Continuing Education Activity

Yellow nail syndrome (YNS) is a rare disorder characterized by slow-growing, yellow, thickened nails, lymphedema, and respiratory tract involvement. Pulmonary symptoms, such as pleural effusions or bronchiectasis, often accompany the nail abnormalities, while lymphedema may involve the extremities. Though YNS primarily affects adults aged 50 and older, it has also been documented in children. The exact cause remains unknown, and the syndrome is often misdiagnosed, leading to unnecessary tests and delayed treatment. Early identification of the triad of symptoms is crucial for effective management.

This educational activity provides healthcare professionals with the knowledge to diagnose and manage yellow nail syndrome accurately. Participants learn to differentiate YNS from other conditions and apply appropriate treatment strategies, including managing respiratory complications and lymphedema. The course also emphasizes the importance of interprofessional collaboration, where dermatologists, pulmonologists, and other specialists work together to enhance patient outcomes and reduce the morbidity associated with the syndrome.

Objectives:

• Differentiate yellow nail syndrome from other conditions that may present with similar symptoms, such as psoriasis or fungal infections.
• Screen patients with yellowing nails for associated conditions, including pleural effusion and lymphedema, to ensure a comprehensive evaluation.
• Implement evidence-based management strategies for yellow nail syndrome, focusing on symptom relief and addressing associated conditions.
• Determine interprofessional team strategies for improving care coordination and communication to advance yellow nail syndrome and improve outcomes.

Introduction

Yellow nail syndrome (YNS) is a rare condition defined by the presence of 2 of the following 3 symptoms:

1. Slow-growing, hard, yellow, and dystrophic nails
2. Lymphedema
3. Respiratory tract disease [1] 

The earliest case of YNS was reported by Heller in 1927.[2] However, in 1947, Samman and  White published the first case series of YNS in patients with nail discoloration and lymphedema.[3] Pulmonary disease, specifically pleural effusion, was added to the diagnostic criteria by Emerson in 1966.[4] The syndrome generally affects adults aged 50 and older. However, case reports of YNS occur in children and even newborns.[5] Anatomically, YNS affects the fingernails, toenails, the respiratory tract, and gravity-dependent areas that can accumulate fluid (typically lower extremities). These signs and symptoms are believed to be due to dysfunction in lymphatic drainage.[3][4][6][7]

Nails

As the name suggests, xanthonychia (yellow nail coloration) is a common feature of YNS; however, yellow nails are not required if 2 of the other clinical signs are present. Discoloration varies from pale yellow to dark green; nails can be opaque or translucent.[8] The manifestations are commonly misdiagnosed as onychomycosis (discoloration due to fungal infection), as the nails may become thickened, hard, and curved.[9] A quick inspection of fingernails and toenails can help expand the differential for a patient with other vague complaints without additional expense.

Respiratory Tract

The respiratory tract is involved in more than half of patients with YNS.[2][7] The most common manifestation is a chronic cough, followed by pleural effusion.[7] In one of the largest reviews of patients with YNS, Valdés et al found nearly all effusions exudative with a lymphocytic predominance. Of the 66 subjects, approximately 70% of effusions were bilateral.[2][10] Other pulmonary manifestations include bronchiectasis, recurrent pneumonia, sinusitis, and pulmonary fibrosis.[11] Pulmonary function testing in YNS is typically unremarkable, and biopsies do not usually contribute to the diagnosis.[10]

Lymphedema

Lymphedema typically manifests in the bilateral lower extremities and does not differ in appearance from primary lymphedema.[2] Lymphedema occurs in 30% to 80% of patients.[2][7][12] Dynamic lymphatic imaging (lymphoscintigraphy) does differ between patients with edema related to YNS and those with primary lymphedema.[13] Edema can be pitting and can be easily confused with fluid accumulation, often seen in patients with decompensated congestive heart failure. This can be especially deceiving if patients present with concurrent pleural effusions. As in primary lymphedema, treatments often involve massage, compression dressing, exercises, and, less commonly, surgical interventions.[14]

