ABNORMALITIES IN DERMAL CONNECTIVE TISSUE Chapter 25

ABNORMALITIES INDERMAL CONNECTIVE TISSUE

Chapter 25

Elastosis perforans serpiginosaEPS Skin colored keratotic papules, 2-5 mm,

confluently grouped in a serpiginous or horseshoe-shaped arrangement

Typically occur on the neck, may involve other sites including the face, arms, legs

Disseminated lesions occur in Down syndrome

MC in young adults, M:F 4:1

Elastosis perforans serpiginosaEPS Runs a variable course with spontaneous

resolution at 6 mo to 5 yrs Atrophic scar often remains Frequent assoc conditions include Down

syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome, Rothmund-Thomson syndrome, acrogeria, systemic sclerosis

Elastosis perforans serpiginosaEPS Distinctive histopathologic changes Elongated tortuous channels in the

epidermis into which elastic tissue perforates and is excruded

Treatment is difficult LN2

Elastosis perforans serpiginosaEPS, penicillamine

Keratotic papules of EPS penicillamine TX

Annular plaques of EPS

EPS

Hyperelastic epidermis 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 collagenosisRPC Rare, familial, nonpruritic skin disorder Papules on the extremities face or buttocks Lesions begin in 2nd decade Involution after 6-8 weeks, with new crops

for years May be a reaction to connective tissue

injury acquired form, may be assoc. with systemic

disease, TX – underlying disease

Keratotic papule of RPC

Lesion followed minor trauma on the upper extremity

Pseudoxanthoma elasticumPXE Inherited skin disorder involving the

connective tissue of the skin, eye, and cardiovascular system

Recessive and dominant inheritance Small, circumscribed, yellowish or cream-

colored, creplike, lax, redundant folds, flecked with yellow papules, “plucked chicken skin”

Characteristic exaggerated nasolabial folds

Pseudoxanthoma elasticumPXE Characteristic retinal change is the angioid

streak, 85% of PXE pts have retinal findings

May be the only sign of disease for years Involvement of the cardiovascular system

occurs with a propensity to hemorrhage The vascular events are caused by the

degeneration of the elastic fibers in the vascular media

Clinical features of PXE

Yellowish papules, calcified plaques, sagging skin

Mucosal lesions

Angioid streaks

Pseudoxanthoma elasticumPXE Mitral valve prolapse, 71% of 14 pts Any patient with hypertension at a young

age should be examined for the PXE Histologically, throughout the mid-dermis

the elastic fibers are swollen and fragmented or granular “raveled wool”

No distinctive therapy is available Progressive loss of vision, 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

Periumbilical perforating PXE, and localized acquired cutaneous PXE

Acquired, localized cutaneous disorder, most frequently found in the obese, multiparous, middle-aged women

Yellowish, lax, well circumscribed, reticulated or cobblestones plaques occur in the periumbilical region with keratotic surface papules

Perforating calcific elastosis

A distinct disorder that shares some features with PXE, without systemic features

It is suggested that repeated trauma of pregnancy, obesity or surgery promotes elastic fiber degeneration

No effective therapy

Ehlers-Danlos syndromes

Cutis hyperelastica, India rubber skin, and elastic skin

A group of genetically distinct connective tissue 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

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 Special features associated with various

subtypes

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

Clinical features of Ehlers-Danlos syndrome

Marfan syndrome

Disorder of connective tissue transmitted as an AD trait

Skeletal, cardiovascular, and ocular involvement, it is one of the more common inherited diseases

Important abnormalities include tallness, loose-jointedness, 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, EPS rarely Gene defect localized to chromosome 15 Abnormal elastic tissue in fibrillin 1 and

fibrillin 2

Cutis laxa (generalized elastosis)

Dermatomegaly, dermatolysis, chalazoderma and pachydermatocele

Characterized by loose, redundant skin, hanging in folds

Drooping skin around the eyelids, cheeks and neck, bloodhound-like facies

Usually entire integument is involved AD, primarily cutaneous, good prognosis AR, significant internal involvement, die

young

Clinical features of cutis laxa

The X-linked recessive cutis laxa, occipital horn syndrome

Nonfamilial forms have been described Some cases have been associated with an

underlying disease or a preceding inflammatory skin process

mid-dermal elastosis is an acquired, nonfamilial condition affecting primarily young women, cause unknown

Treatment has been generally disappointing Multiple surgical procedures have been

largely unsuccessful

Cutis laxa (generalized elastosis)

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

Blepharochalasis

The eyelid skin becomes so lax that it falls in redundant folds over the lid margin

Uncommon, occurs in young people at time of puberty

Recurrent transitory swelling of the lids leads to stretching

Usually bilateral, generally sporadic, AD Lack of elastic fibers, and abundant IgA

deposits have been demonstrated

Blepharochalasis

Ascher syndrome consist of progressive enlargement of the upper lip and blepharochalasis, treatment is surgical

Anetoderma (macular atrophy)

A group of disorders characterized by looseness of the skin, are due to loss of elastic tissue without apparent changes in the skin


Clinical findings in both primary and secondary anetoderma are 5 – 10 mm atrophic plaques that are well defined

