JOURNAL of the

Amesucare Acanemv OF

DerMaTOLOGYVOLUME 3 NUMBER 5 NOVE"IBER, 1980

Continuing medical education

Connective tissue nevi of the skin

Clinical, genetic, and histopathologic classification ofhamartomas of the collagen, elastin, and proteoglycan type

Jouni Uitto, M.D., Ph.D.,* Daniel J. Santa Cruz, M.D., andArthur Z. Eisen, M.D.St. LOllis, MO

Connective tissue nevi of the skin are hamartomatous lesionsconsisting predominantly of one of the components of theextracellular matrix, namely, collagen, elastin, orglycosaminoglycans. On the basis of clinical, histopathologic, andgenetic considerations, the connective tissue nevi can be classifiedinto defined categories. Association with extracutaneous featuresallows further delineation of these disease entities and aids inestablishing an accurate diagnosis. (J AM ACAD DERMATOL

3:441 -461, 1980.)

Connective tissue nevi are hamartomas consist­ing of the various components of the dermal con­nective tissue. The predominant element of theextracellular connective tissue within an indi­vidual nevus can be collagen, elastic fibers, orglycosaminoglycans. Furthermore, lesions charac­terized by the accumulation of adipose tissue or

From the Division of Dermatology, Department of Medicine, and theDivision of Surgical Pathology, Department of Pathology, Wash­ington University School of Medicine.

Supported in part by Grants AM-12129 and GM-28833 from theUnited States Public Health Service, National Institutes of Health,and by a grant from March of Dimes-the Birth Defect Foundation.

~eprint requests to: Dr. Jouni Uitto, Division of Dermatology, De­partment of Medicine, Harbor-UCLA Medical Center, 1000 WestCarson St .. Torrance, CA 90509/213-533-2465.

'Recipient of Research Career Development Award AM-00455 fromthe National Institutes of Health.

1190-9622/80/ II 0441+21S02 .10/0 © 1980 Am Acad Dermatol

various cellular elements in the dermis have alsobeen considered as a type of connective tissuenevus. Numerous cases reported in the literatureappear to fulfill the diagnostic criteria of connec­tive tissue nevi. Classification of the connectivetissue nevi in general, however, has been confus­ing because the histopathologic nature of the le­sions in most cases has not been fully delineatedand the associated clinical features have been in­completely understood. In the present review, wepropose a new classification for connective tissuenevi. Increased knowledge of the basic biology ofthe connective tissues and an advanced under­standing of the genetic role in the expression ofconnective tissue nevi have allowed us to formulatea classification based on clinical, genetic, and his­topathologic considerations.

441

442 Uitto et (II

Table I. Classification of connective tissuenevi of the skin

I. Hamartomas of the collagen typeA. Inherited

I. Familial cutaneous collagenorna2. Shagreen patches in tuberous sclerosis

B. AcquiredI. Eruptive collagcnornas2. Isolated collagcnornas

II. Hamartomas of the elastin typeA. Inherited

I. Dermatofibrosis lenticularis disserninatain the Buschke-Ollendorff syndrome

2. Pseudoxanthoma clasticumB. Acquired

I. Elastosis perforans serpiginosa2. Isolated clastornas3. Pseudoxanthorna elasticurn (rare cases)

III. Hamartomas of the proteoglycan typeA. Inherited

I. Dermal nodules in mucopolysaccharidosisII (the Hunter syndrome)

B. AcquiredI. Lichen myxedcrnatosus2. Focal mucinosis

NORMAL BIOLOGY OF THE DERMALCONNECTIVE TISSUE

Collagen. The extracellular connective tissue inthe dermis consists of several biochemically dis­tinct components whose balanced interactions andnormal quantities are required for physiologicallyfunctional skin. The major fibrillar component ofthe cutaneous connective tissue is collagen, whichcomprises about 70% of the dry weight of thedennis. (For recent reviews on collagen, see refer­ences 1-4.) Collagen appears in the form of fiberswhich are composed of thinner microfibrils. Thesemicrofibrils in turn are built of individual collagenmolecules. Each collagen molecule is a rodlikestructure of 300 nm in length and 1.5 nm in width,and consists of three polypeptide chains, thea-chains. These polypeptides are wrapped aroundeach other in a unique triple helical conformation.The a-chains of collagen are characterized by thepresence of relatively large amounts of hydroxy­proline and hydroxylysine, two amino acids whichare found in few other mammalian proteins. Inaddition, collagen is rich in glycine, and sequencestudies of collagen a-chains have demonstrated

Journal of theAmerican Academy of

Dermatology

that this amino acid is evenly spaced in every thirdposition of the polypeptide. The alignment of col­lagen molecules along the microfibrils is stabilizedby the presence of covalent cross-links, which arederived from lysine or hydroxylysine residues ofthe collagen molecule.

It has been demonstrated that collagen is ac­tually a family of closely related, yet geneticallydistinct proteins, which have a characteristic tissuedistribution.e" In nonnal human skin, the twomajor collagens are type I and type III. r.s Type Icollagen predominates, so that in adult skin itcomprises about 80% of the total collagen whileabout 15% is of type III. The remaining 5% or soconsists of less abundant forms, such as type IV,type l-trimer, and A-B collagens.v!' The geneti­cally distinct collagens evidently contribute to thephysiologic requirements of any given tissue, bUIthe exact functional role of each collagen typeawaits delineation.

