abnormalities in dermal connective tissue chapter 25
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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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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