Abnormalities In Dermal Connective Tissue

Abnormalities In Dermal Connective Tissue
By: 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
* 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
* 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 collagenosis
RPC
* 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
* 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%
* 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
* 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 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
* Blue sclera
* Deafness
* Thin skin; atrophic scars
* EPS has associated
* 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
* 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 AMYLOIDOSIS primary 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
* 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
* Glossitis with macroglossia (20%)
* May cause dysphagia
* Bullous disease is rare and scarring
* Subepidermal: DDx PCT and EBA
* 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
* Macroglossia with dental impression of the tongue
* Periorbital ecchymosis, “raccoon sign”
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 AMYLOIDOSIS primary 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
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
o Congenital erythropoietic porphyria (CEP)
o Erythropoietic protoporphyria (EPP)
o Erythropoietic coproporphyria ECP
* Hepatic forms
o Acute intermittent porphyria (AIP)
o ALA dehydrogenase deficiency
o Hereditary coproporphyria (HCP)
o Variegate porphyria (VP)
o 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
* 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
o 500 ml at 2 week intervals, hemoglobin 10 g/dL
o 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
o 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 coproporphyria HCP
* 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 porphyria VP
* 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 protoporphyria EEP
* 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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