Yellow nail syndrome
Are You Confident of the Diagnosis?
What you should be looking for in the history
Yellow nail syndrome (YNS) is a rare disorder that was first described in 1964 by Samman and White. The syndrome is characterized by the triad of yellow thick nails, lymphedema and respiratory tract disease. The abnormalities of the respiratory tract vary among patients. According to Hiller’s definition, two features of the triad are required for diagnosis, but it is now generally accepted that nail disease alone is enough to make the diagnosis. All three criteria are present simultaneously in only 30% of cases.
Characteristic findings on physical examination
One or all nails (fingernails and/or toenails) may be affected. The affected nail plate is yellow-green or black, thick, smooth or ridged with a longitudinal and/or transverse overcurvature (Figure 1, Figure 2). The affected nails lack cuticles. Lunulae may or may not be missing. Yellow discoloration affects the entire nail plate or only the distal portion. Onycholysis is common and may result in nail shedding. The nail folds are often red and inflamed (chronic paronychia). In severe cases, digit function may be impaired. Dermoscopy often reveals dilated and tortuous capillary loops.
Slow or arrested growth is the most characteristic feature. Affected fingernails grow less than 1mm per month. In contrast, normal fingernails and toenails grow at 3mm per month and 1mm per month, respectively. Both of these estimates decline with age. In most cases, lymphedema is symmetric and nonpitting, with the lower extremities more commonly involved than upper extremities. Signs of respiratory disease vary among patients.
Expected results of diagnostic studies
YNS is a clinical diagnosis based on characteristic findings from the history and physical examination. Biopsy is not routinely performed. Reported histopathological findings include a subungual stroma that is replaced by a dense fibrous tissue with ectatic, endothelium-lined vessels.
Evaluation of pulmonary abnormalities and lymphedema are guided by the patient’s history and physical exam. Imaging (chest radiography, computed tomography, Doppler ultrasonography), pulmonary function tests, lymphangiography and lymphoscintigraphy may assist the diagnosis. If present, a pleural effusion is typically exudative with lymphocytosis and a high protein content or a chylothorax.
The differential diagnosis of discolored thick nails includes: onychomycosis, chronic paronychia, pseudomonal infection, endogenous or exogenous chromonychia, drugs (topical 5-fluorouracil, tetracycline), onychogryphosis, subungual verruca, and squamous cell carcinoma.
Negative histopathology and/or culture can rule out onychomycosis and bacterial infection, although dermatophyte superinfection may be present. A detailed history can rule out drug induced versus exogenous chromonychia. When one nail is affected, a biopsy may be needed to rule out a neoplasm.
Differential diagnosis of lymphedema includes: primary lymphedema (Milory’s, Meige’s, tarda), secondary lymphedema (infection, malignancy, iatrogenic), other causes of edema (congestive heart failure, venous insufficiency, deep vein thrombosis, renal failure, cellulitis) and myxedema.
Who is at Risk for Developing this Disease?
The incidence and prevalence of YNS are not known. It is a rare, idiopathic disorder. Over a hundred and fifty cases have been reported. Although most have been sporadic, familial cases have been described. YNS appears to affect men and women equally. The disease presents in 4th to 6th decades of life.
What is the Cause of the Disease?
The etiology of YNS is unknown. An autosomal dominant inheritance with variable expression (OMIM 153300) has been suggested. Some familial cases harbor a mutation in FOXC2 gene. FOXC2, a gene that codes for a transcription factor, is also implicated in lymphedema-distichiasis syndrome (OMIM 153400). However, in a retrospective study of 11 patients with YNS, only one had a relevant family history, suggesting that most cases are sporadic. Congenital YNS has been reported.
The pathophysiology of YNS is not well understood. It is hypothesized that a functional or structural defect in the lymphatic vasculature is important. A functional lymphatic abnormality is favored because it can better explain the reversibility of the nail changes and lymphedema. However, structural abnormalities in lymphatic vessels have not been reported consistently. It has been argued that in addition to lymphatic blockage, microvasculopathy with protein leakage is required to explain all the features of the YNS, including the characteristic nail changes.
