The Diagnosis and Treatment of Nail Disorders
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Background: Nail disorders can arise at any age. About half of all nail disorders are of infectious origin, 15% are due to inflammatory or metabolic conditions, and 5% are due to malignancies and pigment disturbances. The differential diagnosis of nail disorders is often an area of uncertainty.
Methods: This review is based on publications and guidelines retrieved by a selective search in PubMed, including Cochrane reviews, meta-analyses, and AWMF guidelines.
Results: Nail disorders are a common reason for dermatologic consultation. They are assessed by clinical inspection, dermatoscopy, diagnostic imaging, microbiological (including mycological) testing, and histopathological examination. Some 10% of the overall population suffers from onychomycosis, with a point prevalence of around 15%. Bacterial infections of the nails are rarer than fungal colonization. High-risk groups for nail disorders include diabetics, dialysis patients, transplant recipients, and cancer patients. Malignant tumors of the nails are often not correctly diagnosed at first. For subungual melanoma, the mean time from the initial symptom to the correct diagnosis is approximately 2 years; this delay is partly responsible for the low 10-year survival rate of only 43%.
Conclusion: Evaluation of the nail organ is an important diagnostic instrument. Aside from onychomycosis, which is a common nail disorder, important differential diagnoses such as malignant diseases, drug side effects, and bacterial infections must be considered.
The nail primordia at the ends of the fingers and toes come into being from the 8th and 9th weeks of gestation onward; in the 13th week, the nail field and the nail matrix are formed. The latter gives rise to the nail plate from the 14th week onward. By the 20th week, the nail plate already covers the entire nail bed.
At birth, the nail plate extends beyond the tips of the fingers and toes (cf. eTable for an overview of mutations with relevance to nail organ development).
The mature nail organ comprises the nail matrix, the nail bed, the nail plate, and the nail fold. The proximal portion of the nail matrix is immediately adjacent to the distal interphalangeal joint and the insertion of the extensor tendon. The latter gives rise to a dense superficial connective-tissue lamina enveloping the nail matrix (e1). The distal portion of the nail matrix is attached to the nail bed. The nail plate covers the distal matrix and nail bed and ends in the free edge of the nail plate. The nail plate is covered proximally by the cuticle; it is held within the nail fold both proximally and laterally. The epithelium that directly covers the nail plate proximal to the cuticle is the eponychium. The horns of the nail plate, which lie under the lateral proximal nail fold, are connected to the bony distal phalanx. The nail bed is distally delimited by the nail isthmus, which is continuous with the hyponychium lying under the free edge of the nail plate. The most distally located structure is the distal groove (1). The isthmus of the nail is completely covered in congenital pterygium inversum unguis (2).
The nail plate consists mainly of parallel keratin filaments, which give it mechanical stability. Aside from minerals and cholesterol, about 7% of the content of the nail is water. The nail bed is essential for horizontal nail growth. The nail plate is 1000 times more permeable to water than the intact skin and can also be a site where exogenous substances are deposited, such as medications, drugs of abuse, and arsenic (3). The horizontal growth of the nail depends on an intact connection of the nail plate to the nail bed (e2). Fingernails generally grow faster than toenails (3.5 vs. 1.7 mm/month) (4).
This review is based on pertinent articles retrieved by a selective search in PubMed and the Cochrane Library, along with the pertinent guidelines of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF).
This article aims to enable the reader to
- understand the anatomy of the nail organ,
- recognize nail involvement in skin diseases and other medical conditions,
- diagnose the clinical features of the main types of tumor affecting the nail organ, and
- be aware of the main types of infectious disease affecting the nail organ and their treatment.
Nail involvement in inflammatory skin diseases
Nail involvement in psoriasis often points to the diagnosis. It is independent of the severity of skin involvement and can cause functional and cosmetic disturbances and pain (5, e3, e4). Nail symptoms are seen in two-thirds of all patients with psoriatic arthritis and in about 40% of psoriasis patients without arthritis (6, e5) (Table 1).
Psoriatic arthritis can be distinguished from rheumatoid arthritis by the combination of distal arthritis with nail changes.
A 46-year-old man presented with pain in one big toe with isolated yellowish thickening of the nail plate. His family physician had diagnosed gout, but medication to lower the uric acid level had not led to any sustained improvement.
The diagnosis of psoriatic onychopachydermoperiostitis (POPP) syndrome was established—a special type of psoriatic arthritis and an important element in the differential diagnosis of acute gout. An elevated uric acid level is often seen in psoriasis vulgaris because of accelerated cutaneous metabolism.
Nail symptoms are present in up to 66% of patients with severe alopecia areata, with speckling as the main type (e6, e7). Working with wet hands can cause irritative hand eczema, resulting in distal onycholysis and brittle nails (8). Allergic contact eczema with inflammation of the nail folds can be seen in acrylate sensitization due to the use of artificial nail extensions. Severe cases can be associated with destruction of the nail plate and acquired pterygium inversum unguis. Ordinary disinfection of the hands is ineffective in persons who have artificial nail extensions (9).