The biologic functions of collagen in the skirand otherconnective tissues are manyfold. In theskin, the most apparent function of collagen is tcprovide tensjle strength to the dennis. The propelsynthesis and accumulation of extracellular colla­gen fibers also play an essential role in the norma:wound healing and development of the tissues.Furthermore, collagen serves as an attachment sitefor a variety of cells, including fibroblasts ancepidermal cells. 12

•1:! These attachments are medi·ated through a family of so-called attachment pro­teins, fibronectin being the most extensively stud­ied. H

•15 Finally, interaction of collagen with othe:connective tissue components, as, for examplewith proteoglycans.!" is apparently required fanormal function of connective tissue in the skin.

The elastic fibers. The elastic fibers, anotheiextracellular connective tissue component, anpresent in skin as highly branching structureswhich apparently are responsible for its physio­logic elasticity. (For recent reviews on elastin, setreferences 17-19.) Although present in normahuman skin, the elastic connective tissue protein:represent a relatively small fraction of the dennisthese fibers are more abundant in the aorta ancother vascular connective tissues, in the lungs, ancin various tendons, such as ligamentum nuchaeand the achilles tendon. The elastic fibers consis

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Connective tissue nevi of skin 443

Table II. Clinical, genetic, and histopathologic features of connective tissue nevi of the skin

Condition Cutaneous manifestations Associated features Histopathology

Familial cutaneous Asymptomatic nodules Cardiac involvement (7) AD Accumulation of coarsecollagcnorna symmetrically distrib- collagen fibers in the

uted on the upper trunk dermis

Eruptive collagcnoma Asymptomatic papules NH Thickening of dermisand nodules of varying due to accumulation ofsize collagen

Shagreen patch in tu- Irregular tumor or Mental retardation, cpi- AD Accumulation of col-berous sclerosis plaque lepsy lagen

Isolated collagenoma Solitary nodule or NH Accumulation of col-plaque lagcn

Dermatofibrosis len- 1-3 ern yellowish pap- Osteopoikilosis AD Accumulation of thick,ticularis disserninata ules branching elastic fibers

in the dermis

Pseudoxanthoma elas- Small yellowish pap- Hypertension, claudica- AR, AD, Accumulation of frag-ticum ules coalescing to tion, bleeding tendency, or NH men ted and calcified

plaques on the neck, ax- angioid streaks elastic fibers in the midiliac, thighs, and abdo- dermismen

Elastosis perforans Hyperkeratotic 1-5 rnm Frequent association NH Accumulation of elasticserpiginosa papules grouped on the with heritable disorders fibers with transepider-

face and neck of connective tissue and mal eliminationthe Down's syndrome

Isolated elastoma Yellowish papules or NH Accumulation of thicknodules clastic fibers

Dermal nodules in mu- 1-10 mm papules syrn- Systemic manifestations XR Excessive deposition ofcopolysaccharidosis 11 metrically distributed on of the Hunter syndrome glycosaminoglycans

the upper trunk andanns

Lichen myxedemato- Small, densely grouped NH Excessive deposition ofsus papules glycosaminoglycans in

the upper dermis

*AD: autosomal dominant; AR: autosomal recessive; XR: X-linked recessive; NH: the condition is not a heritable disorder.

of at least two distinct protein components. 20.2t Byelectron microscopic examination, the major com­ponent has an amorphous appearance, and no dis­tinct periodicity can be demonstrated. Biochem­ically, this part of the elastic fibers represents theelastin protein. The amorphous elastin is sur­rounded by distinct fibrillar structures, which,when visualized by electron microscopy, have aregular diameter of 10 to 12 nm. This latter fibrillarcomponent is called elastic tissue microfibrillarprotein. These two protein components, elastin andthe microfibrillar protein, exist in close associationin various connective tissues, but the relative pro-

portions of these two components are variable de­pending on the tissue and the stage ofdevelopment.Electron microscopic estimations of the fully ma­tured elastic tissue indicate that the elastin proteinrepresents well over 90% of the total content ofelastic fibers."!

Light microscopic examination of the elastictissues of normal human skin reveals three differ­ent types of fibers, oxytalan, elaunin, and elasticfibers, when special stains are employed.F'<' Theoxytalan fibers are the most superficial thin fibersdirected perpendicularly to the dermoepidermaljunction. At the electron microscopic level, the

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Fig. 1. Multiple connective tissue nevi on the back of a patient with familial cutaneouscollagenoma.

oxytalan fibers are formed of bundles of tubularmicrofibrils , IOta 12 nm in diameter, and theyappear to be similar, if not identical, to the elastictissue microfibrillar protein described abo ve. Theoxytalan fibers are connected to a plexus of fiberswhich, on the basis of their tinctorial characteris­tics, are termed elaunin fibers . The elaunin fibersin turn are connected with thick elastic fibers ofthe reticular dermis.

Biochemically, the elastin protein consists ofpolypeptides with an approximate molecularweight of 72,000 daltons. 17•2:;- 2 i The amino acidcomposition of elastin is similar to collagen in thatone of every three amino acids is a glycine . Se­quential studies demonstrated that glycine residuesare randomly distributed along the elastin poly­peptide chain, in contrast to collagen where it is inevery third position . Elastin also contains somehydroxyproline, but the relative content of thisamino acid is variable and con siderably lower thanin collagen.P" Unlike collagen, elastin contains nohydroxylysine. The amino acid composition ofelastin is also relatively rich in valine and alanine,whereas tryptophan and methionine appear to beabsent.

