Nail disorders

JOURNAL of the

Amemcae, Acarremv OF

DerMaTOLOGY VOLUME 2

NUMBER 6

JUNE, 1980

Continuing medical education N ail disorders A review Lawrence A. Norton, M.D. Boston, MA The nail is capable of only a limited number of pathologic responses. Some of these alterations, including idiopathic disorders, infections, tumors, and drug-induced reactions, are reviewed in the light of recent observations. Whenever possible, clinicopathologic correlation has been emphasized. Specific suggestions are made for diagnostic technics and treatment modalities. (J AM AC~D DERMATOL 2:451-467, 1980.)

Progress has been made in the past ten years in understanding the basic etiology and pathogenesis of nail disorders. This review attempts to demonstrate how recent increase in knowledge strengthens the clinicians' ability to approach the differential diagnosis and treatment of nail disease. STRUCTURE, COMPOSITION, AND FUNCTION

As a specialized keratinizing appendage, the nail differs from skin in that it does not desquamate and from hair in that its activity is not cyclic. Three questions frequently asked are the following: (1) why is it hard? (2) why doesn't it desquamate? and (3) why don't medications penetrate more easily? From a chemical standpoint, it was previously From the Boston University School of Medicine. Reprint requests to: Dr. Lawrence A. Norton. 332 Washington St., Wellesley Hills. MA 02181.

0190-9622/80/06045 I + 17$0 1.7010 © 1980 Am Acad Dcnnatol

believed that calcium content might be responsible for the hardness of nails, as it is for bone, teeth, and shells, because of findings on histochemical stains.' 'Spectrophotometric analysis, however, has shown that only trace amounts of calcium are present (0.1 to 0.2% by weight)." Furthermore, most of the calcium is on the surface of the nail because of the ability of the calcium ion to exchange for protons. 3 X-ray diffraction studies have shown no evidence of apatite or calcite crystals." The relatively high content of sulfur, predominantly in the form of cystine and its contribution of disulfide bonds, appears to be crucial. There is 9.4% by weight cystine in nails compared to I % in callus, and it is known that disulfide bonds stabilize fibrous proteins. 2.5.6 The relative lack of water in nails contributes to their hardness. The water content of nails in varying percentages of relative humidity is comparable to hair, but it is much less than that of stratum corneum.' Surprisingly, however, the flux of

451

Journal of the American Academy of Dermatology

452 Norton

C 'C,",toc e

p. .p. proximo l nail /old p no;1 pole mat, ...

e . no il H 'h ponfC h:um Fig. I. Diagram depicting longitudinal section of nail and cell movement from the nail matrix into nail plate.

water across nail is ten times that across skin." The key to this apparent contradiction is that nail plate is unable to hold water well because of its low lipid content (less than 5% by weight). Scheuplein and Morgan" demonstrated that lipids prevent water loss in skin by binding action. Chloroform! methanol extraction markedly alters this binding action in the skin but has no effect on water uptake and loss in nail.? X-ray diffraction studies have shown that filaments in nail are oriented parallel to the surface of the nail but at right angles to the growth axis. 2 •7 This rotation may help protect against longitudinal splitting. Investigations by electron microscopy confirm the above filament orientation but also reveal highly developed junctional structures between cells, as compared to skin and hair. 2.10.11 Membrane-coating granules (keratinosomes) are present, but keratohyalin granules are absent. Hashimoto demonstrated that the cell membrane in the nail plate cell more than doubles in thickness from that of a matrix cell by precipitation of a proteinaceous material on the cytoplasmic side of the cell membrane. This forms a "thickened cellular envelope, or marginal band. "12.13 The highly developed junctional structures (tight junctions, intermediate junctions, and desmosome-like junctions) do not degenerate the way they do in skin corresponding with the process of desquarnatlon.v'>'" In summary, the fact that the nail plate is hard and docs not desquamate is contributed to by: (1) high sulfur content in the form of cystine, (2) poor ability to hold water because of low lipid content,

(3) filament alignment, (4) marginal band formation, and (5) highly developed junctional structures . These same biophysical features probably operate in preventing easy delivery of medications into the nail. These data have practical application in treating nail disease by suggesting: (1) what methods are necessary for transporting medications into and throughout nail plate (e.g., for psoriasis, onychomycosis); (2) what modalities could be used for softening the nail when its rigidity is working against the patient rather than protecting him (e.g., ingrown toenails, onychogryphosis, pincer nails); and (3) what may be responsible for soft nails, brittle nails, and splitting nails. Another important advance has been the clarification of cell kinetics in the nail organ and thereby an understanding of which portions of the nail matrix contribute to specific areas of the end product, the nail plate. Although this work antedates the past decade, it is included because it is central in the understanding and treatment of diseased nails. Zaias and Alvarez.' :' demonstrated, by autoradiogrnphic studies in the primate, that the proximal portions of the matrix contribute to the surface of the nail plate, the mid-portion of the matrix to the central nail plate, and the distal matrix to the ventral nail plate (Fig. 1). Subsequently, similar cell movement was shown to occur in man. 15 These findings enable one to predict what areas of the matrix are diseased by recognizing the deformities of the corresponding portions of the nail plate. Treatment may then be directed to the proper area for maximum effectiveness. The nail bed and periungual tissues do not contribute to the formation of nail plate. GENETIC DISORDERS In genetic disease, the physician must not only recognize particular constellations of nail, skin, and hair changes but also must be aware of internal disease and laboratory changes which may be associated. Table I outlines some of these genetic diseases or syndromes, their nail alterations, and associated findings of interest. The nail-patella syndrome (N-P syndrome), with its combination of nail and bone deformities, frequently has a specific pathologic change in the

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453

Table I. Genetic disorders Genetic disease or syndrome

Nail changes

Mode of inheritance

Associated findings of interest

Autosomaldominant

Hemiatrophy, atrophy, triangular lunulae

Hypoplasia of patellae, subluxation of radial heads, iliac horns, joint hyperextensibility, nephropathy with glomerular basement membrane thickening and collagen-like material within it

Pachyonychia congenlta'v-" Autosomal(Jadassohn-Lewandowsky dominant syndrome)

Hypertrophy of nail plates with massive thickening and yellowbrown discoloration

Natal teeth, leukokeratosis, leukoplakia, laryngeal involvement, epithelial cysts, hyperhidrosis palmaris, keratosis pilaris, coarse hair

Nail-patella syndrome":" (onycho-osteodysplasia)

Dyskeratosis" congenita

X-linked or autosomal-dominant

Thinning of the nail plate, fusion with proximal nail fold, ridging, atrophy

Reticulate pigmentation of skin, leukoplakia, anemia and pancytopenia, dental caries, dysphagia

Darier's disease'" (DarierWhite disease)

Autosomaldominant

Distal subungual wedge-shaped keratoses, longitudinal red and white striations; variable thickening .and thinning, splinter hemorrhages, papules on proximal nail folds

Nail pathology shows multinucleated giant cells, sparse inflammatory infiltrate, and no suprabasilar clefts

DOOR syndrome" (deaf- Autosomalrecessive ness onycho-osteodystrophy, mental retardation)

Absent or atrophic nails

Deafness (sensorineural), tripha-· langeal thumbs, biphalangeal digits, dystrophy of distal digits, curved fifth digits

Coffin-Sirls-"?' syndrome

Absent fifth fingernails and toenails; some hypoplasia of other nails

Severe mental retardation, retarded development, wide mouth, thick lips, microcephaly, hypertrichosis of eyebrows, absent fifth terminal phalanx Hypercalcemia, supravalvular aortic stenosis, retarded growth, stellate iris, depressed nasal bridge, antiverted nares, thick lips

Williams elfin facies'" syndrome

?Autosomalrecessive

?

