Leukonychia: What Can White Nails Tell Us?

Punctate true leukonychia is probably the most common clinical presentation of leukonychia, especially in children. Not all nail plates are necessarily affected, and every nail plate may be affected in different ways. The pattern and number of spots may change as the nail grows. It is not related to reduced calcium or iron content of the nail plate, as popularly believed. Usually, it is due to trauma (Fig. 1), but it may also be due to inflammatory diseases such as alopecia areata or psoriasis [14‐16].

Pseudo-leukonychia also often presents as punctate leukonychia. Typical causes are superficial white onychomycosis (Fig. 2) [30] and nail fragility due to nail cosmetics (Figs. 3, 4). Punctate areas of leukonychia due to fungal invasion can eventually coalesce to involve the entire surface of the nail plate or may present with a single or multiple transversal leukonychial bands separated by a normal nail plate [32, 33]. Artificial nails and frequent use of polish removers damage the superficial layers of the nail plate causing dehydration of the nail keratins that clinically appear as fine and scaling white spots (keratin granulation) [34]. The use of cyanoacrylate glue should also be excluded.

In 1919, Mees reported pale transverse, 1–2 mm wide bands of true leukonychia appearing in the proximal part of the nail plate, and running parallel to the lunula, in patients experiencing arsenic poisoning [35]. While multiple lines may be due to multiple episodes of arsenic ingestion, an alternate theory suggests that they do not necessarily reflect the number of episodes of ingestion. The serial form of deposition may be band-like precipitations of arsenic due to alternate diffusion and nucleation of relatively concentrated arsenic within the nail matrices (Liesegang’s phenomenon) [36]. The lines can present as a retrospective indicator of a pathologic state because their onset is correlated with a systemic insult: fingernails grow about 1 mm every 6–10 days and the bands take some weeks to manifest. In acute arsenic poisoning, it has been claimed that the lines usually appear considerably later, after 40–60 days [37]. This discrepancy has been explained by the assumption that arsenic leukonychia is caused by the precipitation of arsenic and not by damage to the nail matrix [36].

Often described with its eponym Mees’ lines, the bands may have other causes. To be more appropriate with the definition, the white lines should be defined in these cases as trauma-induced transverse true leukonychia. When only the fingernails are affected, manicure mistakes are the possible culprits (Fig. 5) [38]. When the toenails are affected, bands may result from pressure on the free edge of the nail plate not trimmed short (Fig. 6) [4]. Among traumatic etiologies, cryotherapy of warts on the proximal nail fold should also be mentioned but also direct occupational contact with aggressive substances such as concentrated chemicals [54]. A single transversal band may be induced by one relevant trauma or skin diseases of the proximal nail fold [20]. When both fingernails and toenails are affected, a systemic cause should be ruled out: a matrix-toxic substance such as thallium [52], strontium [51], and arsenic, for instance, but chemotherapeutic drugs are the therapeutic agents most frequently involved [96]. No specific drug, combination of drugs, or drug class is responsible [97] but cyclophosphamide, doxorubicin, and vincristine are those most frequently involved [98]. Additionally, nutritional deficiencies or systemic diseases such as systemic lupus erythematosus may provoke transverse true leukonychia (Fig. 7) [74, 99], hematologic disorders, neurovascular disorders, empyema, heart failure, severe hypocalcemia, and systemic infections, including COVID-19 [69, 70]. Occasionally transverse bands are reported to be the result of climbing at high altitude (Everest nails) [79] due to severe hypoxia and catabolic stress and to the combined use of drugs for the prevention and therapy of acute mountain sickness such as acetazolamide and naproxen [100].

As stated, when the bands fade with pressure we are dealing with an apparent form of leukonychia (Fig. 8). Initially described in 1956 by their namesake Dr. Robert Muehrcke in patients with severe and long-standing hypoalbuminemia (< 2.2 g/100 mL) [82], currently they are considered indicative of a range of systemic pathologies without hypoalbuminemia, including kidney disease, rheumatoid arthritis, heart transplant [86, 87], and after placement of a left ventricular assist device [88]. Systemic retinoids and various cytostatic regimens have also been observed to cause them. Muehrcke lines are paired, narrow, arcuate pale bands parallel to the lunula that affect all 20 nails and are most prominent on the second, third, and fourth fingernails. They are not permanent and resolve with normalization of the nail bed, for example, with normalization of albumin levels [83].

