1. ABNORMALITIES IN DERMAL CONNECTIVE TISSUE Erik Austin, D.O., M.P.H.

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

3. Keratotic papules of EPS Typical site affected = neck

4. 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

5. Annular plaques of EPS Atrophic scars often form

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

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

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

9. Reactive perforating collagenosis RPC Rare, familial, non-pruritic skin disorder Lesions begin in 2 nd 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

10. Pseudoxanthoma elasticum (PXE) Yellow papules, calcified plaques, sagging skin; chicken skin

11. Pseudoxanthoma elasticum PXE 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

12. Mucosal lesions Retinal change = Angioid streaks; in up to 85%

13. Pseudoxanthoma elasticum PXE 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

14. Histopathology of PXE A. calcium deposits on elastic fibers in advanced PXE B. irregularly clumped elastic fibers, Verhoeff van Giesson

15. 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

16. Perforating calcific elastosis Shares features with PXE, without systemic features Trauma of pregnancy, obesity or surgery promote elastic fiber degeneration No effective therapy

17. 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

18. Clinical features of Ehlers-Danlos syndrome

19. 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

20. 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

21. 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

22. 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

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

24. 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

25. Cutis laxa (generalized elastosis) Premature aging, severe pulmonary emphysema, and fragmentation of dermal elastic fibers

26. 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

27. Anetoderma (macular atrophy) A group of disorders characterized by looseness of the skin due to loss of elastic tissue

28. Anetoderma (macular atrophy)

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

31. Anetoderma: decreased elastic fibers in the papillary and reticular dermis

32. Striae rubra, striae alba: depressed lines or bands

33. 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

34. 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

35. 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

36. 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 1 st week of life Brittle bones, fractures occur early in life, sometimes in utero Loose-jointedness and dislocations

37. Osteogenesis imperfecta Blue sclera Deafness Thin skin; atrophic scars EPS has associated

38. 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

39. 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

40. 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

41. ERRORS IN METABOLISM

42. 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

45. SYSTEMIC AMYLOIDOSIS primary 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

46. SYSTEMIC AMYLOIDOSIS primary systemic amyloidosis Glossitis with macroglossia (20%) May cause dysphagia Bullous disease is rare and scarring Subepidermal: DDx PCT and EBA

47. SYSTEMIC AMYLOIDOSIS primary 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

48. primary systemic amyloidosis Macroglossia with dental impression of the tongue

49. primary systemic amyloidosis Periorbital ecchymosis, “raccoon sign”

50. primary systemic amyloidosis Numerous waxy and translucent papules

51. 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

52. 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

53. Macular Amyloidosis: pruritic, brown macules with a rippled pattern

54. Lichen amyloidosis Pruritic, keratotic, hyperigmented plaques on the legs Tx = high potency corticosteroids, oral retinoids, cyclophosphamide, dermabrasion and occlusion

55. 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

57. 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

58. 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

59. 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

63. 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

64. 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

65. Most common porphyria Photosensitivity leads to bullae, which leads to ulcers, scarring, milia and dyspigmentation Hypertrichosis, fragility and skin thickening

66. Alcoholism is common; Hep C in 94% Associated with DM, LE, HIV, and estrogen therapy

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

68. PCT in chronic renal failure

69. PCT

70. 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

71. 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

72. Histologic features of PCT Subepidermal blister with minimal dermal inflammatory infiltrate. Festooning of dermal papillae.

73. 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

74. Remission may last for years Iron chelation May respond to transplant in renal failure May improve with treatment if assoc. with Hep C

75. 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

76. treatment Sun protection Discontinue inciting medication May resolve over several months

77. 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

78. Abnormal urinary porphyrins as in PCT Elevated erythrocyte protoporphyrins Increased coproporphyrins

79. Hepatoerythropoietic porphyria

80. 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

81. Severe abdominal colic +/- NVDC Elevated urinary porphobilinogen Increased dALA in plasma and urine No specific treatment Avoid precipitating factors Glucose loading

82. Hematin infusions Pain management Oral contraceptives may prevent attacks in women with premenstrual symptoms

83. 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

84. 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

85. 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

86. 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

87. 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

88. 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

89. Skin biopsy confirms diagnosis Tx = sun protection Beta carotene, phototherapy, cysteine Transfusions for anemia

90. Erythropoietic protoporphyria Subtle scarring

91. Erythropoietic protoporphyria Erythema and hemorrhagic crusts

92. 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

93. 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

94. Congenital erythropoietic porphyria Erythrodontia Severe mutilation

95. Fluorescence of circulating red blood cells, CEP with UVA Vs. transient fluorescence in EPP

96. 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

97. 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