The elastin polypeptides form highly branched

fibers and these polypeptides are linked togetherby the formation of complex covalent cross-linksknown as desmosines.!' The microfibrillar proteinof the clastic tissues is clearly distinct from elas­tin, although biochemical isolation and characteri­zation of this protein have not yet been completed.

Glycosarninoglycans. The fibrillar componentsof the dermis, collagen and elastin, are enmeshedin an extracellular material, called the groundsubstance. The major components of the groundsubstance are mucopolysaccharides, a class ofmacromolecules consisting of a polysaccharideportion , glycosaminoglycan, and a protein part.Frequently, the entire polysaccharide-protein com­plex is called a proteoglycan. (For review on gly­cosaminoglycans, see reference 29 .)

The glycosaminoglycan chains consist of hexo­samine units (either glucosamine or galactosamine)alternating with a uronic acid (either glucuronicacid or iduronic acid). Thus, the glycosamino­glycans are linear chains consisting of repeatingdisaccharide units. The length of chains may varyfrom a few disaccharide units to several thousand,and, consequently , the molecular weight of eachindividual glycosaminoglycan chain can vary fromseveral thousand to several million . The glycos-

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Connective tissue nevi of skin 445

Fig. 2. Histology of the skin lesions in familial cutaneous collagenoma. The picturedemonstrates accumulation of coarse collagen fibers in the lower dermis and partialreplacement of the subcutaneous tissue by collagen . Thus, these lesions are connectivetissue nevi of the coJlagen type. (Hematoxylin-eosin stain ; original magnification , X 12.)

aminoglycan chains are linked to a protein core,fanning a proteoglycan monomer unit.

In the skin, the glycosaminoglycans compriseapproximately 0.1 % to 0.3% of the dry weight oftissue. so The predominant glycosaminoglycans inthe skin are hyaluronic acid and dermatan sulfate,while lesser amounts of chondroitin-fi-sulfate andhcparan sulfate are present. 29 The relative pro­portions of these different glycosaminoglycansmay vary not only among species and individuals,but also among body regions and different dermallayers .3 1- 3:1

Glycosaminoglycans in the skin have severalprobable functions. 29 For example, they contributeto the maintenance of salt and water balance byexcluding large macromolecules by lodging waterin the proteoglycan molecule itself. Glycosami­noglycans probably serve as a support for otherdermal components , and they may also regulateconnective tissue metabolism by promoting cellmigration, growth, and differentiation.

CONNECTIVE TISSUE NEVI OF THE SKIN

Definition. The term "nevus" is used in thedermatologic literature at least two differentways."! First, the term refers to lesions composedof nevus cells, such as nevocelJar nevus or pig­mented nevus. Second, the term has been usedfrequently to describe lesions composed of prolif­eration of various mature elements of the skin .Although the term "hamartoma" would probablybe more appropriate to describe those lesionswhich do not contain nevus cells, terms such asconnective nevus are widely employed. In a strictsense , connective tissue nevi refer to lesionscharacterized by excessive deposition of one of thecomponents of the extracellular matrix , either col­lagen, elastic fibers, or proteoglycans. In abroader sense, the term "connective tissue nevus"could be used to describe any hamartomatoustumor consisting of other connective tissue com­ponents of the skin, such as adipose tissue or cellu­lar elements. In this review, however, connective

446 Uitto et {If

Fig. 3. Lesions of adenoma sebaceum in a patient withtuberous sclerosis.

Fig. 4. A large shagreen patch on the back of a patientwith tuberous sclerosis.

tissue nevus will refer to tumors composed of col­lagen, elastic fibers, or proteoglycans. The lesionsconsisting of other components of the extracellularmatrix or of cellular elements are discussed whenconsidering the differential diagnosis of connec­tive tissue nevi.

Journal of theAmerican Academy of

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Classification. Previously, attempts to classifyand categorize connective tissue nevi have beenmade. :1;;-;19 Although these classifications havebeen helpful in delineating some of the clinicalconditions, it is clear that we are now at a juncturewhich allows us to formulate a more definitive anddetailed classification of connective tissue nevibased on increased knowledge of connective tissuebiology. In this study, we are proposing aclassification based on clinical, histopathologic,and genetic features of these conditions (Table I).On the basis of the histologic characteristics, theconnective tissue nevi can be classified as colla­gen, elastin, or proteoglycan type. On the basis ofthe mode of inheritance, or lack of it, these clini­cal conditions can also be categorized either asinherited or acquired ones. And finally, associa­tion of distinct extracutaneous manifestations withskin lesions can serve as a distinguishing feature.The clinical, genetic, and histopathologic featuresof the connective tissue nevi are presented inTable II.