Nail symptoms in general medical disease
Inspection of the nail organs is part of the routine physical examination in internal medicine (Table 2). It can reveal a number of conditions:
- In the differential diagnosis of rheumatoid vs. psoriatic arthritis, the nails should be inspected for typical psoriatic changes (speckled nails, psoriatic oil spot, psoriatic onychomadesis) (5, e4).
- As many as 60% of persons with chronic renal disease have nail manifestations. The double transverse white lines known as Muehrcke lines are a sign of hypoalbuminemia (< 2.2 g/dL) hin (10).
- Distal ischemia of the acral skin in scleroderma is a cause of acquired irreversible pterygium inversum unguis (1, e8).
- Hourglass nails are a secondary phenomenon arising from clubbing of the fingers. Clubbing is due either to thickening of the soft-tissue covering of the distal phalanx, as in cor pulmonale, or to distal hypertrophic osteoarthropathy, as in chronic diseases of the lung or intestines, cancer (as a paraneoplastic phenomenon or as a manifestation of metastases), cardiac valvular anomalies, or Graves’ disease (1).
Drug-induced nail diseases
Nail symptoms arise in 10–60% of patients undergoing anticancer treatment (11) (Table 3). Chronic paronychia causes pain which restricts fine motor activity (12). Immunosuppressants and chemotherapeutic agents can damage the nail plate, leading to Beau-Reil transverse grooves and onychomadesis (reversible, painless, non-inflammatory proximal detachment of the nail plate) (e8).
Subungual and periungual tumors
Warts due to HPV are the most common type of benign growth affecting the nails. About 10% of all children and adolescents have HPV-induced ungual warts; precise data on the their epidemiology are unavailable. Combination therapy is more successful than monotherapy; for example, cryotherapy plus topical salicylic acid is more effective than salicylic acid alone (risk ratio 1.24) (13). Warts should be treated cautiously in order to avoid permanent iatrogenic nail dystrophy (14).
Granuloma teleangiectaticum arises as a sequela of trauma or infection. These lesions tend to bleed (15). Fibrokeratoma is an asymptomatic tumor of adulthood that usually arises as a solitary lesion measuring only a few millimeters (16). Koenen tumors are usually multiple, are of variable size, and appear periungually and subungually; half of all cases arise in persons under age 18. Koenen tumors are a major diagnostic criterion for the tuberous sclerosis complex (e9).
Subungual exostoses and mucoid pseudocysts can cause nail deformities. Painful types of nail tumor include glomus tumor, osteoid osteoma, and acquired digital arteriovenous malformation (ADAVM) (15, 16, 17, 18).
The most common malignancies affecting the nails are squamous cell carcinoma and Bowen’s disease (Figure 2e, f). The clinical manifestations of Bowen’s disease with periungual involvement are erythema, hyperkeratosis, fissures, and scaling; subungual involvement leads to onycholysis. Human pamillomavirus of types 16, 31, 33, 56, and 71 has been demonstrated (19). Nodules, hemorrhages, and ulceration are signs of invasive squamous cell carcinoma (e10). These tumors can arise spontaneously, after chronic arsenic exposure, or after organ transplantation (19, 20).
A 45-year-old woman presented to a dermatologist with progressive onychomadesis of the left thumbnail. Mycological cultures were negative. A nail bed biopsy revealed nonspecific inflammatory changes.
Onychodystrophy with destruction of the nail plate in the absence of fungal infection aroused the suspicion of a malignant tumor of the nail organ. A second biopsy performed some time later yielded the diagnosis of an acrolentiginous melanoma. The definitive treatment was a 3D-guided partial amputation of the distal phalanx of the thumb.
Subungual melanoma accounts for 2% of all melanomas in persons of European ancestry and up to 20% in persons of Asian ancestry (21). Timely nail biopsy enables the definitive diagnosis. Subungual melanoma cannot be reliably distinguished from longitudinal melanonychia by inspection alone.
Pigmentation of the cuticle and proximal nail fold (the Hutchinson sign) is typical of melanoma, though it is not seen in all cases (Figure 2a, c) (22, 23). Dermatoscopy, an optical technique, is useful for the differential diagnosis of nail pigmentation. It reveals individual pigment lines of varying color and intensity (Figure 2b, c–f). The additional information provided by dermatoscopy enables early detection of disease (23).
