1. ABNORMALITIES IN DERMAL CONNECTIVE TISSUE
Chapter 25

2. Elastosis perforans serpiginosa EPS
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

3. Elastosis perforans serpiginosa EPS
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

4. Elastosis perforans serpiginosa EPS
Distinctive histopathologic changes
Elongated tortuous channels in the epidermis into which elastic tissue perforates and is excruded
Treatment is difficult
LN2

5. Elastosis perforans serpiginosa EPS, penicillamine

6. Keratotic papules of EPS penicillamine TX

7. Annular plaques of EPS

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

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

10. Reactive perforating collagenosis RPC
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

11. Keratotic papule of RPC
Lesion followed minor trauma on the upper extremity

12. Pseudoxanthoma elasticum PXE
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

13. Pseudoxanthoma elasticum PXE
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

14. Clinical features of PXE
Yellowish papules, calcified plaques, sagging skin

15. Mucosal lesions
Angioid streaks

16. Pseudoxanthoma elasticum PXE
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

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

18. 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

19. 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

20. 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

24. 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

25. 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

26. Clinical features of Ehlers-Danlos syndrome

27. 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

28. 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

29. 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

30. Clinical features of cutis laxa

31. 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

32. Treatment has been generally disappointing
Multiple surgical procedures have been largely unsuccessful

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

34. 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

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

36. 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

37. Anetoderma (macular atrophy)

39. 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

40. Anetoderma (macular atrophy)

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

42. 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

43. Striae distensae Overtime striae become less noticeable
Topical tretinoin, and vascular lasers

44. Striae rubra, striae alba

45. 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

46. 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

47. 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

48. Osteogenesis imperfecta
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

49. Osteogenesis imperfecta
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

50. 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

51. 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

52. ERRORS IN METABOLISM
Chapter 26

53. SYSTEMIC AMYLOIDOSIS primary 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

56. SYSTEMIC AMYLOIDOSIS primary 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

57. SYSTEMIC AMYLOIDOSIS primary 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

58. SYSTEMIC AMYLOIDOSIS primary 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

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

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

61. primary systemic amyloidosis
Numerous waxy and translucent papules

62. 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

63. CUTANEOUS AMYLOIDOSIS primary 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

64. 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

65. Hyperpigmentation of macular amyloidosis with the characteristic rippled pattern

66. 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

67. Lichen amyloidosis
Keratotic, hyperigmented plaques on the legs

68. 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

70. 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

71. 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

72. 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

73. 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

77. 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

78. 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

79. HEP, hepatoerythrocytic porphyria, has been classified as either a hepatic or hepatoerythropoietic type
Diagnosis should be made by identifying characteristic clinical and biochemical abnormalities

80. 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

81. 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

82. PCT in a patient with Hepatitis C virus infection
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

83. PCT in chronic renal failure

84. PCT

85. 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

86. 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

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

88. 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

89. 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

90. 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

91. treatment Physical sun protection Discontinue inciting medication
May resolve over several months

92. 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

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

94. Hepatoerythropoietic porphyria

95. 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

96. 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

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

98. Hereditary coproporphyria HCP
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

99. Variegate porphyria VP
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

100. 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

101. Suspect VP when finding indicate both PCT and AIP, esp
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

102. 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

103. Erythropoietic protoporphyria EEP
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 nm

104. 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

105. Skin biopsy will confirm diagnosis
Treatment, protection with barrier sunscreens
Beta carotene, phototherapy, cysteine
Transfusions for anemia

106. Erythropoietic protoporphyria
Subtle scarring

107. Erythropoietic protoporphyria
Erythema and hemorrhagic crusts

108. 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

109. 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

110. Congenital erythropoietic porphyria
Erythrodontia
Severe mutilation

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

112. 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

113. 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

114. END