Diseases Affecting the Nail Unit

Brad Merritt MD

Richard K. Scher MD

The nail unit is an essential component of the integumentary system that can be affected by primary diseases, dermatologic disorders with nail involvement, and systemic illnesses that alter the appearance of the nails. Primary nail disorders, as in the case of subungual melanoma and subungual squamous cell carcinoma, can be life threatening. Secondary nail changes can be a sign of underlying life-threatening diseases such as severe renal, hepatic, and cardiovascular disease. The nail unit’s most important functions are to protect the distal digit and to improve dexterity in manipulating small objects. By providing counterpressure, the nail plate enhances the transmission of delicate sensations. Perhaps more important from an evolutionary standpoint, the nail unit facilitates scratching and grooming. Disorders of the nail unit can be physically and psychologically distressing to patients, because nails often serve socially as a cosmetic enhancement. This chapter reviews common and serious nail disorders, including those caused by infectious, traumatic, neoplastic, congenital, and primary dermatologic disorders.

A complete history and physical examination should be included in any evaluation of a patient with a nail disorder. A medication history is important and systemic diseases should be noted, as these factors often affect the appearance of the nail unit. The family history can give clues to hereditary nail abnormalities as can be found in the nail-patella syndrome (osteo-onychodysplasia), ectodermal dysplasia, pachyonychia congenita, and Darier’s disease (keratosis follicularis). An occupational history can provide insight into possible allergic or irritant exposures. Treatments of the nail, including prior medical/surgical modalities, home remedies, and manicures/pedicures, are important to note because they can be factors contributing to persistent nail disease. All 20 nails should be examined. A magnifying glass can be employed to enhance fine details. A dermatoscope can be helpful when evaluating the nail folds for signs of connective tissue disease and the nail plate for melanonychia striata. A complete skin examination, including the oral mucosa, is also important. Subtle lesions can give clues as to the cause of nail disorders. Laboratory tests useful in the evaluation of nail disease include biopsy of the nail plate, cuticle, bed, or matrix, fungal cultures, bacterial cultures, and potassium hydroxide preparations. Imaging modalities including plain film and magnetic resonance imaging (MRI) can be helpful in determining the extent of disease and evaluating possible involvement of bone underlying the nail apparatus.

Anatomy of the Nail Unit

The nail unit is a specialized appendage of the skin, composed of unique structures not found elsewhere in the body. The nail unit consists of the nail plate, proximal and lateral nail folds, cuticle, nail matrix, nail bed, and the hyponychium (Fig. 33-1). What most people commonly consider the nail refers to the nail plate, which is the clear, hard portion of the nail made of keratin. The nail plate is divided into two sections: the dorsal plate that is created by the proximal nail matrix and the ventral plate that is created by the distal nail matrix with some contribution from the nail bed. The nail matrix is composed of a group of germative cells located proximal to the nail plate. The nail matrix contains a layer of actively dividing keratinocytes that mature and, after death, contribute to the formation of the nail plate. The nail plate is bordered by the proximal nail fold and two lateral nail folds. The lunula is the most distal portion of the matrix, visible as a white, half-moon-shaped area under the nail plate bordered by the proximal nail fold. The nail plate rests on the highly vascular nail bed. The hyponychium is the section of the skin located under the free edge of the nail plate between the nail bed and the distal nail groove.

Fingernails grow constantly at a rate of 0.1 mm/d or 3 mm/mo. At this rate, a fingernail can be totally replaced in 4 to 6 months. Toenails, however, grow at about half this rate and can take 8 to 12 months to be totally replaced. Certain disease states including psoriasis, minor trauma, pityriasis rubra pilaris, the brittle nail syndrome, hyperpituitarism, and hyperthyroidism can cause nails to grow at a faster rate than normal. Slower nail growth has been noted in patients with malnutrition, acute infections, peripheral neuropathy, onychomycosis, and hypothyroidism as well as in smokers. The rate of nail growth can also be affected by a variety of medications.

Onychomycosis

Onychomycosis refers to fungal infection of the nail. Onychomycosis is the most common nail disorder and accounts for up to half of all nail problems encountered in clinical practice. The prevalence of onychomycosis increases with age. Other risk factors for developing onychomycosis include
smoking, peripheral arterial disease, recurrent trauma, diabetes mellitus, family history, and immunosuppression including HIV infection. Fungal infections of the nail may be caused by dermatophytes (tinea unguium), nondermatophyte molds, or yeast. More than 90% of cases of onychomycosis are caused by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Onychomycosis has been classified into five major types:

distal and lateral subungual onychomycosis,
superficial white onychomycosis,
proximal subungual onychomycosis,
endonyx onychomycosis, and
total dystrophic onychomycosis.