Dermoscopy of the nail fold capillaries in 15 patients with YNS revealed dilated and tortuous capillary loops, suggesting microangiopathy as the cause for the nail changes.
Recent reports have implicated titanium in the development of YNS. Elevated levels of titanium have been found in patients with YNS, but there was no correlation between titanium levels and thickness of the nails. Titanium exposure may be due to medications, confectionaries, and titanium implants with concurrent gold dental inlays. It is hypothesized that the interaction between amalgam and gold result in a galvanic reaction leading to the yellow nail color.
It has been hypothesized that the upward deflection of nails that arise from the matrix promotes nail growth along the dorso-ventral axis instead of the longitudinal axis. This leads to thick nails with decreased linear growth. The upward deflection results from changes in the nail fold (loss of cuticle) and nail bed. Histological features of the nail bed and matrix in YNS are that the subungual stroma is replaced by a dense fibrous tissue with ectatic, endothelium-lined vessels. The yellow color has been attributed to the conversion of lipids to lipofuscin in nails.
Systemic Implications and Complications
In YNS, nail abnormalities occur in association with either lymphedema and/or respiratory disease. About 89% of patients have nail changes, 29-80% have lymphedema and 63-76% have respiratory disease. The features vary among patients and fluctuate over time.
Lymphedema can be localized to limb(s) or affect other sites such as face and peritoneal cavity. Various respiratory abnormalities have been reported in patients with YNS and they may predate the nail changes in some cases. Pleuropulmonary diseases include chronic obstructive lung disease, chronic bronchitis, pleural effusions, bronchiectasis, chronic sinusitis, and recurrent pneumonia. Other respiratory abnormalities such as chronic cough, and bronchial hyperactivity have also been reported.
YNS has not been consistently linked to any diseases beyond the triad of yellow nails, lymphedema and respiratory abnormalities.
However, multiple associations have been reported in the form of isolated case reports. These include connective tissue disease (Raynaud’s phenomenon, polymyalgia rheumatica, eosinophilia-myalgia syndrome), malignancy (lung, breast, endometrium, larynx, gallbladder, renal, Hodgkin’s and non-Hodgkin lymphomas, melanoma, anaplastic undifferentiated tumor, skin fibrosarcoma, mycosis fungoides), autoimmune disorders (rheumatoid arthritis), endocrine abnormality (diabetes mellitus, thyroid dysfunction), immunodeficiency states, low serum protein states (nephrotic syndrome), exudative enteropathy, Guillain-Barré syndrome, obstructive sleep apnea, xanthogranulomatous pyelonephritis, tuberculosis, myocardial infarction, hemochromatosis and drug induced (thiol).
Due to its various associations, YNS has been regarded by some as a paraneoplastic or an autoimmune disease.
Prognosis appears to be favorable. The respiratory and lymphatic disorders usually do not progress and are often manageable. Respiratory failure is rare. A modest decrease in survival rate due to various causes was noted in the retrospective study of 41 patients with YNS who presented to the Mayo clinic.
To date, no treatment strategy has shown consistent results. High dose oral Vitamin E, at 1200 IU/day has been utilized in the largest studies of YNS with generally good results. Other proposed treatment regimes are:
Topical Vitamin E
Oral zinc supplement
Treatment of pulmonary abnormalities
Management of lymphedema
Optimal Therapeutic Approach for this Disease
There is no cure for YNS. Nail changes spontaneously improve in 10-30% of patients with YNS. Nail abnormalities may improve or regress when the associated respiratory condition is treated. Treatment of the nail changes is undertaken to decrease the psychosocial burden and to improve fine motor function. Due to the rarity of YNS, a standard treatment has not been developed. Most suggested therapies are from case reports or small case series.