Lesions protrude through the skin and on palpation have less resistance than surrounding skin, “button-hole” sign

Trunk, shoulders, upper arms, and thighs Anetoderma of prematurity


Anetoderma, decrease of the elastic fibers in the papillary and reticular dermis

Striae distensae

Striae atrophicae Depressed lines or bands of thin, reddened

skin Become white, smooth, shiny and depressed Can occur during or after pregnancy, on the

breasts, after sudden weight gain or muscle mass

Cushing’s syndrome either endogenous or induced

Prolonged application of topical steroids

Striae distensae

Overtime striae become less noticeable Topical tretinoin, and vascular lasers

Striae rubra, striae alba

Linear focal elastosis(elastotic striae) Asymptomatic, palpable, striaelike yellow

line of the middle and lower back Distinguished from striae in that the linear

bands are not elevated, not depressed, and yellow, not pink or white

Acrodermatitis chronica atrophicans Acquired diffuse thinning of the skin begins with an early reddish appearance on

extensor surfaces Progresses to smooth , soft, atrophic skin Results from infection with Borrelia

Osteogenesis imperfecta

Lobstein’s syndrome Affects the 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


Blue sclera may be a valuable diagnostic clue, minimal functional importance

Deafness develops in many by 2nd decade The skin is thin and rather translucent and

healing wounds result in spreading atrophic scars

EPS has been described


The basic defect is abnormal collagen synthesis, resulting in type I collagen of abnormal structure

The major causes of death are respiratory failure secondary to severs kyphoscoliosis and head trauma, mostly observed in type III

Type I and IV have a normal life span TX – Pamidronate encouraging

homocystinuria

An inborn error in the metabolism if methionine

Characterized by the presence of homocystine in the urine and systemic abnormalities of the connective tissue

cystathionine synthetase enzyme deficient Genu valgum, kyphoscoliosis, pigeon

breast, frequent fractures

homocystinuria

Facial skin has a characteristic flush, malar Other skin is blotchy red, suggestive of

livedo reticularis Hair is fine, sparse and blonde Teeth are irregularly aligned Downward dislocations of lens TX – hydroxocobalamin and

cyanocobalamin, variable results

ERRORS IN METABOLISM

Chapter 26

SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis Involves mesenchymal tissue, the tongue,

heart, gastrointestinal, and skin Cutaneous manifestations in 40% The amyloid fibril proteins are composed of

protein AL Derived from immunoglobulin light chains 90% will have fragment in urine and serum

SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis The cutaneous eruption usually begins as shiny,

smooth, firm, flat-topped, or spherical papules of waxy color, may appear translucent

Lesions coalesce to form nodules and plaques Eyes, nose, mouth, and mucocutaneous junctions,

areas commonly involved Purpuric lesions and ecchymosis occur 15% Most common cutaneous manifestation Results from amyloid infiltration of vessels

SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis Glossitis, with macroglossia, occurs in at

least 20 % May be an early symptom, can cause

dysphagia Tongue becomes enlarged with indentations

from teeth Bullous disease is rare, heals with scarring Subepidermal, DDX PCT and EBA

SYSTEMIC AMYLOIDOSISprimary systemic amyloidosis May present with many systemic findings,

carpel tunnel syndrome, other peripheral neuropathies, arthropathy, GI bleeding, cardiac disease

Prognosis is poor, median survival 13 mo, 5 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”


Numerous waxy and translucent papules

Secondary systemic amyloidosis

Amyloid involvement of the adrenals, liver spleen, and kidney as a result of some chronic disease, such as, tuberculosis, lepromatous leprosy and others

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, most

patients have only one form Asian , Hispanic, and Middle Eastern are

predisposed The deposited amyloid material contains keratin as

its protein Histologic picture is similar for both forms Differ only in size of amyloid deposits Absence of amyloid deposits around blood vessels

excludes systemic involvement

Macular amyloidosis

Typical cases exhibit moderately pruritic, brown, rippled macules

Characteristically located on the interscapular region of the back

Lack of uniformity gives “salt and pepper” appearance

May involve other areas A chronic condition

Hyperpigmentation of macular amyloidosis with the characteristic rippled pattern

Lichen amyloidosis

Characterized by the appearance of paroxysmally itchy lichenoid papules, typically appearing bilaterally on the shins

Small, brown , discrete, slightly scaly papules

Group to form large plaques Treatment is frequently unsatisfactory High potency corticosteroids, oral retinoids,

cyclophosphamide, dermabrasion and occlusion

Lichen amyloidosis Keratotic,

hyperigmented plaques on the legs

Nodular amyloidosis

A rare form of primary localized cutaneous amyloidosis

Single, or rarely, multiple nodules found Extremities, trunk, genitals and face Overlying epidermis may resemble large

bullae 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 seborrheic keratosis

In all cases, this is keratin-derived amyloid

Familial syndromes associated with amyloidosis (heredofamilial amyloidosis)

Familial syndromes have been reported that have either systemic or localized amyloidosis

Muckle-Wells syndrome Multiple endocrine neoplasia IIA

Familial syndromes associated with amyloidosis (heredofamilial amyloidosis) Most forms 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 all the hemoproteins

Produced primarily in the liver, bone marrow and erythrocytes

Each form of porphyria is associated with a deficiency in the metabolic pathway of heme synthesis

Photosensitivity may be seen in some types

Absorption of UV radiation in the Soret band (400-410 nm) by the increased porphyrins

Activated porphyrins are unstable and transfer energy as the return to their ground state.