Clinical signs of onychomycosis include

thickening of the nail bed and nail plate,
subungual debris,
onycholysis (separation of the nail plate from the nail bed),
nail discoloration (white/yellow or orange/brown patches or streaks),
ridging of the nail, and
nail pitting.

FIGURE 33-1 ▪ Anatomy of the nail unit. KZ, keratogenous zone. (Reprinted from Hordinsky MK, Sawaya ME, Scher ME. Histology of the normal nail unit. In: Atlas of Hair and Nails. 1st ed. Philadelphia: Churchill Livingstone; 2000:19. Copyright 2000, with permission from Elsevier.)

Diagnosis

Before treating patients with clinical evidence of onychomycosis, the diagnosis should be confirmed by (1) direct microscopy of nail debris using a preparation of potassium hydroxide (KOH) with or without dimethyl sulfoxide or chlorazol black, or (2) fungal culture, or (3) histologic examination of the nail plate with periodic acid-Schiff (PAS) stain. Collection of an appropriate specimen is crucial to avoid a false-negative or false-positive result. In general, it is best to obtain a sample from the most proximal, central area of involved nail. Direct microscopy allows for rapid diagnosis but does not provide information for speciation. Fungal culture, while the least sensitive test, can be important for identifying the causative organism, especially in treatmentresistant cases. Histologic examination with PAS is the most sensitive test for onychomycosis and has the highest negative predictive value. It is also the most expensive and should be reserved for cases when direct microscopy is unavailable or negative but clinical suspicion is high.

Presentation and Characteristics

Distal and lateral subungual onychomycosis is the most common form of onychomycosis (Fig. 33-2). The first sites of fungal invasion are the hyponychium or the lateral nail fold. Onycholysis occurs when subungual keratotic debris separates the nail plate from the nail bed. Paronychia can also occur. The nail bed is the ideal site for obtaining a specimen for microscopic examination. The most common organisms associated with distal and lateral subungual onychomycosis are the dermatophytes T. rubrum and T. mentagrophytes. Candida albicans and Candida parapsilosis are less frequently responsible, while the nondermatophyte molds, including Scopulariopsis brevicaulis, Aspergillus species, Acremonium species, and Fusarium oxysporum, are the least common causative organisms.

FIGURE 33-2 ▪ Distal and lateral subungual onychomycosis.

Superficial onychomycosis can be divided into white superficial onychomycosis and black superficial onychomycosis. White superficial onychomycosis is the most common of the two and is also known as leukonychia trichophytica and leukonychia mycotica. The first, second, and third toenails are more likely to be affected, and the exposed dorsal surface of the nail plate is the site of fungal invasion. Clinically, white superficial onychomycosis presents on the nail plate as white, opaque islands with distinct edges. Untreated lesions can develop a yellow color. Because of the superficial nature of the infection, organisms can often be scraped from the nail plate surface. White superficial onychomycosis is most often caused by the dermatophyte T. mentagrophytes var. interdigitale but can also be caused by T. rubrum as well as by molds including Aspergillus, Acremonium, and Fusarium spp. White superficial onychomycosis caused by T. rubrum often leads to more extensive nail involvement and is seen in otherwise healthy children and in patients infected with HIV. White superficial onychomycosis secondary to molds can be clinically indistinguishable from disease caused by dermatophytes, but can also lead to deeper, more extensive involvement of the nail. Black superficial onychomycosis presents with black, opaque plaques on the nails secondary to invading fungi that are pigmented. This variant occurs with Scytalydium dimidiatum and T. rubrum.

Endonyx onychomycosis is a fungal infection of the nail in which both the superficial and deep layers of the nail plate are affected without resulting in nail bed inflammatory changes. Tunnels formed by and filled with invading fungi may be present. Clinically, this appears as a milky-white discoloration of the nail plate that is not accompanied by subungual hyperkeratosis or onycholysis. There is lamellar splitting of the nail plate. Endonyx onychomycosis is caused by Trichophyton soudanense and Trichophyton violaceum.