Treatment of YNS begins with the management of concomitant medical problems such as lymphedema and respiratory disease. Improvement in respiratory status and lymphedema have been linked to improved nails. For this reason the nail manifestations have been called the ’barometer’ of YNS. However, treatment of concomitant disease does not always clear the nails.
Prompt treatment of respiratory infections and influenza and pneumococcal immunizations are recommended. Recurrent symptomatic pleural effusions may require pleurodesis or other surgical interventions.
Lymphedema is managed mainly with decongestive therapy: compression garments/wraps, exercise, manual lymph drainage or intermittent pneumatic pump compression. Meticulous skin care and treatment of complications such as open wounds, developing infection and deep venous thrombosis are essential.
The efficacy of oral and topical vitamin E in the treatment of yellow nails is unclear. The use of oral vitamin E is presumably for its antioxidative activity in vitro. It has been speculated that lipofuscin contributes to the yellow color in nails. Oral vitamin E is thought to block the oxidation of lipids to lipofuscin in nails. Sporadic reports have shown some success with oral vitamin E at doses as high as 1200IU daily (600 to 1200IU daily) and for as long as 4 years.
In one study of 21 YNS patients by Piraccini et al, nail improvement was observed in 48% with high dose oral Vitamin E. Completely normal nails were achieved by 25% of patients, with no side effects.
The use of topical vitamin E has been advocated to limit systemic exposure. Topical vitamin E is available in a variety of formulations. It is relatively well tolerated. Side effects include erythema multiforme-like eruption, contact dermatitis and allergy. Its use was first advocated by Williams et al in 1991. They performed a double-blind controlled study on a 64-year-old man with YNS. After 6 months of therapy with a 5% solution of vitamin E in DMSO, the treated nails improved clinically and grew more than the nails that were either untreated or treated with DMSO.
Further application of the vitamin E solution to all ten affected nails resulted in marked clinical improvement. In a study that compared the efficacy of topical vitamin E to vehicle oil in a randomized double-blind study in three children with YNS, there was no statistically significant improvement in the clinical appearance or the growth rate of the treated nails.
Oral zinc supplements and intralesional triamcinolone acetonide injections have been shown to improve yellow nails in some case reports. Data on the efficacy of these two modalities is insufficient.
Newer oral antifungals have been used to treat yellow nails. The rationale comes from the fact that terbinafine, fluconazole and pulse itraconazole increase linear nail growth. In a study in which 13 patients were treated with fluconazole 300 mg weekly (one patient received 400 mg weekly) and oral vitamin E 1000IU daily for 18 to 24 months, 11 patients had complete cure and two patients showed clinical success at 18 months (clinical success was defined as resumption of nail growth by more than 50%).
In another study, two patients with YNS were treated with itraconazole 400 mg daily for 1 week per month (pulse regimen) and oral vitamin E for 12 months. At 1 year, both patients had normal fingernails and improved toenails. However, in another study of eight patients treated with 6 itraconazole pulses for up to 12 months, two patients were cured, two patients improved and 4 patients showed no improvement. This result is consistent with the 10 to 30% rate of spontaneous resolution.
Nail growth is measured from the proximal nail fold. The tip of a scalpel can be used to etch a transverse mark on the nail plate about 2mm above the proximal nail fold. New nail growth is measured at each visit. As the nail grows, the mark on the nail plate moves distally and away from the proximal nail fold. Sequential photography can aid monitoring.
The patient should be advised that nail changes can improve or resolve without treatment. Relapse is common. Large double-blind studies are required to develop a treatment algorithm and prove efficacy. However, YNS is a rare disease and such studies are lacking. Suggested treatment modalities lack sufficient evidence.
Unusual Clinical Scenarios to Consider in Patient Management
It is suspected that YNS is more common than the literature suggests, particularly as symptoms of the triad may go undetected or undiagnosed. Lymphedema may be subclinical and patients may have vague respiratory complaints without a diagnosis. One feature may become apparent months to years prior to the other feature(s). Features can occur at various times and may not overlap. Thus, the clinician evaluating yellow nails must have a high degree of suspicion and carefully elicit a history of respiratory symptoms and/or edema.
