ABNORMALITIES IN DERMAL CONNECTIVE TISSUE

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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 MF ratio of 41
• Runs a variable course of 6 mos to 5 years with
  spontaneous resolution
• Associated with Down Syndrome, Ehlers-Danlos,
  osteogenesis imperfecta, Marfans,
  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 Cushings 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 31 to 51
• 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

• Gunthers 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