Deep-set, brittle atrophic nails

glomerular basement membrarie consistmg of membrane thickening and presence of fibrillar collagenous material. rs.rz Many of these patients have no clinical evidence of renal disease, and the prognosis is generally good. Linkage has been established between loci of the N-P syndrome, ABO blood group, and the enzyme adenylate kinase.J" In pachyonychia congenita, the new finding of extensive involvement of the larynx with verrucous growths and clinical hoarseness in a 3year-old child is added to the other associated changes of keratosis pilaris, hyperhidrosis and hy-

perkeratosis palmaris and plantaris, leukokeratosis, and natal teeth. 19 Anneroth-" pointed out that the natal teeth and leukokeratoses may appear before the nail changes. The natal teeth are due to a hereditary superficial location of the tooth germ. Thorman and Kobayasi'" described lacunae in the horny cells, failure of separation of desmosomes, large keratinosomes, and thickened tonofilaments as electron microscopic evidence of abnormal keratinization in this disease. Dyskeratosis congenita is characterized by nail dystrophy, reticulate pigmentation of the skin, and

Journal of the American Academy of Dermatology

454 Norton

leukoplakia leading to squamous cell cancer of the mucous membranes. Pancytopenia is often associated.P In their review, Trowbridge et aP3 reported anemia in 49% of forty-six cases, with the white blood and platelet counts depressed in many of them. sa They demonstrated that the skin and nail changes are more likely to appear in the first decade and the hematologic changes in the second and third decades of life. Aseptic necrosis of bone and pulmonary fibrosis have also been associated.v' In Darier-White disease, all parts of the nail organ may be involved, but the most prominent changes are in the nail bed. Longitudinal red and white streaks, as well as distal wedge-shaped or more diffuse subungual hyperkeratoses, are characteristic. 25 The histopathology in the nail bed differs from that found in skin by the absence of suprabasilar clefts, presence of multinucleated epithelial giant cells, and by having a sparse inflammatory infiltrate. Zaias and Ackerman'" also felt that the papules often found on the proximal nail fold are lesions of Darier-White disease histologically rather than flat warts. The DOOR syndrome (deafness, onycho-osteodystrophy, mental retardation):" is included in this review because the hand changes are so specific and easy to identify. Absent distal digits are seen in other disorders, 27 but the combination of triphalangeal thumbs and biphalangeal digits is unique. Another genetic syndrome, the Coffin-Siris syndrome, shows the striking finding of absent nails on the fifth digits of the upper and lower extremities. These children show severe mental and developmental retardation, gross abnormality of the cerebellum and fourth ventricle, feeding problems, and lax joints as well as characteristic facies. 28-31 The Williams elfin facies syndrome has brittle, deep-set, atrophic nails associated with aortic stenosis, hypercalcemia, and the facial features listed in Table {.32 While soine of these disorders are extremely rare, awareness of them by the physician doing pediatric consultations is important. There continue to be additional associations of nail, tooth, and mucous membrane changes, emphasizing the

importance of examining the mouth in nail abnormalities.Pr" Finally, nail changes consisting of onycholysis, longitudinal grooving, and subungual hyperkeratosis have occurred as the first manifestations of HLA-B27 inheritance.i" This histocompatibility antigen has shown strong association with Reiter's disease, ankylosing spondylitis, uveitis, and reactive arthritis (arthritis following infections of the intestinal and urinary tracts).36,37 DRUG REACTIONS Iatrogenic disease, self-medication, and environmental exposure are responsible for a spectrum of nail alterations. Some recent reports of drug-induced nail changes are listed in Table II, along with cutaneous and systemic findings when present. Goldman et aP8 reported nail plate changes secondary to topical 5-fluorouracil. This drug may be introduced into the nail not only when surrounding skin is being treated topically for actinic keratoses but also when it is used for treatment of psoriasis of the nails'" and periungual warts.:"':" Two more recent reports on onycholysis, nail dystrophy, and paronychial inflammation all occurred in the treatment of warts when the topical drug was used with occl usion. 42.4:l Systemic administration of 5-fluorouracil has also produced onycholysis;" Onycholysis was published as the presenting sign in a case of oral contraceptive-induced porphyria cutanea tarda (PCT). 45 Since onycholysis is not a usual finding in PCT, the nail changes may have been unrelated, but they did clear on discontinuation of the drug. There are also reports of photo-onycholysis secondary to medications. The mechanism of this change is uncertain, but it is clear that sunburn or other cutaneous reaction is not a prerequisite for its appearance.t''-" To be added to tetracycline and doxycycline are chlortetracycline, chloramphenicol, and demeclocycline.P'P-" Photo-onycholysis has occurred secondary to the use of psoralens, both with natural sunlight 51,52 and with artificial light sources in psoralen and ultraviolet A (PUVA) treatment. 53,51 Zala et aPI examined biopsies of the nail bed after photoinduced onycholysis and noted binucleate and multinucleated cells, but no

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Table II. Drug-induced nail changes Drug

Indication for treatment

Nail change

Associated changes

5·Flourouracil 38- 43

Actinic keratoses, warts, psoriasis

Onycholysis, dystrophy, paronychial inflammation

Oral contraceptive" (Norinyl-l)

Contraception

Onycholysis

Induced porphyria cutanea tarda with ulcerations of skin, hyperpigmentation, hypertrichosis

Psoralen + sunlight5 1,52 + artificial light 53 •54 source

Psoriasis, vitiligo, lymphoma

Photo-onycholysis

Multinucleated giant cells in nail bed epithelium

Practolol'" (Eraldin)

Hypertension

Ridging and subungual blotchy erythema

Psoriasiform skin changes, conjunctivitis, eyelid edema, lupus-like syndrome, oculomucocutaneous syndrome

Bleomycin'f (B1enoxane)

Malignancy

Longitudinal pigmented bands

Sclerodermoid skin changes, fibrosis of lungs, hyperpigmentation

Melphalan'" (Alkeran)

Malignancy

Longitudinal pigmented bands

Diarrhea, gastrointestinal ulcerations, bone marrow suppression

Doxorubicin'" (Adriamycin)

Malignancy

Horizontal pigmented bands

Cyclophosphamide'" (Cytoxan)

Malignancy

Horizontal pigmented bands

Cystitis, alopecia, pancytopenia

Hydroquinone'"

Melasma

Orange-brown pigmentation

Depigmentation of skin

Sodium hypochlo-

Exposure in swimming pool maintenance (occupational)

Onycholysis

rite'"

evidence of solar elastosis on orcein and van Gieson's stains. Small cystlike structures were also noted in the upper malpighian layers, and these were believed to be due to a degenerative process. Practolol (Eraldin) is a beta adrenergic blocking agent which was withdrawn from the European market in 1975. The occurrence of nail ridging and subungual erythema secondary to this medication should alert dermatologists to possible similar changes from closely related pharmacologic beta blockers.P It is not in the province of this paper to review the multiple causes for color change in the nail but merely to mention some of the drug-related changes reported in more recent publications. Baran'" recently reviewed pigmentation of the nails and provided forty-one references. Plewig et aP; also summarized nail plate color changes in

their report of "Silver-Blue Nails" in a case of argyria. Zaias'" pointed out a helpful sign in assessing the cause of nail discolorations. If the discoloration follows the shape of the proximal nail fold, it is more likely due to external factors, while if it corresponds to the shape of the lunula, internal causes predominate. There have been numerous reports of nail pigmentation associated with cancer chemotherapy. It is not always certain if the changes are due to the disease or the therapy, and it is not always specified if the color changes are in the nail plate, bed, or both. The mechanism for pigment production is uncertain, but one hypothesis is that increased levels of adrenocorticotropic hormone (ACTH) and/or melanocyte-stimulating hormone (MSH) are responsible. Lerner and Mcfluire'" noted appearance of horizontal pigmented bands in the

456

Norton

Journal of the American Academy of Dermatology

Fig. 2. Acquired digital fibrokeratoma in a subungual location. Fig. 3. Acral lentiginous melanoma in which the first biopsy was interpreted as benign. Fig. 4. YelIow nail syndrome with discoloration, absent cuticles, arrested growth.

nails of an adrenalectomy patient with Cushing's syndrome following administration of ACTH and MSH. Bondy and Harwick''? subsequently reported longitudinal pigmented bands in two patients with Cushing's syndrome, both of whom

were found to have pituitary tumors after recovery from adrenalectomy. One of these patients had elevated MSH levels. Arakawa et al'" found normal plasma levels of ACTH and MSH in a 10year-old girl who developed horizontal bands and