Hamartomas of the collagen type

Familial cutaneous collagenoma. In 1968,Henderson et al described three brothers withmultiple asymptomatic cutaneous nodules on thetrunk and proximal arms. -io Histologically, thenodules showed thickening of the dermis due toincreased collagen deposition. Because of theunique clinical and histologic presentation and thepresence of the lesions in three siblings, the au­thors named the entity "familial cutaneous colla­genoma. " Subsequently, a female patient withsomewhat similar cutaneous nodules was de­scribed.:" In this case, however, there was nofamily history of similar lesions, and it is, there­fore, unclear whether she indeed had familial cu­taneous collagenoma. Recently, we reported sixpatients, representing a kindred of 53, with a clin­ical picture similar to those described by Hender­son et alY These patients presented with multipledermal nodules symmetrically distributed on thetrunk and upper arms. Most of the lesions werelocalized to the upper two thirds of the back (Fig.1). The individual lesions varied from a few mil­limeters to several centimeters in size, were in­durated, and showed only minimal epidermal

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changes. Histologically, the nodules were charac­terized by an excessive accumulation of dense,coarse collagen fibers in the dermis (Fig. 2). Elas­tic fibers appeared diminished in number, perhapsrepresenting a dilution phenomenon due to exces­sive collagen accumulation. -12 Histologically, thelesions in these patients were connective tissuenevi of the coIlagen type .

Because of the relatively large number of pa­tients affected and the presence of the lesions inthree subsequent generations, we were able, forthe first time, to establish the mode of inheritance'in familial cutaneous collagenoma. Examinationof the pedigree indicated that the dermal nodulesin familial cutaneous coIlagenoma were inheritedin an autosomal dominant pattern. :" Of particularinterest in these patients was the observation thatthe lesions in all patients had an onset at the ageof 15 to 19 years, and the number of lesionssignificantly increased during pregnancy. It isconceivable, therefore, that familial cutaneouscollagenoma is an inherited condition whoseexpression may be under hormonal control, andthat changes which occur during puberty andpregnancy accelerate the phenotypic expression ofthe lesions.

In familial cutaneous collagenoma, the possi­bility of an association of skin lesions with ex­tracutaneous abnormalities also exists. In particu­lar, cardiac findings, such as idiopathic progressivemyocardiopathy with congestive heart failure, andearly R wave transition in the electrocardiogram,have been encountered in some of the patients. -10,-12

On the other hand, skeletal x-ray survey revealedno evidence of osteopoikilosis, thus allowingfurther distinction of familial cutaneous colla­genoma from other conditions, such as theBuschke-Ollendorff syndrome (see below).

Shagreen patch in tuberous sclerosis. An­other inherited condition associated with the pres­ence of connective tissue nevi of the collagen typeis tuberous sclerosis. -13..J-1 Tuberous sclerosis is acomplex of developmental anomalies consisting ofcharacteristic skin lesions, mental retardation , andepilepsy. The classic skin lesions include adenomasebaceum, periungual fibromas , and the shagreenpatches (Figs. 3 to 5). The lesions known as ade­noma sebaceum are histologically angiofibromas,

Connective tissue nevi of skin 447

Fig. s. Multiple connective tissue nevi on the back of apatient with tuberous sclerosis .

and thus, in addition to collagen proliferation,consist of hyperplastic vascular structures (Fig. 6).Shagreen patches are irregularly thickened tumorsor plaques in the skin, which histologically dem­onstrate an excess of collagen deposition in thedennis .

Tuberous sclerosis is inherited as an autosomaldominant condition, but shows great variability inits expressivity. Within a single family, forexample, the presence of a shagreen patch in anindividual may be the only clinical evidence ofabnormality. It should be noted that genetictransmission is reduced due to greatly decreasedfertility , and thus up to 50% of the cases have beenestimated to represent new mutations. Therefore,patients with isolated connective tissue nevi of thecollagen type, even in the absence of family his­tory, should be carefuIly examined for other signsof tuberous sclerosis.

Eruptive collagenoma. Several cases with cu­taneous nodules similar to those seen in familialcutaneous collagenoma, but without a family his­tory , have been called eruptive collagenoma. -1:>--19

..

448 Uitto et al

•

I

,

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/

I

..

Fig. 6. Histology of a lesion of adenoma sebaceum. The picture demonstrates proliferationof collagen and hyperplastic vascular structures. Thus, histologically these lesions areangiofibromas. (Hematoxylin-eosin stain; original magnification, x300.)

Careful examination of the case reports revealsthat these patients consist of at least two differentgroups which can be separated both on clinical andhistologic grounds. Some not only have cutaneouslesions resembling that of familial cutaneous col­lagenoma, but also the histologic picture demon­strates collagen accumulation, thus confirmingthat the lesions represent true collagenomas. Itshould be emphasized, however, that the occur­rence of similar lesions in other members of the

family has not been reported. A few patients de­scribed as having eruptive collagenomas have le­sions which are considerably smaller, and theirdistribution is different from those seen in familialcutaneous collagenoma in that they are located onthe extremities and the lower trunk. Histologi­cally, the lesions also differ in that there is anaccumulation of metachromatically staining muci­nous material in the dermis. ~9 These cases, there­fore, seem to be closely related, if not identical, to

Volume 3Number 5November, 1980

lichen myxedematosus, and should be separatedboth on a clinical and histologic basis from truecollagenomas. In patients described as havingeruptive collagenomas and with the lesions charac­terized by collagen accumulation, a detailed fam­ily history is indicated to establish whether thepatients might indeed have familial cutaneous col­lagenoma.