Natural History 

The diagnosis of YNS can be difficult because patients rarely present concurrently with all 3 clinical criteria. Lymphedema is the initial symptom in approximately one-third of YNS diagnoses.[12] The prognosis and disease course depend on the individual's symptoms and the timing of diagnosis. In some mild cases, the symptoms of YNS can be resolved without intervention. Unfortunately, many symptoms recur despite treatment and require continuous care. YNS can negatively affect one's quality of life, including cosmesis and worsening functional status. Recurring soft tissue infections (eg, cellulitis from severe lymphedema), pulmonary infections (pneumonia/empyema), and pulmonary effusions can lead to complications such as antibiotic resistance, pulmonary scarring, and protein loss.[15] 

Etiology

The specific cause of yellow nail syndrome (YNS) is unclear. The most widely accepted explanation for the signs and symptoms associated with YNS is a dysfunction of the lymphatic system, specifically lymphatic drainage.[2][4][16] Imaging lymphatic system and lymph transport using lymphoscintigraphy is abnormal in YNS.[2] Interestingly, study results have shown a difference in lymphatic drainage in patients with YNS compared to those with primary lymphedema.[2][13] Another proposed etiology of YNS is exposure to titanium, specifically titanium dioxide (used in various products such as dental and joint implants, surgical staples, and cosmetics).[17][18] 

When compared with healthy controls, nail clippings from patients with YNS contained elevated levels of titanium.[17][19] Furthermore, case reports exist in which the removal of titanium-containing implants led to the resolution of YNS.[19] Rare cases have also been reported after mitral valve replacement.[20] Although cases of familial and congenital YNS have been reported, in the majority of cases, YNS is an acquired disorder of the lymphatic system that presents later in life.[21] YNS has also been associated with certain malignancies, autoimmune diseases, and immunodeficiency disorders.[22][23][24] 

Epidemiology

The exact prevalence of YNS is unknown, and most of the literature on YNS involves case reports. The estimated prevalence is less than 1 in 1,000,000.[2] This condition occurs more commonly in those aged 50 and older, affecting men and women equally.[7][12] Congenital and pediatric cases are extremely rare.[5][25][26] If YNS is suspected in a young patient, special care should be taken to rule out other related lymphatic system disorders.

Pathophysiology

As the underlying cause of YNS is unknown, the pathophysiology is also unclear. The most widely accepted cause of YNS is thought to be related to abnormalities in lymphatic flow. Based on their investigations involving quantitative lymphoscintigraphy, Bull et al argued that unlike primary lymphedema, which is due to permanent structural lymphatic abnormalities, the abnormalities observed in YNS appear to be functional and potentially reversible.[13] They propose that perhaps an inflammatory component that leads to altered capillary permeability, fluid shifts, and alterations in blood flow is likely the cause of the edema in YNS.

Histopathology

Histopathological examination of nails is important to rule out other common causes of yellow nails, such as onychomycosis. The appearance of nails in YNS is varied; changes include a thickened nail plate with exaggerated curvature, xanthonychia (yellow discoloration), scleronychia (hardening of the nail), onycholysis (separation of the nail plate and nail bed), and slow growth.[2][9] Thoracentesis and fluid examination typically reveal a serous exudative effusion when a pleural effusion is present.[10] In their case series study, Valdés et al found that pleural fluid samples most often had lymphocytic predominance with low numbers of nucleated cells with a pleural fluid protein greater than 3 g/dL.

History and Physical

History

A thorough history is crucial to diagnosing YNS. Open-ended questioning and a detailed review of the pulmonary, vascular, and integumentary systems can reveal clues that may lead to the diagnosis of this rare syndrome. The pulmonary findings in YNS vary widely; therefore, asking about persistent cough, congestion, and recurrent respiratory infections is important. A review of past medical history, social history (ie, smoking status, respiratory irritant exposure), and previous chest imaging are essential. Symptoms can be mild, intermittent, and may not present concurrently. 

