AIP, esp. with history of South African ancestry
Fecal coproporphyrins and protoporphyrins are always elevated
During attacks, urine porphobilinogen and ALA are elevated
Urinary coproporphyrins are increased over uroporphyrins
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A finding in the plasma of “X porphyrin,” fluorescence at 626 nm is characteristic and distinguishes this form from others
Symptomatic treatment as for PCT and AIP
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Erythropoietic protoporphyriaEEP AD and AR forms Ferochelatase activity is 10 to 25% of
normal in affected persons Typically presents in childhood, 2-5 years Burning of the skin upon sun exposure Elevated protoporphyrin IX absorbs both
the Soret band and also at 500-600 nm
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Severe liver disease in 10% Excessive porphyrins are deposited in liver Diagnosis on clinical grounds Urine porphyrin levels are normal Erythrocyte protoporphyrin is elevated Erythrocyte, plasma, and fecal protoporphyrin
can be assayed to confirm the diagnosis
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Skin biopsy confirms diagnosis Tx = sun protection Beta carotene, phototherapy, cysteine Transfusions for anemia
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Erythropoietic protoporphyria
Subtle scarring
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Erythropoietic protoporphyria
Erythema and hemorrhagic crusts
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Congenital erythropoietic porphyria, CEP Gunther’s disease AR; defect of uroporphyrinogen III
synthase Presents after birth with red urine Severe photosensitivity Blistering, scarring, ectropion and corneal
damage
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Mutilating scars, hypertrichosis, profuse eyebrows, long eyelashes, “monkey face”
Growth retardation, hemolytic anemia, thrombocytopenia, porphyrin gallstones, osteopenia
Suspect in an infant with dark urine and photosensitivity
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Congenital erythropoietic porphyria
Erythrodontia Severe mutilation
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Fluorescence of circulating red blood cells, CEP with UVA
Vs. transient fluorescence in EPP
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High amounts of uroporphyrin I and coproporphyrin I are found in the urine, stool and red cells
Treatment – strict avoidance of sunlight and sometimes splenectomy for the hemolytic anemia
Oral activated charcoal Repeated transfusions to maintain
hematocrit level at 33% - turns off demand for heme
Bone marrow transplantation
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Transient erythroporphyria of infancy (purpuric phototherapy-induced eruption) Report of seven infants exposed to 380 to
700 nm blue lights, for the treatment of indirect hyperbilirubinemia, who developed marked purpura on the exposed skin
All infants had received transfusions Elevated plasma coproporphyrins and
protoporphyrins were found in 4 Pathogenesis is unknown