Isolated collagenoma. In addition to the erup­tive collagenoma syndrome, other cases withhamartomas of the collagen type and without ,afamily history have been reported. These lesionshave been described, for example, as paving stonenevi, or plantar fibromatosis. 50-52 The histology ofthese cases is also consistent with a collagenoma.Connective tissue nevi in a zosteriform patternhave also been described in one patient bySteiner.53 In this case, the collagen bundles ap­peared irregularly arranged and short, while theclastic fibers were also abnormal. Thus, the truenature of the zosteriform connective tissue nevussyndrome, as described by Steiner, is unclear.Several additional cases with connective tissuenevi characterized by collagen accumulation havebeen reported in patients without occurrence ofsimilar lesions in the family. 35 ,36 ,:;4-5, As indicatedabove, careful examination of these patients toexclude tuberous sclerosis is indicated. In addi­tion, these cases can be clearly separated fromfamilial cutaneous collagenoma or eruptive colla­genorna by the appearance and distribution of theindividual lesions.

Hamartomas of the elastin type

Dermatofibrosis lenticularis disseminata inthe Buschke-Ollendorff syndrome. Another in­herited disorder characterized by the presence ofconnective tissue nevi is the Buschke-Ollendorffsyndrome. 3 , ,5s - 62 The complete form of thissyndrome consists of cutaneous lesions, calleddermatofibrosis lenticularis disseminata, in asso­ciation with osteopoikilosis. This condition is in­herited in an autosomal dominant pattern. Cases inthe family presenting .with only skin lesions orwith osteopoikilosis have been reported. Clini­cally, the skin lesions appear as small papules ordiscs which are asymmetrically distributed andhave predilection sites on the lower trunk or ex-

Connective tissue nevi of skin 449

Fig. 7. Skin lesions of derrnatofibrosis lenticularis dis­semi nata on the lower back of a patient with theBuschke-Ollendorff syndrome.

tremities (Fig . 7). The onset of the skin lesions isusually before puberty, and they may be present atbirth. Histologically, the lesions of dermato­fibrosis lenticularis disseminata are characterizedby the accumulation of elastic fibers in the dermis(Fig. 8). Characteristically, the elastic fibers ap­pear broad and interlacing without fragmentation.The accumulation of elastin in dermatofibrosislenticularis disserninata has also been demon­strated by a four- to eightfold increase in the des­mosine content in the lesions when compared touninvolved skin.?" Therefore, the cutaneous le­sions of the Buschke-Ollendorff syndrome areconnective tissue nevi of the elastin type. Inroentgenologic examination, the bone lesions ap­pear as sclerotic densities, primarily in the ends ofthe long bones, pelvis, and the hands. These le­sions are asymptomatic and of no apparent clinicalimportance. Occasionally, ' however, the osteo­poikilotic changes have been mistaken for meta­static bone lesions, and inappropriate treatment fora presumed malignant process, such as carcinomaof the prostate, has been initiated,

Pseudoxanthoma eIasticum (PXE). Another

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Fig. 8. Histology of the skin lesions in the Buschkc-OIIendorff syndrome. The picturedemonstrates accumulation of broad, interlacing elastic fibers in the dermis. Thus, theselesions are connective tissue nevi of the elastin type. (Verhoeff stain; original magnifica-tion, x 350.) .

Fig. 9. Typical skin lesions in a patient with pseu­dox anthoma clasticum, demonstrating redundant, in­elastic skin in a plaque composed of yellowish papulesin the axillary fold.

skin disease affecting the elastic connective tissuesis PXE. This is a generalized disorder and includesdistinct skin lesions, ocular changes, and vasculardisturbances.Vr'V'"?" Relative severity of thesechanges can produce a wide variety of clinicalpictures. Genetically, PXE is heterogenous withboth autosomal dominant and autosomal recessiveinheritance patterns.44. 68.69 A spectrum of severityis seen, varying from a highly debilitating diseasewith severe angina, claudication , hypertension,and the development of blindness, to a relativelymild form with symptoms limited to the skin.

Typical skin lesions in PXE consist of small,1-3 mrn yellowish papules which tend to coalesceinto thickened, leathery plaques (Fig. 9). Thepredilection sites are the neck , axillary and ingui­nal folds, thighs, and abdomen. Yellowish lesionssomewhat similar to those seen in the skin can alsobe encountered on the buccal mucous membranes .

Histologic examination of the skin reveals anaccumulation of abnormal elastic fibers (Fig. 10).In contrast to the elastic fibers seen in normal skin

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Connective tissue nevi of skin 451

Fig. 10. Histology of the skin lesions in pseudoxanthoma elasticum. The picture demon­strates accumulation of fragmented and irregularly clumped elastic fibers in the middermis in pseudoxanthoma elasticum (A), whereas the elastic structures in normal dermis(B) appear as narrow fibers. (Verhoeff stain; original magnification, x350.)

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Fig. 11. Electron microscopy of a skin lesion in pseudoxanthoma elasticum. The picturedemonstrates an elastic fiber containing electron-dense deposits of calcium apatite. (Orig­inal magnification, X54,OOO.) (The picture was kindly provided by Dr. Lis Danielsen,University of Copenhagen, Denmark.)

or in derrnatofibrosis lenticularis disseminata, thefibers in PXE appear coarse, irregularly clumped,and show marked fragmentation and degeneration.Electron microscopic examination reveals dys­trophic calcification of the elastic fibers (Fig. 11).lt appears, therefore, that in addition to prolif­eration, the elastic fibers undergo degenerativechanges which lead to destruction and to a loss ofphysiologic function.

