Yellow Nail Syndrome

Yellow nail syndrome is a rare disorder defined by the triad of slow growing, thickened yellow nails, lymphoedema and respiratory disease. Any two of the three, with exclusion of other causes, support the diagnosis.

It presents in middle age, between 40 and 60 years, in both sexes. Respiratory features include chronic cough, bronchiectasis, chronic sinusitis and recurrent pleural effusions. It can be linked to rheumatoid arthritis, malignancy, thyroid disease, immunodeficiency and drugs such as penicillamine.

Pathophysiology. Hypoplasia or functional impairment of lymphatic vessels leads to lymph stasis, with leaky pulmonary and pleural lymphatics causing effusions, and nail changes from lymphoedema of the nail bed with slowed growth (under 0.2 mm each week).

Nails are thickened, yellow to green, curved with loss of the cuticle and lunula, and lifting from the nail bed (onycholysis). Lymphoedema is usually of the legs, and sometimes the face, with pitting. Respiratory features include chronic cough, dyspnoea, recurrent pneumonia, sinusitis and pleural effusions that are often bilateral.

Large pleural effusion with dyspnoea or respiratory failure needs urgent drainage, and weight loss with new effusion needs a search for malignancy.

• Clinical diagnosis from the nail changes, lymphoedema and respiratory disease. Nail clippings for fungal culture and microscopy, since fungal infection is common but does not account for the syndrome.
• Pleural fluid analysis: yellow, lymphocyte predominant exudate with high protein (over 3 g/dL), and often with low LDH. Exclude chylothorax (triglycerides over 1.24 mmol/L) and infection, malignancy and tuberculosis.
• High resolution CT: bronchiectasis, sinus disease, pleural effusion and thickening.
• Lymphoscintigraphy to show delayed lymphatic drainage.
• Screen for associated conditions: thyroid function, immunoglobulins, rheumatoid factor and anti-CCP antibodies, and a malignancy screen directed by symptoms, with a review of drugs (penicillamine, gold).

Differential diagnosis.

• Fungal onychomycosis and psoriatic nail disease
• Other causes of recurrent pleural effusion (malignancy, tuberculosis, heart failure)
• Primary lymphoedema
• Cystic fibrosis and primary ciliary dyskinesia causing sinus and bronchial disease
• Drug induced nail changes

• Nails: vitamin E (alpha tocopherol) 800 IU orally daily for 6 to 12 months, with or without itraconazole 200 mg daily for 1 week each month (pulse therapy) or 400 mg daily for 1 week monthly, with liver function checks and attention to interactions. Improvement is slow. Stop penicillamine if used.
• Pleural effusion: therapeutic thoracentesis for dyspnoea (maximum 1.5 L at once), and talc pleurodesis (4 to 5 g) or an indwelling pleural catheter for recurrent effusion. Pleuroperitoneal shunt or thoracic duct ligation in refractory cases, and octreotide has been used in a few cases.
• Bronchiectasis and sinusitis: airway clearance, azithromycin 250 mg daily or 500 mg three times weekly for recurrent infection, antibiotics directed by culture for exacerbation (amoxicillin-clavulanate 625 mg three times daily for 10 to 14 days), and nasal saline irrigation with intranasal corticosteroid.
• Lymphoedema: compression stockings, skin care, elevation and manual lymphatic drainage. Treat cellulitis early.
• Treat any associated rheumatoid arthritis, thyroid disease or malignancy.
• Vaccination against influenza, pneumococcus and COVID-19.

Monitoring. Review every 3 to 6 months with chest imaging for effusions, spirometry, nail growth and limb oedema measurements, and screen for malignancy as indicated.

Referral and escalation. Refer to a respiratory physician for effusion management, and to a vascular or lymphoedema service. Refer urgently for new effusion with weight loss.