Longitudinal true leukonychia is caused by alterations of a section of the matrix, resulting in focal parakeratosis and disorganization of keratin filaments, which, if present for a long time, results in a longitudinal white band. It is a typical sign of Darier’s disease where it is associated with longitudinal erythronychia (candy cane nails) (Fig. 9) [101]. The white lines correspond to epithelial hyperplasia of the matrix and the red lines represent thin nails due to matrix disease. Longitudinal true leukonychia without red lines can also be, even if less frequent, a sign of other genodermatoses, including Hailey-Hailey disease [102], and tuberous sclerosis complex [103]. Other nail disorders presenting with linear true leukonychia include onychomatricoma (Fig. 10) [104], onychocytic matricoma [105], and nail matrix lichen planus. A longitudinal band in the great toenail has been associated with chronic trauma in hallux valgus deformity [106].

Longitudinal apparent leukonychia is also mostly present in one isolated digit. It is often seen in disorders that present with linear erythronychia, in which erythronychia is the result of increased vascularization and leukonychia, the result of decreased vascularization (some nail tumors for example, including longitudinal subungual acanthoma and squamous cell carcinoma) [107]. Apparent leukonychia is also a presenting sign of onychopapilloma, a benign nail bed tumor where leukonychia is due to metaplasia of the nail bed epithelium with a mount of horny cells causing altered light refraction and fibrosis of the nail bed stroma [108‐111].

Longitudinal pseudo-leukonychia can be instead caused by onychomycosis. The infection may be recognizable as irregular dense longitudinal white or yellowish bands (spikes) [112].

Congenital partial or total true leukonychia can be idiopathic or inherited. The nails are typically milky/chalky/porcelain white (Fig. 11). In publications reporting on idiopathic congenital true leukonychia, all patients were male, with only one single exception [113]. This sex preference is hard to explain. It could indicate that idiopathic true leukonychia rather is an inherited leukonychia with a recessive X-linked pattern of inheritance. It could also be due to Y-chromosomal inheritance with a variable penetrance.

Hereditary leukonychia may exist as an isolated feature, or in association with other cutaneous or systemic pathologies [204]. An autosomal dominant pattern of inheritance is most frequent, but an autosomal recessive pattern has also been reported. A pathogenic mutation in the gene coding for phospholipase C delta-1 (PLCd1) on chromosome 3p22.2, which regulates nail formation downstream of FOXn1 [205], has been identified as relevant in both hereditary autosomal dominant and recessive leukonychia [114, 115, 206] and probably also in leukonychia with sebaceous cysts [150]. Occurring within the context of other pathologies, it has been postulated that congenital familial leukonychia is a symptom of a more complex ectodermal dysplasia involving inconstantly other keratinizing structures and most probably is related to deficiency of a gene regulating the structure of hard keratin [131]. The 12q13 chromosome that encodes the basic and hard keratins is responsible for hereditary leukonychia [116]. In certain cases of the Carvajal/Naxos syndrome, a dominant desmoplakin mutation is associated with leukonychia and oligodontia [129]. The GJB2 gene located on chromosome 13 encodes for connexin 26, which is responsible about half of cases of inherited sensorineural deafness. GJB2 mutations often present with varying cutaneous manifestations, including in Bart–Pumphrey syndrome (MIM: 149200), hystrix-like ichthyosis with deafness (MIM: 602540), keratitis-ichthyosis-deafness syndrome (MIM: 148210), palmoplantar keratoderma with deafness (MIM: 148350), and Vohwinkel syndrome (MIM: 124500), with significant overlap of clinical features [117]. Because leukonychia may be part of some of these syndromes [123, 144, 145], a correct function of connexin 26 appears to be relevant for translucency of the nail plate. It seems reasonable to assume that mutations in genes both responsible for keratins and for proteins important for intercellular connections between epithelial cells are important in several hereditary leukonychia: Connexin 26 is in gap junctions and plays a role in the exchange of ions and small molecules between adjacent cells by forming intercellular channels, and desmoplakin is a critical component of the desmosome, which is also essential in epidermal cell-to-cell contact. Recently, a new autosomal recessive form of the generalized peeling skin syndrome, termed PLACK syndrome (OMIM 616295), has been described. In the acronym, L stands for leukonychia and this is associated with the loss of function mutations in the CAST gene encoding calpastatin [146, 147]. Calpastatin is an endogenous specific inhibitor of calpain, a protease that plays a role in regulating epidermal end differentiation. Congenital leukonychia has a possibility of gradual improvement over the lifetime of an individual [162, 207] and sometimes improves with age, but sometimes not. The improvement seems to be related to maturation of the cells that start producing normal keratins losing the keratohyalin granules.