The Hutchinson sign is often absent in in situ or early invasive melanoma (Figure 2a) (24). Advanced melanoma is associated with ulcerations, hemorrhages, loss of parallelism of the bands, multiple colors, blurry borders, and marked invasion into the neighboring skin. Thicker tumors are more likely to infiltrate the bone as well (21). Subungual melanomas can also be amelanotic, in which case they are harder to recognize clinically. A biopsy to rule out melanoma is necessary for any patient with nail dystrophy, subungual hyperpigmentation, or persistent “hematomas” of unknown cause. Unfortunately, the mean delay from the onset of symptoms to surgery is 2.2 years. The prognosis of subungual melanoma is, therefore, much worse than that of cutaneous melanoma, with a disease-specific 10-year survival rate of only 43% (25, 26). It is treated with micrographically guided surgery (21, 22).
Infectious diseases of the nails
Onychomycosis is an infection of the nail apparatus by dermatophytes, yeasts, or molds. Tinea unguium (this is the plural form; if only one nail is affected, tinea unguis) is caused exclusively by dermatophytes. Fungal infections of the nails are stigmatizing for the patient, causing difficulties in both personal and professional life (27).
Onychomycoses are found all over the world (28). In Europe and the USA, their population-based prevalence is 4.3%; hospital-based studies reveal a prevalence of 8.9% (29). The prevalence increases with age and is highest in persons over age 65. Men are more commonly affected than women, children markedly less so.
The pathogen most commonly causing onychomycosis is Trichophyton rubrum, accounting for about 65% of cases. Molds are found in 13.3% of cases, yeasts in 21.1% (29). In the authors’ own retrospective study, the pathogens were dermatophytes in 68% of cases, yeasts in 29%, molds in 3%, and mixed flora in 5–15% (30).
Of all the dermatophytes isolated from patients with onychomycosis, T. rubrum is the most common species (ca. 91%), followed by T. interdigitale (earlier name: T. mentagrophytes var. interdigitale) (ca. 7.7%) (30). Rarely isolated organisms include Epidermophyton floccosum and T. tonsurans. These are anthropophilic dermatophytes, i.e., they cause disease only in humans.
Yeasts are emerging pathogens of onychomycosis that are now being more commonly diagnosed as the causative organisms of onychomycosis. Candida parapsilosis is the most common one, followed by C. guilliermondii. C. albicans causes chronic mucocutaneous candidiasis, which involves the entire nail apparatus (e11).
Molds, also called non-dermatophyte molds (NDM), are also being increasingly diagnosed as the causative organisms of onychomycosis (31). Scopulariopsis brevicaulis causes onychomycosis of the big toenails. Fusarium spp. is considered an emerging pathogen (28). Further mold pathogens include Onychocola canadensis (e12), Aspergillus fumigatus, Acremonium spp., Chrysosporium pannorum, Neoscytalidium dimidiatum (earlier name: Hendersonula toruloidea), Arthrographis kalrae, Chaetomium globosum as well as T. interdigitale, and Chaetomium globosum (31, 32, e13).
These infections can be transmitted within the family, e.g., in the home bathtub, either horizontally (from one spouse to the other) or vertically (across generations). Further sources of infection include swimming pools, bathhouses, saunas, sporting facilities, etc. Predisposing factors include prior nail trauma, advanced age (slower nail growth, poorer limb circulation), vascular diseases, lymph edema, diabetes mellitus, immune compromise, tinea pedis, psoriasis vulgaris, psoriasis unguium, and hyperhidrosis. Older persons often have multiple risk factors. Candida onychomycoses often affect immunosuppressed persons (33).
There is an autosomal dominant genetic predisposition to distal subungual onychomycosis due to T. rubrum (e14).
Onychomycosis is present in only about half of all pathological changes of the nails that visually suggest a fungal infection (e14). The differential diagnosis includes non-infectious nail diseases such as psoriasis unguium, lichen ruber, yellow nail syndrome, and tumors.
Toenails are affected much more often by onychomycosis than fingernails because of trauma (shoes) and underlying vascular diseases. Onychomycosis most commonly appears in the form of distal and/or lateral subungual onychomycosis. The pathogens invade the distal/lateral portion of the nail bed, leading to subungual hyperkeratosis, discoloration (dyschromia), and onycholysis (Figure 3).
In white superficial onychomycosis (leukonychia trichophytica), a rarer condition, the fungal pathogens invade from the surface of the nail plate. This condition exclusively affects toenails. The most common pathogen is T. rubrum; T. interdigitale is rare. The mold Fusarium spp. is a further cause.
In proximal subungual onychomycosis, the infection proceeds from the cuticle (particularly in immunosuppressed patients). The maximal variant of fungal disease of the nail is total dystrophic onychomycosis. In endonyx onychomycosis—caused in the tropics by T. soudanense—the nail plate is thickened. Candida onychomycosis is generally associated with paronychia (inflammation of the nail fold) (34).