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Table III. Differential features of exostosis, osteochondroma, enchondroma, and epidermoid cyst Tumor

Sex ratio

Exostosis

20-40

Female

Osteochondroma

10-25

Male

Enchondroma

20-40

8-83

Epidermoid cyst (traumatic cyst, epithelial irnplantation cyst)

> male 2: 1

History oCtrauma

X-ray

Occasionally

Moderate

Trabeculated osseous growth with expanded distal portion covered with radiolucent fibrocartilage

> female 2: I

Often

Slow

Well-defined sessile bone growth with hyalin cartilage cap

Male

= female

Often

Rapid

Loculated bone cyst showing radiolucent defect, bone expansion, and flecks of calcification

Male

> female 2: I

Almost always

Rapid

Radiolucent cyst: no calcification

one longitudinal band following combination therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone. Longitudinal pigmented bands were found following bleomycin'" and melphalan'" therapy, while horizontal pigmented bands were associated with adriarnycin'" and cyclophosphamide.f" Various patterns of pigmentation have also been reported with 5-fluorouraciI. 6 6 Orange-brown discoloration of the nail plates may occur in patients treated topically with hydroquinone for melasma." And, finally, contact with sodium hypochlorite used in swimming pools has produced onycholysis and represents an occupational hazard in lifeguards.!" While there is general awareness of the nail and paronychial changes that may be produced by formalin-containing nail hardeners, it should be pointed out that several nail polishes on the market now contain formalin; thus, the patient should be questioned about both types of these cosmetics. These various reports serve to emphasize the time that must be spent in detailing systemic and topical drug therapy as well as cosmetic and occupational exposure. TUMORS

The clinical appearance of benign and malignant tumors of the nail and periungual tissues tends to be nonspecific. Furthermore, their behavior is often different than that of the same type of

tumor seen elsewhere on the skin. Diagnosis is usually made comparatively late because of a failure to differentiate inflammatory from neoplastic changes, reluctance to biopsy, and failure to obtain diagnostic x-rays. Finally, the history of preceding· trauma is more common, and chronic infection may be present, particularly in squamous cell carcinoma and melanoma.

Benign tumors Acquired digital fibrokeratoma'P' P appears to be a benign hyperplasia of fibrous tissue initiated by trauma to the digits, although similar pathology has been seen on the skin elsewhere.?" Clinically, the lesions present as firm hyperkeratotic nodules which may impinge on the nail plate and cause a groovelike deformity similar to that seen with mucinous cysts and Koenen's tumors (periungual fibromas in tuberous sclerosis). They may also be subungual (Fig. 2). The differential diagnosis includes superumerary digit, recurring digital fibrous tumor of childhood, and neurofibroma. Histologically, collagen bundles are seen in longitudinal arrangement with absent neural elements, sparse elastic tissue, and a hyperkeratotic epidermis.?" Simple excision is usually curative, With a very low incidence of recurrence or persistent nail plate deformity. Four subungual benign tumors that have received considerable attention in the past decade are exostosis.I'"?" osteochondroma;" enchon-

458 Norton

droma,i9,8o and epidermoid cyst. 8\,82 Table III reviews some of the differential features drawn from these references, the most helpful of which are the male predominance in osteochondroma and epidermoid cysts, female predilection in exostoses, relatively slow growth in osteochondroma, and, finally, the x-ray features, All of these conditions produce pain, and the patient complains of discomfort in the subungual region with or without a visible mass, Paronychia and/or nail plate deformity and discoloration may occur. Surgical excision with or without bone grafting is required under sterile operating room conditions. Another painful subungual tumor, the glomus tumor, was recently reviewed, and a series of eighteen patients was described by Schneider. 83 In this tumor, pain is not only elicited by pressure but also by heat and cold. A purple to red spot mayor may not be seen through the nail plate, and there may be associated ridging. Patients usually have symptoms for years before curative surgery. The tumor consists of a hamartomatous overgrowth of the normal glomus body, which consists of arteriovenous anastomoses associated with unmyelinated nerves. Camirand and Giroux'" pointed out that pressure atrophy of the distal phalanx with radiolucent defect on x-ray may be found and diagnosis confirmed by arteriography, in which an irregular-shaped telangiectatic mass is seen. This may be particularly helpful for surgical guidance when clinical evidence of tumor and conventional x-ray changes are absent. Recurrence following adequate surgical excision is rare. PREMALIGNANT AND MALIGNANT LESIONS

The full spectrum from solar keratosis through Bowen's disease to squamous cell carcinoma may be found subungually. Since melanomas and basal cell carcinomas also occur in this area, it would appear that the nail offers little protection against solar damage. Bowen's disease of the nail bed has been reported by several authors. 8,,-8i A review of these cases, plus three cases followed by me, reveals that the tumor is slow-growing, insidious, and different in appearance from Bowen's disease on the skin. Mikhail'" pointed out that it usually starts in

Journal of the American Academy of Dennatology

the lateral nail fold and subsequently involves the nail bed, with secondary onycholysis and nail plate destruction. Males predominate over females, the average age is in the 50s, and the duration prior to surgery is 3 to 5 years. The tumor tends to recur following curettage and desiccation and with topical 5-fluorouracil treatment. At least part of the time this is due to the fact that a focus of frank squamous cell carcinoma is present and not included in the biopsy specimen (four out of four in Mikhails'" series). Inadequate depth of penetration of 5-fluorouracil has also been blamed for recurrence. In any event, amputation or microscopically controlled chemosurgery is the treatment of choice. The latter affords greater preservation of the digit. This can be a very important functional consideration, particularly with the thumb. Squamous cell carcinoma must be differentiated from keratoacanthoma (Table IV). Both of these tumors behave somewhat differently under the nail than they do elsewhere on the skin. Squamous cell tumors grow slowly, invade bone late, metastasize infrequently and late, and are often accompanied by infection. 88-91 Keratoacanthoma grows rapidly, may be multiple, causes early bone erosion visible on x-ray, and shows less tendency to spontaneous recovery than keratoacanthomas elsewhere. 88.92,93 Shapiro and Baraf'" felt that this is due in part to the fact that some of these are of the multiple eruptive type, which show less resolution, or that they are treated earlier because of pain. Histologically cellular atypia and increased mitotic figures are seen in squamous cell cancer, while individual cell keratinization and pseudoepitheliomatous hyperplasia are observed in keratoacanthoma.vv'" Treatment for keratoacanthoma is usually successful with local excision. Amputation, sparing as much of the digit as possible, or, when available, the Mohs surgical technic is the treatment of choice for squamous cell cancer. Although squamous cell carcinoma is by far the most common malignant tumor of the nail bed, basal cell epitheliomas have been reported. As in the case of Bowen's disease, biologic behavior and resistance to treatment may be different because of foci of squamous cell cancer. Alpert et

Volume 2 Number 6 June, 1980

aJ!H; reported a basal cell epithelioma on the nail bed of a 51-year-old man who had had chronic infection of the finger for 19 years. Following amputation, after initial incomplete excision, histology revealed one section of bowenoid .changes. Hoffman"? subsequently reported a basal cell epithelioma on the thumb of a 65-year-old woman with a 5-year history of paronychia. Curettage and grenz-ray treatment failed to eradicate the tumor, but amputation was successful. In melanoma of the nail bed and periungual tissue, classification as elsewhere on the skin into histologic variety, level of invasion, thickness of lesion, and degree of inflammation is helpful in evaluating the prognosis. Unfortunately, it is-seldom possible clinically to differentiate between the three major types of melanoma (i.e., nodular (NM), superficial spreading (SSM), and lentigo malign a (LMM), when they occur in the subungual location. Diagnosis tends to be made late because of masking by chronic infection and absence of pigment in some tumors. Kopf et al feel that NM and SSM are rare in this location and that most melanomas in the sub- and periungual areas fit into the classification of acral lentiginous melanoma (ALM) first described by Arrington et apoo (Fig. 3). Seiji et al'?' used the term' 'palmar-plantar-subungual-mucosal type melanoma" (PSM melanoma) for this tumor. Regardless of nomenclature, the tumor has an initial radial growth phase of extremely variable duration, at which time the histology resembles lentigo maligna, but may be distinguished at times by the presence of giant melanocytes and large dendrites in the basal layer with an accompanying lymphocytic infiltrate in the adjacent dermis. It is important to realize that the histologic picture may appear benign, and multiple biopsies or even total excision may have to be performed before the true histologic picture is appreciated. Once the vertical growth phase intervenes, this tumor is much more aggressive than lentigo maligna melanoma of equal level, and biologically it behaves more like SSM, which had invaded the dermis. To date, the small number of tumors studied precludes any accurate prognosis on the basis of depth and level of invasion. The ALM has many clinical and his-