The acquired form of partial and total true leukonychia is, however, significantly more common and can be associated with several comorbidities, drugs, and exogeneous-acting compounds. Neuropathic disorders, as reflex sympathetic dystrophy, and autonomic abnormalities or vascular diseases can also be responsible. According to Vanhooteghem et al. [151], this leukonychia is secondary to the combination of two phenomena: neurovascular deterioration and chronic slow and progressive trauma to the nail matrix applied by the persistent edema of the fingers and terminal phalanges. Usually, in the latter cases, periungual skin is also involved and the growth rate of the nail plate might be slower.

Apparent partial/total leukonychias can be seen rather frequently and are often medical relevant leukonychias. Half-and-half nails, also known as Lindsay’s nails, are characterized by a sharply demarcated red, pink, or brown discoloration of 20–60% of the distal nail-bed, leading to two-colored nails with a transverse border (Fig. 12). The proximal nail has a whitish ground glass-like appearance, obscuring the lunula, and all nails are involved. It has been defined that if the distal portion is less than 20% of the total nail length, we are instead facing Terry’s nails (Fig. 13) [208].

Half-and-half nails are detected in approximately in 10–30% of patients with chronic renal disease (uremic patients and patients undergoing hemodialysis) [28, 209, 210]: the discovery should therefore prompt the clinician to evaluate the patient for kidney disease. They also have been reported occasionally in several other circumstances, including Kawasaki’s disease, Behcet’s disease, hepatic cirrhosis, Crohn’s disease, in pellagra, human immunodeficiency virus, after isoniazid therapy but also in healthy persons. In kidney patients, complete disappearance is sometimes noted within 2–3 weeks after successful transplantation [210] while others report even a higher prevalence in renal transplant patients than in patients undergoing hemodialysis [28].

In 1954, Terry described a nail abnormality characterized by a bilaterally symmetrical white nail bed of the fingernails with a distal band, 1–2 mm in length, that had a normal pink or erythematous color [180]. All nails are uniformly involved and often the lunula is not visible. Although the hallmark distal band is typically well defined and contiguous with the end of the nail bed, it may possess an uneven border. It has been supposed that the distal erythematous crescent probably is a prominent onychodermal band. Histological studies of the nail bed have shown vascular changes (telangiectasias) in the bands [181]. The brown tint in the band region observed in some patients could not be explained. Staining did not show abnormal melanin or iron deposition in the band area [181]. The true reasons for the color variations remain unclear. One possibility is that the proximal and distal nail bed have separate blood supplies. Terry found the nail changes in 82% of patients with “alcoholic, postnecrotic, and cholangiolitic” liver cirrhosis but also noticed similar nail changes, currently known as “Terry’s nails” in other underlying medical conditions. While being promoted as one of the most reliable physical signs of cirrhosis [211] and an early sign of autoimmune hepatitis [183], Terry’s nails can also be an indication of chronic renal failure, congestive heart failure, hematologic disease [186], and adult-onset diabetes mellitus [181], but also occur with normal aging. Holzberg and Walker proposed that Terry’s nails are a part of aging and speculated that each of the associated diseases “ages” the nail earlier than normal. The presence of Terry’s nails has also been reported in isolated cases of widely metastatic carcinoma, and in a plethora of infectious and non-infectious diseases.

Sometimes, the circumstances in which total apparent leukonychia appears can easily be explained by changes of the nail bed. For example, by nail bed edema in lymphoedema, paleness of the nail bed in severe anemia, and cicatricial changes after total skin electron beam irradiation therapy. Among the other culprits, selenium deficiency has been reported several times. It has been assumed that selenium deficiency may be responsible for apparent leukonychia in vegetarians in selenium-deficient areas, patients undergoing long-term hemodialysis, long-term parenteral nutrition [157], weight loss, phenylketonuria, malabsorption disorders, and human immunodeficiency virus [195]. Remarkably, selenium deficiency has also been attributed to true leukonychia in Crohn’s disease [156] where selenium supplementation was able to induce complete regression.

Partial/total pseudo-leukonychia can be instead caused by onychomycosis, especially proximal subungual, but also by onycholysis. In these instances, scraping is not possible, and differentiation from true leukonychia can be difficult.