In addition to the inherited forms of PXE, sev­eral acquired cases with similar clinical,· his­tologic, and electron microscopic picture, butwithout family history, have been presented. '()-'2

Sometimes the development of skin lesions is re­lated to an external chemical trauma. For exam­ple, ten patients reported by Otkjaer-Nielsen etal 70 developed papular lesions on their forearmsfollowing an exposure to Norwegian saltpeter (amixture of calcium and ammonium nitrates). Thelesions showed by light and electron microscopicexamination changes indistinguishable from thoseseen in the inherited form of PXE. None of thesepatients had a family history of PXE, and nosystemic manifestations of the disease werepresent.

Recently, patients with an unusual perforating

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variant of PXE have been described. i:l In these .patients the lesions are confined to the abdomen,most often in a periumbical distribution (Fig.12). i:l.i~ None of these patients had a family his­tory of PXE, suggesting that periumbilical per­forating pseudoxanthoma elasticum is a distinctacquired form of the disease.

It should be noted that some studies have sug­gested ultrastructural abnormalities in the collagenin PXE, such as the appearance of irregularly ar­ranged and twisted collagen fibrils. Gi These find­ings, however, are not specific for PXE, sincesimilar ultrastructural changes have been seen in avariety of unrelated conditions. Also, the synthe­sis of collagen by skin explants is normal inPXE.i5·,G

Elastosis perforans serpiginosa (EPS). Thisskin condition frequently appears in associationwith heritable connective tissue disorders, such asthe Ehlers-Danlos syndrome, the : Marfan syn­drome, and osteogenesis imperfecta, but it hasalso been reported in otherwise healthy individualsand in several patients with the Down's syn­drome.li.~~.ii.'8 The coexistence of inherited PXEand EPS has also been reported . Since PXE has aperforating variant histologically similar to EPS, ithas been suggested that most of the reported asso­ciations of PXE and EPS in fact represent perforat­ing PXE.i9 Also, in general the genetic componentin the development of EPS and its possible modeof inheritance have not been delineated. It shouldbe pointed out that some patients receivingn-penicillamine, a drug interfering with elastinand collagen cross-linking, have developed clini­cal lesions of EPS. 1;0

The skin lesions in EPS consist of 1-5 mmpapules which appear hyperkeratotic and are typi­cally grouped in a circular or arciform configura­tion (Fig. 13). The sites of predilection are on theneck and face. The histopathologic change in EPSconsists of a focal increase in the amount of elasticfibers which also appear larger than normal. i8.8I.S:!In addition, the epidermis contains several narrowchannels which contain necrotic and degeneratedelastic material being extruded through the skin .EPS, therefore, appears to be a reactive perforat­ing dermatosis characterized by proliferation

Connective tissue nevi of skin 453

Fig. 12. Typical skin lesions in a periumbilical perforat­ing variant of PXE.

Fig. 13. Skin lesions of EPS, demonstrating groups ofhyperkeratotic papules in an arciform configuration onthe side of the neck.

of elastic fibers in the upper dermis . For un­known reasons, this material is extruded fromthe skin.

Isolated elastomas. Several isolated cases withconnective tissue nevi of the elastin type havebeen reported previously. These have been de­scribed under various names, such as juvenileelastoma, nevus elasticus, nevu s conjunctivus ,and naevus pseudocolloide perifolliculaire. S:I-SS Inseveral patients, the skin lesions are similar, both

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Fig. 14. Skin lesions of lichen myxedernatosus, demonstrating small papules on the back.

clinically and histologically, to those observed inthe Buschke-Ollendorff syndrome, but no detailedfamily history or radiologic investigations of thebones have been carried out. It is unclear, there­fore, whether some of these patients actuallyrepresent the Buschke-Ollendorff syndrome orwhether. some of them are true isolated cases ofelastoma.

The first to use the term nevus elasticus wasLewandowsky who, in 1921, reported three casesof connective tissue nevi, using the term "naevuselasticus regionis mammariae.' '89 The lesionswere characterized as groups of small, yellowishperifol1icular papules on the pectoral region. His­tologically, these lesions were found to lack elas­tic fibers, and thus are not nevi of the elastin type.This same condition was subsequently called byWith and Kissmeyer'" as dystrophia elastica fol­licularis thoracis and by Staricco and Mehregan'"as nevus anelasticus.

In 1931, Weidman et al8:l reported a young childwith numerous discrete nodules on the lower trunkand anterior aspects of the thighs. No family his­tory of similar skin lesions was obtained. His­tologically, there was a marked accumulation of

elastic fibers which appeared in relatively largeaggregations. Because of the clinical and his­tologic presentation, the authors called this condi­tion juvenile elastoma. Subsequently, severalcases with a histologic presentation similar to thatof juvenile elastoma have been reported (seeabove). Since these lesions consist of hyperplasiaof normal-appearing elastic fibers, they have fre­quently been called nevus elasticus. Staricco andMehregan'" described four cases with a distinctaccumulation of elastic fibers in the lesions. Sinceone of the cases presented, in addition to hy­perplasia of the elastic fibers, a well-developedvascular component, an additional term, "nevuse1asticus vascularis," was suggested for this par­ticular condition. It appears then that the exactnature of the lesions described as nevus elasticus isunclear in some cases, and in subsequent studiesskin samples should be examined by adequate his­topathologic procedures to establish the diagnosisof connective tissue nevus of the elastin type.