Nail disorders

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Table IV. Differentiation between squamous cell carcinoma and keratoacanthoma*

Parameter

Subungual squamous cell cancer

Subungual keratoacanthoma

Sex Age Incidence Rate of growth Duration of symptoms History of trauma Bone invasion or alteration X-ray

Male > female 60-75 Common Slow Long

Male > female 40-60 Rare Rapid Short

Sometimes

Rarely

Late

Early

Bone destruction

Multiple tumors

Rare

Erosion, radiolucent defect, or bone destruction More common

*Adaplcd from Shapiro L, Baraf CS: Cancer 25:150, 1970.

tological similarities to mucous membrane melanoma, and it is noteworthy that when melanoma occurs in blacks, it usually is in the plantar, subungual, or mucous membrane location.?" In the largest published series of subungual melanomas, 65% of the tumors were either on the thumb or great toe. 102 Nearly half of them gave a history of trauma. Thirty-six percent of the seventy-two patients had node metastases at the time of surgery. Leppard 10:1 reported bilateral subungual malignant melanoma involving both great toes, treated as ingrown toenails for 2 years prior to diagnosis. It would appear that the best chance for increasing survival is to have a high index of suspicion for any chronic paronychia, subungual pain, or visible mass and to biopsy early. Finally, the problem of pigmented longitudinal bands under the nail plate continues to be a difficult one. It has long been appreciated that these lesions are quite common in blacks and apparently of no significance. However, in Pack and Oropeza's 102 series of seventy-two subungual melanomas, five were in black patients. Pigmented bands occurring in Caucasians, unrelated to drug therapy or Cushing's syndrome, demand biopsy to rule out malignancy. However, Baran'?"

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Norton

Chart I. Organisms in onychomycosis Toenails I. Distal subungual onychomycosis: Dermatophytes: T. rubrum, T. mentagrophytes, Epidermophyton floccosum Yeasts and molds: Candida parapsilosis, Scapulariopsis brcvicaulis, Aspergillus, Cephalosporium. Fusarium 2. Proximal subungual onychomycosis: T . rubrum, Trichophyton megninii, T. schoenleini, Trichophyon tonsurans 3. Superficial white onychomycosis: T . mentagrophytes, Cephalosporium, Aspergillus. Fusarium Fingernails I. Distal subungual onychomycosis: Dermatophytes: T. rubrum Yeasts and molds: Rarely present 2. Proximal subungual onychomycosis: T. rubrum, T. megninii 3. Superficial white onychomycosis do es not occur on fingernails 4. Paronychial infection: Candida albicans Note: C. albicans invades nail plate only in immunologically impaired individuals with chronic cutaneous candidiasis.

called attention to a benign condition, Laugier's \0;; dise ase, in which pigmented nail bands arc associated with spotty pigmentation of the lips and mucosa . This is a benign condition unassociated with any malignancy or internal disease and does not require biopsy. In summary, tumors under and about the nail should be suspected whenever there is persistent infection, discomfort, or a visible mass. X-ray and biopsy ex amination should be done early and repeatedly, if necessary, prior to institution of adequate treatment. MYCOLOGY

New insight has been gained into two problems which have for many years disturbed mycologists dealing with nail disease. The first problem is the low yield of fungal clements on microscopic examination of nail material and the associated difficulty in obtaining positive cultures. The second problem is the decision as to whether isolated organisms represent pathogens or not. Several

Journal of the American Academy of Dennalolog y

series have shown percentages of positive microscopic findings to be only 40 % to 50 %, even in the hands of experts in the field. lilli-lilt! Furthermore , only about 50% of cases showing positive microscopic findings on direct smear yield positive cultures. While error in clinical diagnosis might account for some of these, it would appear far more likely that failures are due to the fact that the areas of the nail organ usually sampled (i.e., distal subungual debris, distal nail plate) often contain nonviable fungi. Zaias ct aPOG increased this yield by using a mechanical homogenization of subungual debris, while English 10!! preferred multiple samplings from the nail plate and bed with a dental drill and attached suction apparatus. She pointed out that many fungi like to live near living tissue for their nutrients and are more likely to be found in the ventral portions of the nail plate and adj acent nail bed . Fungi must either adapt to the dry , nutrition-poor distal nail plate or survive in competition with viabl e skin cells where nutrient s are more plentiful. This host-parasite relationship accounts for the variation in location of different dermatophytes, yea sts, and molds. Zaias 110 divided onychomycosis into four clinical types: (I) distal subungual onychomycosis, (2) proximal subungual onychomycosis, (3) superficial white onychomycosis (leukonychia trichophytica), and (4) candidal onychomycosis. Chart I shows a brief summary of the organisms most likely to be found in each category of infection. Trichophyton tnentagrophytes does not adapt well to the growth demands in fingernails, and most infections by dermatophytes in the fingernails arc due to Trichophyton rubruni. In the same fashion, Candida parapsilosis is rarely found in fingernails but is isolated often from toenails. It is important to realize that the primary site of fungal invasion in distal onychomycosis is the stratum corneum of the nail bed , while in proximal onychomycosis it is the stratum corneum of the proximal nail fold. Only in superficial white onychomycosis is the nail plate invaded initially . 1111 As in the groin, there may be a combination of dermatophyte and yeast invading the nail organ, and one should suspect yeast if onycholysis is present . English'!" called attention to the fact that molds

Volume 2 Number 6 June. 1980

and yeasts are not keratolytic in vitro and appear to depend upon disease, trauma, or aging to alter conditions favoring their invasion. In one survey of elderly patients, English and Atkinson 111 found twice as many cases of onychomycosis due to molds as to dermatophytes. The plant pathogens Hendersonula toruloidea and Scopulariopsis brevicaulis appear to be exceptions to this rule and capable of acting as primary pathogens in nails. II2 - 1 1-t The separate entity of candidal onychomycosis in chronic cutaneous candidiasis is not an exception, since here the organism is acting in a diseased state most probably a deficiency of humoral and/or cellular immunity. As to whether a yeast or mold is a contaminant or truly responsible for a diseased nail, English IO!J suggested the following criteria: 1. If a dermatophyte is isolated it is considered the pathogen. 2. If molds or yeasts are isolated, they are significant only if mycelia, arthrospores, or yeast cells are found on direct microscopic examination of the nail specimen. 3. Final confirmation of mold infection requires isolation of the mold on at least five of twenty inocula and no dermatophyte found on either Actidione [cycloheximide]-containing or Actidione-free medium.