Proximal subungual onychomycosis is a relatively uncommon subtype that occurs secondary to fungal invasion at the proximal nail fold through the cuticle. Clinically, it is a whitish discoloration of the proximal nail plate along with proximal subungual hyperkeratosis and onycholysis. The distal end of the nail plate appears normal in early infection. Proximal subungual onychomycosis can be seen with or without paronychia. In patients without paronychia, proximal subungual onychomycosis is usually caused by T. rubrum. In patients with paronychia, proximal subungual onychomycosis is usually secondary to C. albicans. Proximal subungual onychomycosis can also be caused by Aspergillus, Fusarium, and Scopulariopsis spp. Proximal white subungual onychomycosis with rapid progression is a variant most often associated with immunocompromised conditions, especially HIV infection. T. rubrum is the most common pathogen. Because of the association with HIV, clinicians should consider laboratory testing to investigate the patient’s immune status when a diagnosis of proximal white subungual onychomycosis is made.

Total dystrophic onychomycosis can be primary or secondary. Secondary total dystrophic onychomycosis usually occurs because of extensive fungal infection involving the entire nail plate from distal and lateral subungual onychomycosis or proximal subungual onychomycosis. The entire nail plate is extensively thickened and can easily collapse. Primary total dystrophic onychomycosis is seen in patients with chronic mucocutaneous candidiasis and is caused by infection of all portions of the nail unit by Candida.

Differential Diagnosis

A variety of diseases of the nail can mimic onychomycosis and must be considered in the differential diagnosis. Only 40% to 50% of abnormal appearing toenails are actually due to onychomycosis. Possible simulators of onychomycosis include psoriasis, chronic onycholysis, lichen planus, alopecia areata, chronic paronychia, hemorrhage/trauma, onychogryphosis, aging, median canaliform dystrophy, pincer nail deformity, yellow nail syndrome, subungual malignant melanoma, and subungual squamous cell carcinoma. Any of these disease states can coexist with onychomycosis, and proof of dermatophyte infection in the nail (Fig. 33-3) does not exclude a separate, concurrent disease of the nail unit.

Treatment

Therapy for onychomycosis depends on the pattern of infection, pathogen, and degree of involvement. Treatments include oral and topical medications, as well as periodic clipping and filing of infected portions of the nail plate. White superficial onychomycosis involving less than the distal two thirds of the nail plate and moderate distal and lateral subungual onychomycosis can be treated effectively with the topical fungicidal lacquers ciclopirox and amorolfine. These lacquers have a broad range of antifungal activity against dermatophytes, as well as C. albicans. Additionally, ciclopirox has antibacterial and anti-inflammatory actions. Lacquers are less effective than oral treatments, but can be useful in patients with onychomycosis who cannot tolerate oral antifungals because of liver or kidney disease, or those taking multiple systemic medications where drug interactions may be a concern.

FIGURE 33-3 ▪ High-power microscopic view of a dermatophyte in the nail plate (PAS stain; original magnification 400×). (Courtesy of Dr. George W. Niedt.)

The first-line treatment for onychomycosis is oral terbinafine, an allylamine fungicidal medication. A metaanalysis of randomized clinical trials found terbinafine to be superior to placebo, itraconazole, fluconazole, and griseofulvin in achieving mycological cure in patients with onychomycosis. Terbinafine also demonstrates the lowest post-treatment recurrence rates. Typical dosing for terbinafine is 250 mg daily for 12 weeks for toenails and 6 weeks for fingernails. While previously considered cost-prohibitive by many patients, the cost of treatment with terbinafine has been significantly reduced with the advent of $4 generic plans that are now available at many pharmacies.

Other systemic medications used to treat onychomycosis include the azole antifungals itraconazole and fluconazole. Itraconazole can be given as 100 mg twice daily for 12 weeks for toenails or 6 weeks for fingernails. Alternatively, itraconazole can be pulsed at 200 mg twice daily for 1 week per month for 3 months for toenails and 2 months for fingernails, lowering the risk for hepatotoxicity. Various pulse therapies have also been advocated for oral terbinafine therapy but are generally less effective than continuous therapy. Fluconazole can be dosed from 150 to 300 mg once per week until the nails are clear but has a low clearance rate. Griseofulvin is a fungistatic medicine that must be taken until the entire nail is replaced. For this reason, as well as inferior efficacy compared to newer treatments and potential interactions with warfarin and oral contraceptives, griseofulvin is no longer used frequently for onychomycosis. Ketoconazole is also used infrequently for onychomycosis because of possible hepatotoxicity. Hepatotoxicity has been reported with itraconazole, fluconazole, and terbinafine, in decreasing order of frequency. Monitoring of liver enzymes is advised during continuous therapy. Systemic treatments for onychomycosis are generally well tolerated, with gastrointestinal side effects and headaches occurring most commonly. Combining oral and topical treatments may allow for shorter courses with higher cure rates.