Two cases of a connective tissue nevus whichappears to be a clinically distinct entity have reocently been reported.P'<" In both studies a youngpatient with a bilateral eruption on the face leading

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Connective tissue nevi of skill 455

Fig. 15. Histology of the skin lesions in lichen myxedematosus. The picture demonstratesdeposition of proteoglycans in the dermis, causing widening of the spaces between colla­gen fibers. (Hematoxylin-eosin stain; original magnification, x90.)

to formation of plaques on both cheeks was de­scribed. Clinically the lesions were characterizedby wrinkling, furrowing, and irregular thickeningof the skin. No history of a familial occurrence ofsimilar lesions or the association with systemicabnormalities was noted. Histologically, an in­crease in the elastic fibers was noted in both cases.The epidermis appeared thickened . The sebaceousglands were either absent or not well developed.In one case the hair follicles were immature andappeared to be increased in number, while in theother case, deposits of perifollicular mucin werereported. Therefore, both clinically and histologi­cally, these two cases are separate from any otherpreviously described elastoma. The role of actinicdamage, as implied in one of the reports, to theskin in these young individuals is unclear but

could be clarified when further reports of similarcases are presented.

Hamartomas of the proteoglycan type

Dermal nodules in mucopolysaccharidosis II.Although the skin in most cases of the geneticmucopolysaccharidoses shows generalized thick­ening, the only inherited mucopolysaccharidestorage disease demonstrating distinctive skinchanges is mucopolysaccharidosis II, the Huntersyndrome. -14.93-9;; This syndrome is classically in­herited in an X-linked recessive pattern, althougha less frequent autosomal recessive form mayexist. It should be noted that all the othermucopolysaccharidoses are autosomal recessive.The biochemical defect in the Hunter syndrome isexcessive accumulation of both dermatan sulfate

456 Uitto et alJournal of the

American Academy ofDermatology

Fig. 16. Typical skin lesions of nevus lipomatosus superficialis, demonstrating multiplesoft nodules in a zonal distribution on the lower trunk.

and heparan sulfate due to iduronate sulfatasedeficiency.

The skin changes in mucopolysaccharidosis IIconsist of small, usually 1-10 mm papules, whichhave been described as a "pebbling" of the skin.The lesions are symmetrically distributed with thepredilection sites being the scapular and pectoralregions as well as the arms. By light and electronmicroscopic examination, the fibroblasts in theskin, both in normal-appearing areas and in thepapules, contain metachromatically staining cy­toplasmic material and characteristic vacuoles."In addition, the papules demonstrate an extracel­lular accumulation of metachromatic material.Thus, the cutaneous papules encountered in theHunter syndrome are due to excessive depositionof glycosaminoglycans in the dermis.

Lichen myxedematosus. The cutaneous erup­tion in this acquired clinical condition and inits variant, scleromyxedema, consists of small,densely grouped papules (Fig . 14). The predilec­tion sites are the exterior aspects of the forearmsand the axillary folds, but any part of the skin canbe affected in localized areas .?" Most patients aremiddle-aged adults, and no associated endocrineabnormalities have been demonstrated. Histologi­cally , the lesions show a deposition of glycosam­inoglycans mostly in the upper third of the dermis,causing a separation of the collagen fibers (Fig.15),uG.9; Since this material can be digested withhyaluronidase, it appears that hyaluronic acid is

the predominant component which accumulates inthe skin. These changes are accompanied by aproliferation of large stellate and elongated fibro­blasts.P" Thus, the increased presence of muco­polysaccharides in the skin may be explained bythe excessive synthesis by these cells.

It should be pointed out that in several instancesscleromyxedema is associated with the presence ofa circulating monoclonal IgG, and immu­nofluorescence studies have shown deposition ofthe same protein in the skin." The relation ofthese observations to deposition of proteoglycansin the skin is unclear, and it may be that thesepatients represent a distinct subgroup ofscleromyxedema.

Cutaneous focal mucinosis, a condition distinctfrom lichen myxedematosus, presents with soli­tary asymptomatic papules or nodules.P" The le­sions usually occur on the face, trunk , or ex­tremities, but not in proximity to the joints of thehands, wrists, or feet. The pathologic changeconsists of a marked proliferation of fibroblastsand an increased production of hyaluronic acid bythese cells. Hyaluronic acid then accumulates be­tween the collagen fibers, eventually replacingmost of the collagen. This process occasionallyresults in the formation of cystic spaces, such asseen in myxoid cysts of the fingers and toes. Itmay be that the pathogenesis of these two condi­tions is similar and the clinical variation might beexplained by the anatomic differences of the in-

Volume 3Number 5November, 1980

volved sites, although the myxoid cyst may beconnected to the synovial space.

Two further conditions characterized by de­position of glycosaminoglycans in the skin are dif­fuse myxedema and pretibial myxedema. In theformer, generalized thickening of the skin withpuffy edema and xerosis takes place. In the latter,localized edematous plaques and tumors are seenin the pretibial area. Both of these conditions areassociated with thyroid disorders. Diffuse myx­edema is usually a sequela of hypothyroidism,while pretibial myxedema is associated with hy­perthyroidism. The long-acting thyroid stimulator(LATS) has been implicated in the appearance ofthe pretibial lesions. Recently, the presence of aserum factor, different from LATS, which stimu­lates proteoglycan synthesis by human skin fibro­blasts has been described; this factor has been pro­posed to be somatomedin.w-'?"