While these criteria might seem rigid ·and too demanding for many clinical practices, they serve to highlight the need for caution before concluding that an altered nail is due to a dermatophyte. Further progress in this area of organism identification wiII lead to less inappropriate treatment. MARKERS OF INTERNAL DISEASE

Certain alterations of the normal nail unit have been associated with internal disease and may serve as diagnostic markers. The yellow nail syndrome, first described by Samman and White II;; in 1964, consists of lymphedema, pleural effusion, emphysema, bronchiectasis, sinusitis, and diffuse yellow discoloration of the nails, with increased curvature and thickness, marked reduction in growth rate, absent cuticles, spontaneous shedding, and onycholysis (Fig. 4). Recent associations with this syndrome have been chronic nasal obstruction and rock hard cerumen, Iu; plus reports of internal malignancy,

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including cancer of the larynx.!" lymphoma, and sarcoma.'!" It should be emphasized that yellow nails have been found in congenital lymphedema, cardiac failure, familial amyloidosis with polyneuropathy, and in the lower extremities of diabetics with purpura, edema, and diabetic dermopathy.l19 Kleinman 120 pointed out that the yellow nails in congenital lymphedema may precede the edema by many years. To be added to the Peutz-Jeghers and the Gardner syndromes as a marker of intestinal polyposis is the Cronkhite-Canada syndromc.P'v''" This condition appears to be acquired rather than genetic. The associated polyps are predominantly benign and may be distributed all the way from the stomach to the rectum. The nail findings are atrophic nail plates with distal shedding and longitudinal splitting. Additional skin changes include diffuse hyperpigmentation of the face, neck, and extremities and alopecia of scalp and body hair. Spoon nails (koilonychia) are usually associated with iron deficiency anemia and the PlummerVinson syndrome. Chevrant-Breton et ap:!:l found koilonychia in forty-nine of one hundred cases of idiopathic hemochromatosis not associated with anemia. It has been demonstrated that the cystine content in koilonychia is low, I:!~ which probably accounts for the thinning and softness. Paraneoplastic acrokeratosis of Bazex is an acquired condition of psoriasiform changes in the nails and acral areas associated with malignancy of the upper respiratory or gastrointestinal tract.I:!;;.I:!(; According to Baran."? the nail changes are an early manifestation and are consistently present. As in psoriasis, there is subungual hyperkeratosis, smooth- and rough-surfaced leukonychia, and irregularity of the nail plate. The skin changes consist of erythema, scaling, and pustule formation in a symmetric distribution over the hands, feet, ears, and nose. Histology shows nonspecific inflammation with vasculitis but absence of the changes seen in psoriasis. DISEASES OF UNKNOWN ETIOLOGY

Although their cause is unknown, two diseases of the nail, namely psoriasis and lichen planus, have had their clinicopathologic correlation carefully worked out and are exemplary of what is

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needed in the understanding of other nail disorders. In psoriasis, the presenting clinical signs in the nails are (1) pits in the surface of the nail plate, (2) leukonychia with smooth or rough surfaces, (3) transverse grooves, (4) crumbling of the nail plate, (5) onycholysis, (6) subungual hyperkeratosis, (7) red-brown oval to round spots under the nail plate (oil spot sign), and (8) splinter hemorrhages. Zaias l 28 correlated these signs with the site of origin of the pathology. Again, since the proximal matrix produces the cells that form thesurface of the nail plate, items 1, 2, and 3 above result from disease activity in the proximal matrix. He hypothesized that the foci of parakeratotic cells seen in nail sections are less adherent to each other than normal plate cells, allowing them to tumble off the surface as the nail grows out leaving the pits. Rough-surfaced leukonychia have a similar genesis, while transverse grooves more likely reflect temporary ineffectual keratinization. Extensive crumbling of the entire nail plate points to diffuse involvement of the matrix, while smoothsurfaced leukonychia indicate foci of parakeratotic cells with origin in the median portions of the matrix. Zaias 128 felt that items 6, 7, and 8 all reflect nail bed and hyponychium activity. Histochemical stains show the oil spots to be a glycoprotein which is periodic acid-Schiff (PAS)positive, diastase-resistant. Onycholysis is felt to be due mainly to disease in the area of the hyponychium.P'v'" An alternative explanation could be focal disturbance of the distal matrix, since evidence has been offered that cells from that area contribute to attachment cells between the nail plate and bed.P The onset of onycholysis distally could then be explained by greater mechanical forces exerted on the distal plate. Finally, it should be emphasized that although this constellation of signs strongly suggests psoriasis, none are pathognomonic, and complete examination of the skin should be done to seek out confirmatory evidence of psoriasis when present. Lichen planus produces nail changes which can be traced to disease activity in one or more parts of the nail unit. The most frequent alterations are 1:10-1:12: (l) thinning of the nail plate, (2) alternating longitudinal ridges and grooves (onychor-

rhexis), (3) focal destruction of the proximal nail plate with fusion of the proximal nail fold to the nail bed (pterygium), (4) complete loss of nail plate, (5) red to violaceous dots or streaks seen through the nail plate, and (6) subungual hyperkeratosis. The predominant feature of this disease process is destruction and atrophy following inflammation. Thinning of the nail plate results from a marked reduction in size and function of the rnatrix.I'" Focal areas of more pronounced atrophy lead to grooves and ridges, or, with more inflammation, pterygium formation with local absence of nail. The extreme end of the spectrum is complete absence of nail. Items 5 and 6 are manifestations of nail bed and hyponychium involvement and are of less significance. However, nail bed histopathology, as well as that of the matrix, shows the characteristic changes of lichen planus seen in the skin. As in psoriasis, the signs of lichen planus are not absolutely specific for the disease, but confirmatory evidence may usually be found by examination of the 'scalp, mucous membranes, and glabrous skin. There are, however, circumstances in which the nails alone appear to be involved, and only histology can confirm the clinical impression. 1:1:1.I:ll Scher et ap:l;; demonstrated that the entity "twenty-nail dystrophy" I:lfi appears to be a variant of lichen planus most of the time, although there may be other etiologies for this dystrophic process. Baran 1:1. feels that alopecia areata and psoriasis may also produce this clinical picture, in addition to lichen planus, and suggests the term "vertical striated sandpaper nails. "J:l< In my experience' the most common condition which may mimic lichen planus changes other than genetic disorders is the destruction brought about by severe erythema multiforme.v'v':" TREATl\IENT

The treatment of nail disease is often prolonged and unsatisfactory, but a greater degree of success is achieved when the diagnosis is established prior to treatment. Realization of this goal is more likely with liberal use of direct microscopic examination, culture, biopsy, and x-ray. The introduction to this country of a chemical means for avulsion of

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the nails by Farber and South'?" extends physicians' ability to treat psoriasis, onychomycosis, and mechanically disturbing nails. Their formula utilizes either 22.25% urea, 22.25% anhydrous lanolin, 5.50% white wax, 50% white petrolatum, or 40% urea, 20% anhydrous lanolin, 5% white wax, and 35% white petrolatum. HII For nail removal, Baran offers the alternative treatment of 50% potassium iodide in lanolin occluded with plaster for 8 to 10 days. I~I Precaution must be taken to protect the skin; sometimes the usual 7 to 10 days of treatment are not adequate, necessitating repeat treatment. Nonetheless, it affords a means for direct application of topical antifungal agents to the nail bed without subjecting the patient to multiple surgical procedures. It also provides treatment for the patient who is intolerant of or allergic to griseofulvin; avulsion shortens the time of treatment necessary. Currently, it is felt that 1.0 gm/day of microsize griseofulvin or 0.5 gm/day of the ultramicrosize griseofulvin is required. Following chemical or surgical avulsion, this would have to be given for 3 to 4 months for disease of the upper extremity, 6 to 8 months on the lower extremity, and proportionately longer if avulsion was not performed. My preference for topical treatment is either 2% miconazole, 1% c1otrimazole, or 1% haloprogin. In psoriasis, topical high-potency corticosteroids, e.g., 0.2% fluocinolone acetonide, 0.5% triamcinolone acetonide , may be applied after chemical avulsion with or without occlusion. A measure of success has been achieved without avulsion by intralesional injection of the proximal nail fold with triamcinolone, 2.5 mg/cc to 5 mg/cc in a quantity of 0.2 to 0.3 cc per nail. 1~2-IH I prefer the Dermo-Jet to needle injection because in my experience patients have less pain. It delivers approximately O. I cc per injection. Topical treatment with corticosteroids may be potentiated by occlusion at night and 10% benzoyl peroxide gel, or O. 1% retinoic acid cream, during the day. Whether PUVA treatment will have a place in nail psoriasis is still uncertain, but there are some preliminary encouraging unpublished results. H~ In lichen planus, the same approach recommended for psoriasis may be used, but in severe

