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

EPS

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

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

primary systemic amyloidosis

Periorbital ecchymosis, “raccoon sign”

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

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

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