Physical Exam

Special attention should be paid to analyzing fingernails and toenails and removing polish if necessary. Nail findings can be subtle; the discoloration can range in intensity from pale yellow to green.[8] Nails can be thickened or irregular and are often slow-growing and brittle.[9] The physical appearance of lymphedema in YNS is no different than what is seen in primary lymphedema. Based on case reports, lymphedema is the initial symptom of YNS in approximately one-third of patients, and it is present in approximately 30% to 80% of those diagnosed with the syndrome.[2][7][12] Lymphedema is most commonly found in the bilateral lower extremities and other gravity-dependent areas.[2] Although clinical signs have poor diagnostic reliability, the Kaposi-Stemmer sign (inability to pinch and lift the skin at the dorsum of the base of the second toe) is the most useful.[27] Pitting is present early in the course of lymphedema; however, as it progresses and the skin thickens and hardens, pitting is less clear.[28] Edema associated with venous obstruction and lymphedema is often difficult to distinguish. 

Respiratory tract manifestations in YNS occur in 60% to 70% of patients, the most common of which is a chronic cough.[2][7] A careful history can help direct a thorough physical exam. Pleural effusions can be detected through auscultation and percussion. Facial fullness, tenderness to palpation of sinuses, and edematous nasal turbinates can be signs of chronic sinusitis.[29] Other pulmonary manifestations can occur, such as bronchiectasis and fibrosis.

Evaluation

The diagnosis of YNS is clinical, and no specific test is required or diagnostic. More commonly encountered diagnoses, such as heart failure, primary lymphedema, and onychomycosis, should be ruled out. This can be done by thoroughly investigating the patient's history and physical exam or by requiring additional tests. Potential testing may include the following:

• Echocardiography to rule out heart failure
• Chest radiography to identify pneumonia or other pulmonary pathology
• Computed tomography of the sinuses to assess for chronic sinusitis
• Testing for infection, such as sputum analysis or complete blood count
• Analysis of nail scrapings or clippings to rule out onychomycosis
• Thoracentesis with an evaluation of pleural fluid
• Lymphoscintigraphy to identify lymphatic insufficiency

Treatment / Management

The management of yellow nail syndrome focuses on treating symptoms. If thought to be a paraneoplastic syndrome, the treatment of underlying cancer may lead to resolution.[30] Sometimes, YNS can be resolved without intervention.[2]

Pulmonary Symptoms

Pleural effusions are usually treated with thoracentesis. Octreotide is effective in some cases of chylous effusions associated with YNS.[31] Unfortunately, pleural effusions tend to recur and may require definitive interventions, including decortication, pleurodesis, or thoracic duct embolization.[10] Antibiotic prophylaxis can be offered if the patient has recurrent infections or advanced bronchiectasis.[11] Pneumococcal and seasonal influenza vaccines are recommended.[2] 

Dystrophic and Discolored Nails

Nail disease in YNS can resolve spontaneously. Evidence for using oral vitamin E to treat nail discoloration has mixed success.[32] Antifungals, combined with vitamin E, have been used despite the absence of fungal infection.[33] Other proposed treatments, such as oral zinc, clarithromycin, and corticosteroid injections, have poor evidence to support their use.[34][35][36]

Lymphedema

Lymphedema observed in YNS is treated with the same interventions used in primary lymphedema. Generally, nonsurgical interventions include compression garments, bandaging, skin care, manual lymph drainage, and exercises.[37]

Differential Diagnosis

Because YNS involves multiple symptoms from various organ systems, the differential diagnosis is broad. The pulmonary manifestations of YNS, such as pleural plaques and pleural thickening, have characteristics similar to those of asbestos-related lung disease.[38] Heart failure, which is far more prevalent than YNS, is commonly associated with lower extremity edema and pulmonary effusions in its decompensated state.[39] Edema due to vascular congestion is usually improved with diuresis, which is not the case with lymphedema. Systemic illnesses, such as connective tissue disease, autoimmune conditions, various malignancies, endocrine abnormalities, and immunodeficiency states, can be associated with yellow nails.[2] Onychomycosis must also be considered in patients with yellowed dystrophic nails.[40]

Prognosis

The prognosis in YNS depends on the patient's symptoms and co-existing illnesses. Symptoms range from mild (poor nail cosmesis and chronic cough) to severe (marked and recurring edema, persistent pulmonary infections). There is no cure for YNS; treatment aims to improve symptoms.