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cases with marked destruction systemic corticosteroids are justified, given orally on a once-aday early morning regimen as recommended by Storrs. r.ro The tape occlusion method of treatment for periungual and subungual warts described by Litt':" works surprisingly well in my experience. In those patients who have not responded to tape occlusion, there is usually a definite reduction in size of the warts, making subsequent destructive approaches easier and less painful. Immunotherapy also offers encouraging results in this difficult treatment problem. The recent concern about possible carcinogenicity of dinitrochlorobenzene should not cause abandonment of this modality, and safer sensitizers should be sought. Another painless, simple approach to a common problem is the multiple puncture and expression technic for mucus (myxoid) cysts on the digits. Epstein"!" instructs the patient on how to do this with sterile precautions, and a variable number of needlings is required before the cyst subsides. It would appear that there are two types of mucus cysts on the digit, those that connect with the joint and those that do not. If there is connection, then probably nothing short of careful surgical excision with dye demonstration of the sinus connection to the joint will result in cure. This will usually require grafting or a rotation flap. Surgical treatment of the nail has advanced markedly in the past decade. For the physician interested in performing nail surgery, two procedures of high priority are biopsy of the nail bed and/or matrix, and avulsion of the nail plate. One of several biopsy technics may be used, namely: ( I) punch biopsy through the nail plate, (2) partial nail excision followed by punch or ellipse excision, (3) total nail avulsion plus punch or ellipse, or (4) longitudinal, lateral, and horizontal nail biopsies. The availability of disposable biopsy punches should encourage nail plate biopsy. Adequate anesthesia is achieved with local block utilizing 1% or 2% lidocaine hydrochloride without epinephrine. A size 30 needle is introduced into the lateral margins of the digit distal to the distal interphalangeal joint. The anesthetic should be injected slowly and the needle extended to reach across the

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proximal nail fold and up to the tip of the finger in order to block the nerve branches. A 3- or 4-millimeter punch is used, and moderate force is necessary to penetrate the nail plate. H9 Once the punch enters the nail bed epithelium, a plug of epithelium frees up attached to a circular specimen of nail plate, and it is seldom necessary to use iris scissors or a scalpel to sever the base of the specimen. Very little postoperative discomfort is experienced. Should a larger biopsy have to be performed or better visualization of a specific lesion be required, it is preferable to first carry out partial nail excision or total nail avulsion. The' latter is performed under local anesthesia by blunt dissection with either a small curved hemostat, dental spatula, or dermal elevator.':" The essential thing is to free the proximal nail fold, lateral nail folds, and nail bed from the plate by blunt dissection before attempting to lift the nail plate off. The dissection does not have to be carried any farther than the distal edge of the lunula, since the matrix is not firmly attached to the plate. Biopsy of the matrix requires more surgical skill and usually the formation of a flap for visualization, as outlined by Fosnaugh.P' In a similar fashion, longitudinal.P?: lateral,153.154 and horizontal biopsies!" are more appropriate for those individuals with a special interest in nail surgery. It should not be overlooked that most patients have a significant fear of having surgical procedures on their nails compared to other areas of their skin. Thorough explanation and good anesthesia are required for patient acceptance. REFERENCES I. Jarrett A, Spearman RIC: The histochemistry of the human nail. Arch Dermatol 94:652-657. 1966. 2. Forslind B: Studies of the normal nail. Acta Derm Venereol (Stockh) 50:161-168, 1970. 3. Forslind B: Calcium and sulfur location in human nail. J Invest Dermatol 67:273-275, 1976. 4. Forslind B: Quantitative microradiography of the normal human nail. Acta Derm Venereol (Stock h) 51:8992, 1971. 5. Pruzanski W, Amon R: Cystine and other amino acids in fingernails of cystinuria patients and list of normals. Lancet 2:60-61, 1965. 6. Greaves M. et al: Amino acid composition of human nail as measured by gas-liquid chromatography. Clin Chern 22:1608-1613, 1976. 7. Baden H: Physical properties of nails. J Invest Dcrmatol 55:115-122, 1970.

Journal of the American Academy of Dermatology

8. Burch GE, Winsor T: Diffusion of water through dead plantar, palmar, and torsal human skin and through toenails. Arch Dermatol Syph 53:39-41. 1946. 9. Scheuplein RJ, Morgan LJ: Bound water in keratin membranes measured by a microbalance technique. Nature 214:156-158, 1967. 10. Caputo R, Dadati E: Preliminary observations about the ultrastructure of the human nail plate treated with thioglycolic acid. Arch Klin Exp Derm 231:344-354, 1969. II. Caputo R, et al: Ultrastructure of the human ungual lamina. G Ital Derm 82:454-457, 1970. 12. Hashimoto K: Marginal band: Demonstration of the thickened cellular envelope of the human nail cell with the aid of lanthium staining. Arch Dermatol 103:387393, 1971. 13. Hashimoto K: Ultrastructure of the human toenail. II. Keratinization and formation of marginal band. J UItrastruct Res 36:392-410, 1971. 14. Zaias N, Alvaraz J: The formation of the primate nail plate. An autoradiographic study in squirrel monkey. J Invest Dcrmatol 51:120-136, 1968. 15. Norton LA: Incorporation of thymidinc-rncthyl-H, and glycine-z-H, in the nail matrix and bed of humans. J Invest Dermatol 56:61-68, 1971. 16. Bennet WM, Musgrave JE, et al: The nephropathy of the nail-patella syndrome. Am J Med 54:304-319, 1973. 17. Morita T, Laughlin LO, Kawaro K, Kimmelstiel P. Suzuki Y, Cheng J: Nail-patella syndrome: Light and electron microscopic studies of the kidney. Arch Intern Med 131:271-277, 1973. 18. Schlcuterman DA: Linkage of the loci for the nailpatella syndrome and adenylate kinase. Am J Hum Genet 21:606-630, 1969. 19. Cohn AM: Pachyonychia congenita with involvement of the larynx. Arch Otolaryngol 102:233-255, 1976. 20. Anneroth G: Pachyonychia congenita. A clinical, histological and microradiographic study with special reference to oral manifestations. Acta Derm Venereol (Stockh) 55:387-394, 1975. 21. Thorman J, Kobayasi T: Pachyonychia conge nita Jadassohn- Lewandowsky: A disorder of keratinization. Acta Derm Venereol (Stockh) 57:63-67, 1977. 22. Gutman A: X-linked dyskeratosis congenita with pancytopenia. Arch Dermatol 114:1667-1671. 1978. 23. Trowbridge AA, et al: Dyskeratosis congenita: Hematologic evaluation of a sibship and review of literature. Am J Hematol 3:143-152, 1977. 24. Inoue S: Dyskeratosis congenita with pancytopenia. Another constitutional anemia. Am J Dis Child 126: 389-396, 1973. 25. Zaias N, Ackerman AB: The nail in Darier-White disease. Arch Dermatol 107iI93-199, 1973. 26. Cantwell R: Congenital sensorineural deafness associated with onycho-osteodystrophy and mental retardation (D.O.O.R. syndrome). Humangenetik 26:261265, 1975. 27. Swart E, et al: Congenital ectodermal defect with nail dystrophy and resorption of terminal phalanges. Br J Dermatol 82:93, 1970. 28. Coffin GS, Siris E: Mental retardation with absent fifth

