ABNORMALITIES IN
DERMAL CONNECTIVE
TISSUE
Chapter 25
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

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

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

Elastosis perforans serpiginosa
EPS, penicillamine
Keratotic papules of EPS
penicillamine TX

Annular plaques
of EPS
EPS

Hyperelastic
epidermis
clutches the
increased dermal
elastic fibers like
a claw
EPS

Transepidermal
elimination of
neutrophils and
elastic fibers from
the dermis
through a channel
in the epidermis
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

Keratotic papule of RPC

Lesion followed minor trauma on the upper
extremity
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 creamcolored, creplike, lax, redundant folds,
flecked with yellow papules, “plucked
chicken skin”
 Characteristic exaggerated nasolabial folds

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

Clinical features of PXE

Yellowish papules, calcified plaques, sagging skin
Mucosal
lesions

Angioid
streaks
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

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

Clinical features of
Ehlers-Danlos syndrome
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

Clinical features of cutis laxa
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
Anetoderma (macular atrophy)
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

Anetoderma (macular atrophy)

Anetoderma, decrease of the elastic fibers in
the papillary and reticular dermis
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

Striae distensae
Overtime striae become less noticeable
 Topical tretinoin, and vascular lasers

Striae rubra, striae alba
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

ERRORS IN METABOLISM
Chapter 26
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

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
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

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

primary systemic amyloidosis

Macroglossia with dental impression of the
tongue
primary
systemic
amyloidosis

Periorbital
ecchymosis, “raccoon
sign”
primary systemic amyloidosis

Numerous waxy and translucent papules
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 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
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


Hyperpigmentation of macular amyloidosis
with the characteristic rippled pattern
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

Lichen
amyloidosis

Keratotic,
hyperigmented
plaques on the
legs
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
PCT in chronic renal failure
PCT
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

treatment
Physical sun protection
 Discontinue inciting medication


May resolve over several months
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

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 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 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

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

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 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 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

Erythropoietic protoporphyria

Subtle scarring
Erythropoietic protoporphyria

Erythema and hemorrhagic crusts
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

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 phototherapyinduced 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

END