Complications

Because YNS involves multiple organ systems, complications depend on which specific symptoms the patient exhibits. Dystrophic and discolored nails can cause psychological distress from embarrassment, and onycholysis can be painful.[2] There are potentially life-threatening complications related to the pulmonary and lymphatic manifestations observed in YNS.

Pulmonary

Large and persistent pleural effusions are uncomfortable and can cause a significant decline in functional status. Effusions are associated with other potentially fatal complications, such as infection and respiratory distress.[10] Often, serial thoracenteses are required and carry the risk of infection, bleeding, pneumothorax, and significant discomfort.[41] Frequent draining of pleural effusions (which are high in protein) can lead to hypoalbuminemia, which further exacerbates edema and the recurrence of effusions.[42] Frequent prescribing of antimicrobials due to recurring respiratory infections can lead to antibiotic resistance.

Lymphatic

Significant edema usually affects the bilateral lower extremities, leading to difficulty with ambulation and deconditioning. Furthermore, longstanding lymphedema leads to changes in skin texture and color, which can be esthetically unappealing and can lead to cellulitis and other infections.[43][44] Additional areas for fluid accumulation include the peritoneal space, which may require paracentesis, genitalia, leading to tissue breakdown and discomfort, and the periorbital area, which can cause difficulty with vision.[45]

Deterrence and Patient Education

Yellow nail syndrome is an extremely rare diagnosis that can go undiagnosed or misdiagnosed for years before other more common conditions are ruled out. If standard therapy is not successful, the interprofessional team and caretakers must advocate for further investigation and consideration of differential diagnoses. There is no specific treatment for YNS; therefore, patients must be aware of any intervention's potential harms and limited success.

Pearls and Other Issues

Key facts to keep in mind about YNS are as follows:

• The diagnosis of YNS requires 2 of the following: yellow nails, lymphedema, and pulmonary disease.
• YNS is often misdiagnosed as onychomycosis; however, histopathological analysis of nail samples is negative for fungus. Similarly, examination under Wood lamp is typically negative.
• YNS can mimic heart failure, a far more common condition, as it also can present with dyspnea on exertion, pleural effusion, and lower extremity edema.
• Treatment for YNS is generally supportive and focused on treating symptoms. Symptoms often improve regardless of intervention but usually recur.
• Lymphoscintigraphy is a method used to assess lymphatic function. Testing is typically abnormal in patients with YNS but is less severe than those with primary lymphedema.
• The exact mechanism of YNS is unknown, but it is thought to be due to functional impairment in the lymphatic system that leads to changes in capillary permeability.

Enhancing Healthcare Team Outcomes

YNS frequently goes undiagnosed or misdiagnosed for many years. Patients with this condition may exhibit nonspecific signs and symptoms, including cough, recurrent infection, lower extremity edema, and nail discoloration, present in conditions far more prevalent than YNS, such as heart failure, venous insufficiency, infection, or medication-adverse events. This can lead to patients being referred to many specialists in cardiology, infectious disease, endocrinology, and pulmonology. Although a more common illness is more likely in patients who present with 2 or 3 signs and symptoms of the triad of YNS, health professionals must communicate effectively and rule out these other illnesses to limit unnecessary testing, treatment, and consultation. Healthcare professionals must keep YNS on the differential as it is a clinical diagnosis. Approximately one-third of patients with YNS have all 3 signs or symptoms simultaneously.[6] Furthermore, a single symptom may be present for several months or even years, making diagnosis difficult and delayed.[46] Detailed documentation of signs or symptoms and resistance to anchoring bias is essential to prompt diagnosis of YNS.

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Disclosure: Megan Cheslock declares no relevant financial relationships with ineligible companies.

Disclosure: Douglas Harrington declares no relevant financial relationships with ineligible companies.