DIFFERENTIAL DIAGNOSIS OF THECONNECTIVE TISSUE NEVI

The term "connective tissue nevi," as em­ployed in the present study, refers to skin lesionsconsisting predominantly of the elements of theextracelIular connective tissue, colIagen, elastin,or proteoglycans. Previously, the term has beenused more broadly, and it has been extended toinclude hamartomas consisting of other dermalcomponents, such as the adipose tissue and thecellular elements. Clinically, many of these le­sions are included in the differential diagnosis ofthe connective tissue nevi, and only a his­topathologic examination of the skin definitivelyallows to establish the correct diagnosis.

One of the conditions entering in the differentialdiagnosis is nevus lipomatosus superficial is. 101.103

This relatively rare malformation consists ofpapules usually occurring on the lower trunk. Twoclinically distinct types are recognized: the classictype, as originally described by Hoffmann andZurhelle;'?' consists of multiple lesions in a zonaldistribution (Fig. 16), while another form consistsof a solitary papule or nodule. 103 The characteris­tic histopathologic change in the skin is replace­ment of the dermal connective tissue by ectopicadipose tissue. The amount of ectopic fat variesmarkedly, and the lesions also show additional

Connective tissue nevi of skill 457

changes in the dermal connective tissue. 10:1 Theseinclude the presence of excess amounts of colla­gen as well as a proliferation of small blood ves­sels. Such changes probably explain the formationof elevated papules with a characteristic cere­briform outline. In addition to the superficial formof this entity, cases with folded skin associatedwith underlying, more deeply seated nevus lipo­matosus have been described. 101 When gen­eralized, this condition has been called "theMichelin tire baby. "10;;

It should be mentioned that focal dermal hypo­plasia (the Goltz syndrome) shows histologicchanges similar to nevus lipomatosus super­ficialis. 106• lOi Clinically, however, focal dermalhypoplasia is clearly a distinct entity and can beseparated from nevus lipomatosus superficialis bythe clinical appearance of the lesions, absence offat herniation, and the presence of widespread as­sociated anomalies of the osseous, ocular, anddental structures.

Another condition frequently entering the dif­ferential diagnosis of connective tissue nevi isleiomyoma. Clinically, leiomyomas present asfirm dermal nodules of varying size which mayoccur as a solitary lesion or, more commonly, asmultiple tumors. Many cases with multiple leio­myomas have a family history of similar lesions.Histologically, the leiomyomas are composed ofsmooth muscle cells which can be derived fromthe arrector pili muscle, the media of the bloodvessels, or from smooth muscle of the nipples or ­genital area. On the basis of histopathologicexamination and, in particular, when special stainsare employed, these lesions can be distinguishedfrom those consisting of collagen. Of interest is arecent report suggesting that Becker's nevus, inaddition to the characteristic epidermal changes,also has a distinct dermal component consisting ofnumerous bundles of smooth muscle cells. 108

An interesting group of patients has been re­cently described by Birt et al 109 as hereditary mul­tiple fibrofolliculomas. These patients presentwith multiple, 2-4 mm fibromatous papules fre­quently involving the head but also seen elsewhereon the skin. These lesions are inherited in an au­tosomal dominant pattern. Histologically, themultiple fibrofolliculomas have in the center a

458 Uitto ct al

well-formed hair follicle which is surrounded by aproliferation of fine collagen fibers embedded inabundant ground substance. Intere stingly, thefibrofolliculomas may be associated with a largeconnective tissue nevus similar to a shagreenpatch, multiple acrochordons, and trichodis­comas, a benign skin tumor related to Haarscheibe(the hair disc) . 109-112

In addition to the lesions discussed above, a fewother hamartomas can rarely be confused withdermal connective tissue nevi. Such entities mayinclude vascular hamartomas, .as, for example,cavernous hemangioma, rubber bleb nevus, an­giofibroma, lymphangioma circumscriptum, andglomus tumor. These lesions , however, havespecific histologic presentations and can be readilyseparated from connective tissue nevi. Severalother disease entities which show ectopic orhamartomatous growth of some forms of connec­tive tissue, such as fibrous papul e of the nose,accessory tragus, or enchondromas in Maffucci'ssyndrome, can also be separated from connectivetissue nevi by their typical clinical presentation. Ineach case, however, histopathologic examinationof the skin is helpful in substantiating the clinicalimpression.

We thank Drs . Jerome Aronberg and Lis Danielsen forproviding some of the illustrations.

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108. Huneke E: The dermal component in melanosis naevi­formis Becker. J Cutan Pathol 6:53-58, 1979.

109. Birt AR, Hogg GR, Dube WJ: Hereditary multiplefibrofolliculomas with trichodiscornas and acrochor­dons. Arch Dermatol 113:1674-1677, 1977.

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III. Delacretaz J, Balsiger F: Harnartorne folliculaire mul­tiple familial. Dermatologica 159:316-324, 1979.

112. Pinkus H. Coskey R, Burgess GH: Trichodiscorna: Abenign tumor related to Haarscheibe (hair disc). J InvestDerrnatol 63:212-218, 1974.