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fingernail and terminal phalanx. Am J Dis Child 119:433-439, 1970. 29. Weiswasser WH: Coffin-Siris syndrome. Two new cases. Am J Dis Child 125:838-840, 1973. 30. Feingold M: The Coffin-Siris syndrome. Am J Dis Child 132:660-661, 1978. 31. Carey JC: The Coffin-Siris syndrome: Five new cases including two siblings. Am J Dis Child 132:667-671, 1978. 32. Jones KL: The Williams elfin facies syndrome. J Pediatr 5:718-723, 1975. 33. Hudson CD: Autosomal dominant hypodentia with nail dysgenesis. Report of twenty-nine cases in six families. Oral Surg 39:409-423, 1975. 34. Giansanti JS: The "tooth and nail" type autosomal dominant ectodermal dysplasia. Oral Surg 37:576-582, 1974. 35. Pajarre R, Matti K: Nail changes as first manifestations of HLA-B27 inheritance. A case report. Dermatologica 154:350-354, 1977. 36. Aho K: HLA antigen 27 and reactive arthritis. Lancet 2:157, 1973. 37. Aho K: HLA 27 in reactive arthritis. A study of yersinia arthritis and Reiters disease. Arthritis Rheum 17:521526, 1974. 38. Goldman L, Blaney DS, Cohen W: Onychodystrophy after topical 5-fluorouracil. Arch Dermatol88:529-530, 1963. 39. Fredriksson T: Topically applied fluorouracil in the treatment of psoriatic nails. Arch Dermatol 110:735736, 1974. 40. Gonglaves JCA: 5-Fluorouracil in treatment of common warts of the hands. Double blind study. Br J Dermatol 92:89-91, 1975. 41. Hursthouse M: Treatment of warts with 5-fluorouracil. Br J Dermatol 83:218, 1980. 42. Shelley W: Onycholysis due to topical 5-fluorouracil. Acta Derm Venereol (Stockh) 52:320-322, 1972. 43. Tanenbaum MH: Onychodystrophy after topically applied fluorouracil for warts. Arch Dermatol 103:225226, 1971. 44. Katz ME, Hanson TW: Nail plate-nail bed separation. An unusual side effect of systemic fluorouracil administration. Arch Dermatol 115:860-861, 1979. 45. Byren JP: Contraceptive pill-induced porphyria cutanea tarda presenting with onycholysis of the fingernails. Postgrad Med J 52:535-538, 1976. 46. Kestel JL: Tetracycline-induced onycholysis unassociated with photosensitivity. Arch Dermatol 106:766, 1972. 47. Baker H: Photo-onycholysis caused by tetracyclines. Br Med J 2:519-520, 1977. (Letter.) 48. Bethell HJ: Photo-onycholysis caused by dernethylchlortetracycline. Br Med J 2:96, 1977. 49. Bettley FR, Samman PD: Photo-onycholysis. Proc R Soc Med 67:600, 1974. 50. Rothstein MS: Onycholysis through phototoxicity. Arch Dermatol 113:520-521, 1977. (Lettcr.) 51. Zala L, et al: Photo-onycholysis induced by 8 methoxypsoralen. Dermatologica 154:203-215, 1977. 52. Rau RC: Photo-onycholysis secondary to psoralen use. Arch Dermatol 114:448, 1978. (Letter.)

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53. Briffa DV, et al: Photo-onycholysis caused by photochemotherapy. Br Med J 2:1150, 1977. (Letter.) 54. Warin AP: Photo-onycholysis secondary to psoralen use. Arch Dermatol 115:235, 1979. (Letter.) 55. Kirkham N: Nail dystrophy after practolol. Lancet 2:1137,1976. 56. Baran R: Pigmentations of the nails (chromonychia). J Dermatol Surg Oncol 4:250-254, 1978. 57. PIewig G, Lincke H, Wolff H H: Silver-blue nails. Acta Derm Venereol (Stockh) 57:413-419, 1977. 58. Zaias N: III The nail. New York, 1980, Spectrum Publishers, p. 123. 59. Lerner AB, McGuire JS: Melanocyte-stimulating hormone and adrenocorticotrophic hormone. N Engl J Med 270:539-546, 1964. 60. Bondy PK, Harwick HJ: Longitudinal banded pigmentation of nails following adrenalectomy for Cushing's syndrome. N Engl J Med 281:1056·1057, 1969. 61. Arakawa S, Takamatsu T, Imashuky S, Kusunoki T: Plasma ACTH and melanocyte-stimulating hormone in nail pigmentation. Arch Dis Child 53:249-255, 1978. 62. Shetty MR: Case of pigmented banding of the nail caused by bleomycin. Cancer Treat Rep 61:501-502, 1977. 63. Malacarne P, Zavagi G: Melphalan-induced melanonychia striata. Arch Dermatol Res 258:81-83, 1977. 64. Morris D: Horizontal pigmented banding of the nails in association with adriamycin chemotherapy. Cancer Treat Rep 61:499;501, 1977. 65. Shah PC, Rao KRP, Pate AR: Cyclophosphamideinduced nail pigmentation. Br J Dermatol 98:675-680, 1978. 66. Moore G, Meiselbaugh D: Hyperpigmentation after cancer chemotherapy. Lancet 2: 128, 1975. 67. Carcia RL: Hydroquinone nail pigmentation. Arch DermatoI114:1402-1403, 1978. (Letter.) 68. Coskey RJ: Onycholysis from sodium hypochlorite. Arch Dermatol 109:96, 1974. 69. Bart RS, Andrade R, Kopf AW, et al: Acquired digital fibrokeratomas. Arch Dermatol 97:120-129, 1968. 70. Steel HH: Garlic-clove fibroma. JAMA 191: 10821083, 1965. 71. Cahn RL: Acquired periungual fibrokeratoma, a rare benign tumor previously described as garlic-clove fibroma. Arch Dermatol 113:1564-1568, 1977. 72. LoBuono P, Jotikumar T, Kornblee L: Acquired digital fibrokeratoma. Cutis 24:50-51, 1979. 73. Verallo VVM: Acquired digital fibrokeratomas. Br J Dcrmatol 80:703-736, 1968. 74. Mathewson MH: Subungual exostoses of the fingers. Are they really uncommon? Br J DermatoI98:187-189, 1978. 75. Zimmerman EH: Subungual exostosis. Cutis 19:185188, 1977. 76. Cohen HJ, Frank SB, Minkin W, Gibbs RC: Subungual exostoses. Arch Dermatol 107:431-432, 1973. 77. Evison G, Price CHG: Subungual exostosis. Br J Radiol 39:451-454, 1966. 78. Apfelberg DB, Druker D, Maser M, Lash H: Subungual osteochondroma. Arch Dcrmatol 115:472-474, 1979. 79. Yaffee H: Peculiar nail dystrophy caused by an enchondroma. Arch Dermatol 91:361,1965.

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80 . Shelley WB, Ralston EL: Paronychia due to an enchondroma. Arch Dennatol 90:412-413, 1964. 81. St. Onge RA, Jackson IT: Uncommon sequel to thumb traum a: Epidermoid cyst. Hand 9:52-55, 1977 . 82 . Zodak I, Cohen HG: Epidermoid cy st of the terminal phalanx of a finger . With a review of the literature . Am J Surg 85:771-774, 1953. 83 . Schneider LH : The glomus tumor. Am Fam Physician 12:140-141, 1975 . 84 . Camirand P, Giroux JM : Subungual glomus tumor, radiological manifestations. Arch Dennatol 102:677679, 1970. 85 . Coskey RJ, Mehregan A, Fosnaugh R: Bowen's disease of the nail bed. Arch Dennatol 106:79 -80, 1972. 86 . Dietman DF: Bowen disease of the nail bed . Arch Dermatol 108:577-588, 1973. 87 . Mikhail GR: Bowen disease and squamous cell carcinoma of the nail bed. Arch Derm atol 110:267-270, 1974 . 88. Shapiro L, Baraf CS: Subungual epithelial carcinoma and keratoacanthoma . Cancer 25:141-152, 1970. 89. Nelson L, Hamilton CF : Primary carcinoma of the nail bed . Arch Derm atol 101:63-67 , 1970 . 90 . Long PI , et al: Squamous cell carcinoma of the nail bed. JAMA 239:2154-2155, 1978 . 91. Albom MJ: Squamous-cell carcinoma of the finger and nail bed: A review of the literature and treatment by the Moh s ' surg ical technique. J Denn Surg 1:43-48, 1975. 92. Macaulay WL: Subungual keratoacanthoma. Arch Dermatol 112:1004-1005, 1976. 93 . Mehregan AH: Keratoacanthoma of nail bed. Int J Dennatol 12:149-151, 1973. 94 . Lamp JC, Graham JH, Urbach F, Burgoon CF : Keratoacanthoma of the subungual region . J Bone Joint Surg 46:1721-1731, 1964. 95. Canipe TL, Howell JA, Howell CM: Subungual carcinoma. Plast Reconstr Surg 33:263-265, 1964. 96. Alpert LI, Zak FG, Werthamer S: Subungual basal cell epithelioma. Arch Dermatol 106:599, 1972. 97. Hoffman S: Basal cell carcinoma of the nail bed. Arch Dermatol 108:828, 1973. 98 . Kopf AW, Bart RS: Malignant melanoma. J Dennatol Surg Oncol 3:49-53, 1977. 99 . Kopf AW , Bart RS, Rodriguez-S ains RS, Ackerman AB : 11/ Malignant melanoma. New York, 1979, Masson Publi shing USA, Inc., pp . 109-123 . 100. Arrington JH , Reed RJ , Ichinose H, et al: Acral leniiginous melanoma: A distinctive vari ant of human cutaneou s malignant melanoma . Am J Surg Pathol 1:131-136, 1977. 101. Seiji M, Mihm MC, Sober AJ , Takahashi M, Kato T, Fitzp atrick TB : Malignant mel anoma of the palmarplantar-subungual-mucosal type: Clinical and histopathological features, in Proceedings of 10th Internation al Pigment Cell Conference, Boston, 1977. Basel, S. Karger AG. (In press.) 102. Pack GT , Oropeza R: Subungual melanoma. Surg Gynecol Ob stet 124:571-582, 1967. 103. Leppard B: Subungual mali gnant melanoma: Difficulty in diagnosis. Br Med J 1:310-312, 1974 . 104. Baran R: Longitudinal melanot ic streaks as a clue

105.