Factors indicating a likely poor response to treatment with oral therapy include lateral nail disease, proximal nail disease, involvement of the entire nail unit, longitudinal streaks of fungal infection in the nail plate, presence of a dermatophytoma (a mass of fungi between the nail plate and the nail bed), and extensive onycholysis. If a dermatophytoma is present, removing the portion of nail plate overlying it and removing the concentration of fungi can help to achieve a cure. Candida onychomycosis can be more difficult to treat. Terbinafine is slightly less effective than itraconazole in achieving cure in onychomycosis secondary to Candida spp.

Onychomycosis is difficult to cure permanently. Many patients have recurrent infections. Factors associated with recurrent disease include persistent predisposing conditions such as peripheral vascular disease, diabetes mellitus, recurrent trauma, older age, as well as insufficient treatment from early termination or an insufficient dose of medication. Several measures have been suggested to avoid recurrence of onychomycosis. These include wearing footwear when walking in areas of high concentrations of dermatophytes (e.g., communal areas by pools, spas), avoiding shoes that may have dermatophytes present, drying feet (and interdigital spaces) after a bath or shower, using socks made of absorbent material (highly wicking socks), treating concurrent tinea pedis, using powder such as Zeasorb AF (very absorbent and has miconazole) to shake into shoes or socks, and prophylactic use of topical antifungal agents.

Paronychia

Paronychia is defined as acute or chronic inflammation of the nail fold, typically with an associated infection. Acute paronychia is usually preceded by trauma that facilitates bacterial inoculation of the nail fold. It affects the digit with rapid development of erythema, tenderness, and in more advanced disease, purulent discharge. Untreated, acute paronychia can lead to a subungual abscess and nail dystrophy. The most commonly associated organism is Staphylococcus aureus, but Streptococcus pyogenes, Pseudomonas pyocyanea, Proteus vulgaris, and anaerobic bacteria have also been cultured from acute paronychia. Herpes simplex virus can cause recurrent acute paronychia in the form of herpetic whitlow. Pemphigus vulgaris is also associated with acute paronychia.

Chronic paronychia is defined as inflammation of the nail fold present for at least 6 weeks that develops from repeated exposure to moisture, irritants, and allergens. Patients present with erythema, swelling, and tenderness of the nail
folds. Nail plate thickening, ridging, and discoloration can occur. Chronic paronychia most commonly affects patients with repeated exposure to a moist environment, including cooks, dishwashers, laundry workers, and nurses. Candida is often present, but its role in the pathogenesis is unclear. Chronic paronychia has been associated with isotretinoin (Accutane), protease inhibitors, and the epidermal growth factor inhibitors.

Diagnosis

Squamous cell carcinoma, subungual melanoma, and metastatic carcinoma can simulate paronychia and are important to exclude. In patients with acute paronychia that responds poorly to conventional treatment, cultures can be beneficial in identifying the causative organism. The prevalence of skin infections secondary to methicillin-resistant S. aureus is increasing, and culture may be necessary to rule out this pathogen. If vesicles are present, herpetic whitlow should be suspected and a Tzanck smear and/or HSV culture or less often PCR should be performed. Biopsy should be considered in treatment of refractory cases or if there is any suspicion of a neoplastic process.

Treatment

Mild acute paronychia responds well to warm compresses and topical antibacterial treatment. More severe and persistent disease often requires oral antibiotics or incision and drainage. Surgical drainage effectively treats acute paronychia and is indicated if an abscess has formed. Herpetic whitlow can be treated with acyclovir, valacyclovir, or famciclovir. Incision and drainage should be avoided if the presence of HSV is confirmed.

Chronic paronychia is best treated by avoidance of moisture and irritants. Patients should be advised to avoid manipulation of the cuticle, which is important in preventing entry of microorganisms. Topical antifungal treatment is also recommended because of the presence of Candida. Topical corticosteroids are the treatment of choice, however, especially if inflammation is prominent. A randomized trial found greater improvement of chronic paronychia treated with topical steroids compared to topical antifungal therapy.

Nail Psoriasis

Nail involvement in psoriasis is common, occurring in up to half of all patients with psoriasis. Psoriatic nail changes are especially common in patients with psoriatic arthritis. Most patients with nail involvement have classic skin lesions as well, but nail disease can occur in the absence of cutaneous psoriasis. Clinical features of nail psoriasis include