Onychomycosis has broad differential diagnosis and cannot be diagnosed on clinical grounds alone (Figure 3). Mere inspection has the highest false-positive rate of any diagnostic method. Rather, the diagnosis should be based on mycological laboratory tests—either a potassium hydroxide preparation or an optical fluorescence preparation, along with growth of the pathogenic fungus in culture—in treatment-naive patients (the diagnostic gold standard). The histologic demonstration of fungi causing nail infections by means of the periodic acid Schiff (PAS) reaction after a punch biopsy of the nails, or nail clippings, is likewise highly sensitive. Neither the native preparation nor the histologically examined specimen enables determination of the genus or species of the responsible fungus; culture alone enables identification down to the species level (e15, e16). There are also newer molecular-biological methods such as the polymerase chain reaction (PCR) for the direct demonstration of dermatophyte DNA in nail specimens. A PCR enzyme immunoassay (EIA) with primers specifically directed against the topoisomerase II gene can directly detect the dermatophytes T. rubrum, T. interdigitale, and Epidermophyton floccosum in clinical material (35). Used as a complement to conventional fungal culture, the direct demonstration of pathogenic fungi in nail tissue by PCR, multiple-fungus PCR for the simultaneous identification of (for example) 20 relevant types of fungus, or real-time PCR for the detection of dermatophyte DNA enable much faster, highly sensitive, and very specific diagnosis (33). In vitro sensitivity testing, although a routine part of the work-up of bacterial infections, is not commonly done for fungi.
A limited onychomycosis that does not involve the matrix often responds to topical treatment alone. On the other hand, matrix involvement—often recognizable from the so-called yellow streaks—should be treated with a systemic antimycotic drug, generally in combination with a topical one. The decision on the optimal type of treatment is also based on the number of affected fingernails or toenails, the extent of nail involvement, multimorbidity, drug interactions, and the identified pathogen (Table 4). For topical use, water-soluble ciclopiroxolamine nail varnish is more effective than amorolfin (36).
Confirmed dermatophyte infections should be treated with terbinafin, fluconazole, or itraconazole, while confirmed Candida spp. infections are preferably treated with fluconazole. Either continuous or intermittent therapy is possible, depending on the preparation; terbinafin yields the highest response rate (37). Persons with liver disease should only be given systemic antimycotic drugs for strict indications. The recurrence rate of fungal nail infections within 36 months of the end of treatment ranges from 20% to 50% (e17).
Onychomycosis due to molds generally does not respond to systemic antimycotic treatment. In infections with Aspergillus species and Scopulariopsis brevicaulis, a trial of oral terbinafin may be successful. There remains the option of atraumatic nail removal with 40% urea (34). The utility of laser treatment for onychomycosis is debated (38, 39, 40).
Bacterial infections of the nails
Bacterial infections of the nails often arise out of acute or chronic paronychia, from which Staphylococcus aureus bacteria or streptococci can spread under the nail. Subungual bacterial infection can also be caused by Pseudomonas aeruginosa. Risk factors include repetitive minor trauma, working in damp conditions, onychotillomania (compulsive nail-picking or nail-tearing), psoriasis, thumb-sucking, diabetes mellitus, and immunosuppression. The greenish nail discoloration characteristic of Pseudomonas infection is probably caused by the diffusion of pyocyanin into the nail tissue, or else by bacterial invasion of the nail plate (e18).
There have not been any controlled clinical trials on the treatment of bacterial nail infections. There have been reports of the successful topical treatment of fingernail infections due to Pseudomonas aeruginosa and other Gram-negative bacteria with nadifloxacin (e18, e21). 0.1% octenidine also appears to be effective (e19).
Ciprofloxacin is used for the systemic antibiotic treatment of Pseudomonas infections of the nails.
Nail infections due to Staphylococcus aureus and Gram-negative bacteria, such as Klebsiella spp., are treated according to the sensitivities and resistances revealed by the antibiogram.
Conflict of interest statement
Dr. Nenoff owns Pfizer stock. He has served as a paid consultant for Galderma and has received lecture honoraria from Hermal, Galderma, and MSD.
Prof. Wollina, Dr. Haenssle, and Prof. Haroske state that they have no conflict of interest.
Manuscript received on 8 January 2016, revised version accepted on
25. April 2016.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Uwe Wollina
Klinik für Dermatologie und Allergologie
Akademisches Lehrkrankenhaus der TU Dresden
Friedrichstr. 41, D-01309 Dresden, Germany
For eReferences please refer to:
Prof. Dr. med. Wollina
Laboratory for Medical Microbiology, Mölbis: Prof. Dr. med. Nenoff
Georg Schmorl Institute of Pathology, Dresden-Friedrichstadt Hospital, Academic Teaching Hospital of the Technical University of Dresden:
Prof. Dr. med. Haroske
Department of Dermatology, Heidelberg University Hospital:
PD Dr. med. Haenssle
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