106. 107. 108. 109. 110. III . 112.

113.

114.

115. 116.

117. 118.

119.

120. 121. 122.

123.

124. 125.

126.

to Laugier-Hunziker syndrome . Arch Dermatol 115: 1448-1449, 1979. Laugier P, Hunziker N, Olmo s L: Pigmentation Melaniq ue lenticulaire es sentielle de la mugeuse ju gale et des leures, Ann Dennatol Venereol 104:181-184, 1977 . Zaias N, Oertel I, Elliot DF: Fungi in toen ails. J Invest Dcrrnatol 53:140-142, 1969. Gentles JC : Laboratory investigation of dermatophyte infections of nails. Sabouraudia 9:149-152 , 1971. Davie s RR : Mycological test s and onychomycosis. J Clin Pathol 21:729-730, 1968. English MP: Nails and fungi. Br J Dermatol 94:697701, 1976. Zaias N: Onychomycosis. Arch Derm atol 105:263-274, 1972. English MP, Atkinson R: Onychomycosis in elderly chiropody patients. Br J Derm atol 91:67-69, 1974. Campbell CK: Fungal infection of the skin and nails by Hendersonula toruloidca. Br J Dcrm atol 89:45-52, 1973 . Campbell CK: Studies on Hcndersonula toruloidca isolated from human skin and nail. Sabouraudia 12: 150156. 1974. Gentles JC, Evans EGV: Infection of the feet and nails with Hendersonula toruloidea. Sabouraudia 8:72-75, 1970 . Sarnm an PD, White WF: The yellow nail syndrome. Br J Dcrmatol 76:153-157 , 1964. Moran MF, et al: Upper respiratory problems in the yellow nail syndrome. Clin Otolaryngol 1:333-336, 1976 . Qu in JD , Elleman JH : Yellow nail syndrome . Arch Dermatol 115:734-735, 1979. Hiller E, Rosenow EC, Olson AM : Pulmonary manifestations of yellow nail syndrome . Chest 61:452-458, 1972. Lithner F: Purpura, pigmentation and yellow nails of lower extremities in diabetics . Act a Med Scand 199: 203-208, 1976. Kleinman PK: Congenital lymphedema and yellow nails. J Pediatr 83:454-456. 1973. Chan HL, Kok TH, Khoo OT: Cronkhite-Canada syndrome in a Malay. Arch Dcrmatol 115:98-99, 1979. Cronkh ite LW, Canada WJ: Generalized ga strointestinal polyposis, pigmentation, alopecia, and onychotrophia . N Engl J Med 252 :1011-1015 , 1955. Chevrant-Breton J, Simon M, Bourel M, Ferrand B: Cut aneous manife station s of idiopathic hemochromatosis. Arch Dermatol 113:161-165. 1977. Jalili MA, Al-Kassab S: Koilonychi a and cystine content of nails. Lancet 2:108-110 , 1959. Bazex A, Salvador R, Durpre A, et al: Syndrome paraneoplasique a type dhyperkeratose des extrernites: Gueri son apres traitement de I'cpithelioma larynge. Bull Soc Fr Dermatol Syphiligr 72:1 82 , 1965. Bazex A , Dupre A, Christol B: Dcrmatose psoriasiforme d 'etiologic canccreuse: Acrokcratose paraneopla stique, ill Report of the 13th Congress of the Associat ion of French-speaking Dermatologists, Turin, June 7-9.1969. Paris, 1971, Ma sson & Cie ., p . 368.

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127. Baran E: Paraneoplastic acrokeratosis of Bazex , Arch DermatoI113:1613, 1977. 128. Zaias N: Psoriasis of the nail. A clinical-pathologic study. Arch Dermatol 99:567-579, 1969. 129. Lewin K, et al: Pathology of the finger nail in psoriasis. A clinicopathological study. Br J DermatoI86:555-563, 1972. 130. Zaias N: The nail in lichen planus. Arch Dermatol 101:264-271, 1970. 13l. Sarnrnan P: The nails in disease. Springfield, 1972, Charles C Thomas, Publisher, pp. 61-65. 132. Ronchese F: Nail in lichen planus. Arch Dermatol 91:347-350, 1965. 133. Burgoon CF Jr, Kostrzewa RM: Lichen planus limited to the nails. Arch DermatoIIOO:371, 1969. 134. Cornelius CE III, Shelley WB: Permanent anonychia due to lichen planus. Arch DermatoI96:434-435, 1967. 135. Scher R, Fischbein R, Ackerman AB: Twenty-nail dystrophy. Arch Dermatol 114:612-613, 1978. 136. Hazelrigg DE, Duncan C, Jarratt M: Twenty-nail dystrophy of childhood. Arch Dermatol 113:73-75, 1977. 137. Baran R: Vertical striated sandpaper nails. Arch Dermatol 113:1613, 1977. 138. Wenscher B, Thormann J: Permanent anonychia after Stevens-Johnson syndrome. Arch Dermatol 113:970, 1977. 139. Chanda JJ, Callan JP: Stevens-Johnson syndrome. Arch Derrnatol 114:626, 1978. (Letter.) 140. Farber EM, South DA: Urea ointment in nonsurgical avulsion of nail dystrophies. Cutis 22:689-692, 1978. 14l. Arnold HL, Rees RB: Report of Pacific Dermatologic Association, Sept. 18-21, 1978. J AM ACAD DERMATOL 1:83-94, 1979.

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142. Abell E, Sarnman PD: Intradermal triamcinolone treatment of nail dystrophies. Br J Dermatol 89: 191-197, 1973. 143. Abell E: Treatment of psoriatic nail dystrophy. Br J Dermatol 86:79-82, 1972. 144. Bedi TR: Intradermal triamcinolone treatment of psoriatic onychodystrophy. Dermatologica 155:24-27, 1977. 145. Marx JL, Scher RK: The response of psoriatic nails to oral photochemotherapy. Arch Dermatol, 1980. (In press.) 146. Storrs FJ: Use and abuse of systemic corticosteroid therapy. J AM ACAD DERMATOL 1:95-105, 1979. 147. Lilt JZ: Don't excise-exorcise. Treatment for subungual and periungual warts. Cutis 22:673-676, 1978. 148. Epstein E: A simple technique for managing digital mucous cyst. Arch Dermatol 115:1315-1316, 1979. 149. Scher RK: Punch biopsies of nails: A simple valuable procedure. J Dermatol Surg Oncol 4:528-530, 1978. 150. Alborn MJ: Avulsion of a nail plate. J Dermatol Surg Oncol 3:34-35, 1977. 151. Fosnaugh RP: Surgery of the nail, ill Epstein E, Epstein E Jr, editors: Skin surgery. Springfield, 1977, Charles C Thomas, Publisher, pp. 728-732. 152. Zaias N: The longitudinal nail biopsy. J Invest DermatoI49:406-408, 1967. 153. Bennett RG: Techniques of biopsy of nails. J Dermatol Surg 2:325-326, 1976. 154. Baran R, Sayag J: Nail biopsy. Why, when, where, how? J Dermatol Surg 2:322-324, 1976.