A reactive oxygen species is created 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

HEP, hepatoerythrocytic porphyria, has been classified as either a hepatic or hepatoerythropoietic type

Diagnosis should be made by identifying characteristic clinical and biochemical abnormalities

Porphyria cutanea tarda

The most common type of porphyria Characterized by photosensitivity resulting

in bullae These rupture easily to form erosions or

shallow ulcers and heal with scarring, milia and dyspigmentation

Patients may complain of skin fragility Hypertrichosis and sclerodermatous

thickening

Liver disease is frequent Alcoholism is common, Hep C in 94% in

US Frequently associated with other diseases DM in 15-20%, lupus erythematosis HIV Estrogen treatment is associated with the

appearance of PCT by an unknown mechanism

PCT in a patient with Hepatitis C virus infection. Multiple erosions with hemorrhagic crusts are seen as well as an intact blister on the lateral fourth finger

PCT in chronic renal failure

PCT

Deficiency in uroporphyrinogen decarboxylase

Most common is the sporadic nonfamilial form, 80%, abnormal enzyme activity in the liver

Patients present in midlife, 45 Familial type, AD, deficiency in liver and

RBCs Nonfamilial, (acquired toxic PCT),

associated with acute or chronic exposure to hepatotoxins

Diagnosis is strongly suspected on clinical grounds Coral red fluorescence in random urine 24 hour urine, 300 to several thousand micrograms Uroporphyrins to coproporphyrins 3:1 to 5:1 Biopsy – noninflammatory, subepidermal bulla with

an indulating, festooned base Caterpillar bodies, basement membrane material DIF of involved skin 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 all precipitating environmental factors

Physical barrier protection, barrier 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 years, with relapse repeat treatment

Iron chelation May respond to transplant in renal failure May improve with treatment if assoc. with

Hep C

pseudoporphyria

Blistering and skin fragility identical to PCT, histologic features of PCT

Normal urine and serum porphyrins Hypertrichosis, dyspigmentation, and

cutaneous sclerosis do not occur Most commonly caused by medications Typically NSAIDs, noproxen Sunbed use, hemodialysis

treatment

Physical sun protection Discontinue inciting medication

May resolve over several months

Hepatoerythropoietic porphyria

Very rare form Inherited as an AR trait Deficiency of uroporphyrinogen

decarboxylase, 10% of normal in both the liver and erythrocytes

Dark urine at birth Vesicles, sclerodermoid 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 trait, deficiency in porphobilinogen

deaminase Only 10 % develop disease, all are at risk for

primary liver cancer

Severe abdominal colic is most often the initial symptom of AIP, NVDC may accompany the pain

Elevated levels of urinary porphobilinogen Increased dALA in plasma and urine No specific treatment is available 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 similar to AIP and VP Fecal coproporphyrin is always increased Urinary coproporphyrin, ALA, and PBG are

only increased during attacks

Variegate porphyriaVP Mixed porphyria, South African genetic

porphyria, mixed hepatic porphyria, AD inheritance Decreased activity of protoporphyrinogen

oxidase Majority of relatives have silent VP,

reduced enzyme activity but no clinical lesions

Characterized by the combination of the skin lesions of PCT and the GI and neurologic disease of AIP

705 of patients develop skin lesions Vesicles and bulla with erosions Hypertrichosis and hyperpigmentation Facial scarring and thickening of skin

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 is for PCT and AIP

Erythropoietic protoporphyriaEEP AD and AR forms Ferochelatase activity is 10 to 25% of

normal in affected persons Typically presents early in childhood, 2-5

years Immediate burning of the skin upon sun

exposure Elevated protoporphyrin IX absorbs both

the Soret band and also at 500-600 nm

Infants cry when exposed to sunlight Severe liver disease develops in 10% Excessive porphyrins are deposited in the

liver Suspect diagnosis on clinical grounds, with

acute symptoms and chronic skin changes Urine porphyrin levels are normal Erythrocyte protoporphyrin is elevated Erythrocyte, plasma, and fecal protoporphyrin

can be assayed to confirm the diagnosis

Skin biopsy will confirm diagnosis Treatment, protection with barrier

sunscreens 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 the enzyme uroporphyrinogen

III synthase Presents soon after birth with the

appearance of red urine Severe photosensitivity Blistering, scarring, ectropion and corneal

damage may occur Erythrodontia is characteristic

Mutilating scars, hypertrichosis, profuse eyebrows, long eyelashes, “monkey face” or “werewolf”

Other features – growth retardation, hemolytic anemia, thrombocytopenia, porphyrin gallstones, osteopenia

Diagnosis of CEP should be suspected with an infant with dark urine and severe 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

END

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ABNORMALITIES IN DERMAL CONNECTIVE TISSUE Chapter 25