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ABNORMALITIES IN DERMAL CONNECTIVE TISSUE. Erik Austin, D.O., M.P.H. Elastosis perforans serpiginosa – Serpiginous arrangement of confluent, keratotic papules on the arms, face/neck, legs. Keratotic papules of EPS Typical site affected = neck. Elastosis perforans serpiginosa EPS.

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ABNORMALITIES IN DERMAL CONNECTIVE TISSUE

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ABNORMALITIES INDERMAL CONNECTIVE TISSUE

Erik Austin, D.O., M.P.H.


Elastosis perforans serpiginosa – Serpiginous arrangement of confluent, keratotic papules on the arms, face/neck, legs


Keratotic papules of EPSTypical site affected = neck


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


  • Annular plaques of EPS

  • Atrophic scars often form


Hyperelastic epidermis that clutches the increased dermal elastic fibers like a claw

EPS


Transepidermal elimination of neutrophils and elastic fibers from the dermis through a channel in the epidermis

EPS


Reactive perforating collagenosis (RPC)Keratotic papules on upper extremity, face or buttocks


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


Pseudoxanthoma elasticum (PXE)

  • Yellow papules, calcified plaques, sagging skin; chicken skin


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


Mucosal lesions

  • Retinal change = Angioid streaks; in up to 85%


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


Histopathology of PXE

  • A. calcium deposits on elastic fibers in advanced PXE

  • B. irregularly clumped elastic fibers, Verhoeff van Giesson


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


Perforating calcific elastosis

  • Shares features with PXE, without systemic features

  • Trauma of pregnancy, obesity or surgery promote elastic fiber degeneration

  • No effective therapy


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


Clinical features of Ehlers-Danlos syndrome


  • 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


  • 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


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


  • 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


Cutis Laxa – loose, hanging skin – usually entire integument is involved


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


Cutis laxa (generalized elastosis)

  • Premature aging, severe pulmonary emphysema, and fragmentation of dermal elastic fibers


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


Anetoderma (macular atrophy)

  • A group of disorders characterized by looseness of the skin due to loss of elastic tissue


Anetoderma (macular atrophy)


Anetoderma – macular atrophy and atrophic plaques – buttonhole sign. Typical location: trunk, arms, shoulders, thighs


  • Anetoderma: decreased elastic fibers in the papillary and reticular dermis


Striae rubra, striae alba: depressed lines or bands


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


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


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


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


Osteogenesis imperfecta

  • Blue sclera

  • Deafness

  • Thin skin; atrophic scars

  • EPS has associated


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


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


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


ERRORS IN METABOLISM


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


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


SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis

  • Glossitis with macroglossia (20%)

  • May cause dysphagia

  • Bullous disease is rare and scarring

  • Subepidermal: DDx PCT and EBA


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


primary systemic amyloidosis

  • Macroglossia with dental impression of the tongue


Periorbital ecchymosis, “raccoon sign”

primary systemic amyloidosis


primary systemic amyloidosis

  • Numerous waxy and translucent papules


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


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


  • Macular Amyloidosis: pruritic, brown macules with a rippled pattern


Lichen amyloidosis

  • Pruritic, keratotic, hyperigmented plaques on the legs

  • Tx = high potency corticosteroids, oral retinoids, cyclophosphamide, dermabrasion and occlusion


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


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


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


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


  • 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


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

Current grouping of the porphyrias is based on the primary site of increased porphyrin production


Porphyria cutanea tarda

  • Most common porphyria

  • Photosensitivity leads to bullae, which leads to ulcers, scarring, milia and dyspigmentation

  • Hypertrichosis, fragility and skin thickening


  • Alcoholism is common; Hep C in 94%

  • Associated with DM, LE, HIV, and

    estrogen therapy


Multiple erosions with hemorrhagic crusts, as well as an intact blister on the lateral fourth finger


PCT in chronic renal failure


PCT


  • 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


  • 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


Histologic features of PCT

  • Subepidermal blister with minimal dermal inflammatory infiltrate. Festooning of dermal papillae.


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


  • Remission may last for years

  • Iron chelation

  • May respond to transplant in renal failure

  • May improve with treatment if assoc. with Hep C


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


treatment

  • Sun protection

  • Discontinue inciting medication

    • May resolve over several months


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


  • Abnormal urinary porphyrins as in PCT

  • Elevated erythrocyte protoporphyrins

  • Increased coproporphyrins


Hepatoerythropoietic porphyria


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


  • Severe abdominal colic +/- NVDC

  • Elevated urinary porphobilinogen

  • Increased dALA in plasma and urine

  • No specific treatment

  • Avoid precipitating factors

  • Glucose loading


  • Hematin infusions

  • Pain management

  • Oral contraceptives may prevent attacks in women with premenstrual symptoms


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


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


  • 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


  • 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


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


  • 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


  • Skin biopsy confirms diagnosis

  • Tx = sun protection

  • Beta carotene, phototherapy, cysteine

  • Transfusions for anemia


Erythropoietic protoporphyria

  • Subtle scarring


Erythropoietic protoporphyria

  • Erythema and hemorrhagic crusts


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


  • 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


Congenital erythropoietic porphyria

  • Erythrodontia

  • Severe mutilation


Fluorescence of circulating red blood cells, CEP with UVA

Vs. transient fluorescence in EPP


  • 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


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


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