It has been suggested that yellow-colored nails are common in various types of lymphedema such as Meige, Milory and lymphedema with distichiasis. They propose that the discolored nails of YNS are smooth, translucent and over curved. This is contrary to other types of lymphedema where nails are yellow but also thick, rough, and opaque.
What is the Evidence?
Maldonado, F, Ryu, JH. “Yellow nail syndrome”. Curr Opin Pulm Med. vol. 15. 2009. pp. 371-5. (A review of literature regarding the diagnosis and management of YNS.)
Maldonado, F, Tazelaar, HD, Wang, CW, Ryu, JH. “Yellow nail syndrome: Analysis of 41 consecutive patients”. Chest. vol. 134. 2008. pp. 375-381. (41 consecutive cases of YNS who presented to the Mayo clinic were analyzed to clarify the clinical features and the course of the disease.)
D’Alessandro, A, Muzi, G, Monaco, A, Filiberto, S, Barboni, A, Abbritti, G. “Yellownail syndrome: does protein leakage play a role”. Eur Respir J. vol. 17. 2001. pp. 149-152. (The authors report a case of YNS with persistent hypoalbuminemia and increased loss of albumin. Based on this case report and the literature, they speculate that increased microvascular permeability may contribute to the pathogenesis of YNS.)
Hoque, SR, Mansour, S, Mortimer, PS. “Yellow nail syndrome: not a genetic disorder? Eleven new cases and a review of the literature”. Br J Dermatol. vol. 156. 2007. pp. 1230-4. (A retrospective chart review of 11 patients with YNS plus a postal questionnaire revealed one relevant family history and four complete recoveries. Therefore, the authors suggest that YNS may not be a genetic disease as currently classified.)
Lambert, EM, Dziura, J, Kauls, L, Mercurio, M, Antaya, RJ. “Yellow nail syndrome in three siblings: A randomized double-blind trial of topical vitamin E”. Pediatr Dermatol. vol. 23. 2006. pp. 390-395. (The first report of YNS in siblings and the trial of topical vitamin E for treatment in children. The application of either vitamin E solution or placebo oil to the nail plate and the periungual skin improved the condition of nails in all three patients with YNS. However, vitamin E solution did not affect fingernail growth or the global appearance score significantly when compared to placebo oil.)
Fiallo, P. “Yellow nails as an adverse reaction to the topical use of 5-fluorouracil for the treatment of nail psoriasis”. J Dermatolog Treat. vol. 20. 2009. pp. 299-301. (Three patients with fingernail psoriasis developed yellow nail discoloration with the use of topical 5-fluorouracil (5-FU). The author suggests that while 5-FU is an effective therapy for nail psoriasis it should be avoided in those patients with slow nail growth (bad responders).)
Baran, R, Thomas, L. “Combination of fluconazole and alpha-tocopherol in the treatment of yellow nail syndrome”. J Drug Dermatol. vol. 8. 2009. pp. 276-8. ( A case series of 13 patients with YNS who received combination therapy for their nail discoloration. Oral fluconazole pulse therapy (300mg weekly except one case who received 400mg weekly) and oral alpha-tocopherol (1000IU daily) for 18-24 months. Two cases of clinical success and 11 clinical cures were reported.)
Piraccini, BM, Urciuoli, B, Starace, M, Tosti, A, Balestri, R. “Yellow nail syndrome: clinical experience in a series of 21 patients”. J Dtsch Dermatol Ges. vol. 12. 2014 Feb. pp. 131-7. (A case series of 21 patient with YNS, documenting clinical findings, presence of respiratory and lymphatic disease, and treatment.)
Decker, A, Daly, D, Scher, RK. “Role of Titanium in the Development of Yellow Nail Syndrome”. Skin Appendage Disord. vol. 1. 2015 Mar. pp. 28-30. (Review on hypothesis of titanium dioxide with dental gold or amalgam causing galvanic reaction leading to yellow nail discoloration.)
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