Title PageYELLOW NAIL SYNDROME: a case reportIntroductionYellow Nail Syndrome (YNS) is a rare disorder characterised by the triad of yellow and thickened nails, respiratory manifestations and lower limbs lymphedema. Two out of three clinical characteristics are required to diagnosis [1]. Less than 400 cases are described in literature with a prevalence of < 1/1.000.000. The diagnosis is clinical, particularly based on nail abnormalities, pulmonary manifestations, lymphedema and sinusitis. YNS is a condition of unknown aetiology, usually sporadic or presenting as a paraneoplastic syndrome, associated with cancer. To date there is not a specific treatment for YNS [1]. Resolution has been observed in up to 30% of patients, either spontaneously, or after cancer treatments in case of a paraneoplastic condition [1]. Herein we present a paraneoplastic case of YNS in a 67-years old never-smoker female, complaining chronic productive purulent cough for the last two years, after diagnosis of breast cancer.Key Clinical MessageYellow nail syndrome is a rare disorder affecting multiple districts. The diagnosis is clinical, based on nail abnormalities, pulmonary manifestations and lymphedema.The aetiology is unknown, usually presenting spontaneously or as a paraneoplastic syndrome.There is not an established treatment, while resolution is scarce.Case ReportCase History . A 67-years old never-smoker female was referred to a Respiratory outpatient clinic complaining productive purulent cough for the last two years despite treatments with mucolytic and antitussive. Two years before, following a diagnosis of left ductal mucinous breast cancer (G2 pT1No), she underwent quadrant surgery and local radiotherapy. Since then in remission and currently receiving hormonal therapy with anastrozole. She has a history of atrial fibrillation treated with warfarin and she refers otitis and sinusitis of recent onset (3 months). The high resolution thoracic CT scan highlighted bronchiectasis in the lower right inferior bronchus with mucus plugs. Spirometry was performed in stable conditions showing mild obstruction. A short course of oral clarithromycin was not effective in reducing respiratory symptoms. The thoracic CT scan performed after 6 months showed a parenchymal consolidation (organising pneumonia) in the lower right lobe (Fig 1A). She was then referred to our Outpatient clinic.Methods . She reported that during the last year her nails turned yellow, thicker and frail with slowed growth of both finger and toenails (Fig. 1B). Onychomycosis was excluded by a Dermatologic evaluation and Wood’s lamp test. No history of lower limb lymphedema was reported. Due to persistent respiratory symptoms resistant to antibiotic therapy a bronchoscopy was performed showing purulent material dripping from the nasal districts and mucous-purulent secretions in the lower right bronchus, in the absence of sign of malignancy. Based on xantonychia, bronchiectasis and sinusitis a diagnosis of yellow nail syndrome was performed.Conclusion and Results . A short course of azithromycin was started although the bronchoscopy culture resulted negative, with partial remission of the productive cough. The patient was subsequently chronically treated with low dose azithromycin (500 mg twice/week), a cycling combination of N-Acetyl-L-Cysteine + Lactoferrin + Resveratrol; cycling oral Vitamin E and inhaled umeclidinium. After six-months the patients referred remission of the chronic productive cough, otitis and sinusitis; the yellow nails condition remained unchanged. She is continuing the regular oncologist follow up, still in remission.DiscussionYellow Nail Syndrome (YNS) - OMIM 153300; ORPHA662 - is a rare disorder characterised by the triad of yellow and thickened nails, respiratory manifestations and primary lymphedema [1]. Two out of three clinical characteristics are required to diagnose YNS [1]. First described in 1927, the current definition dates back to 1966 [2]. There are less than 400 cases described in literature with a prevalence < 1/1.000.000. YNS is a condition of unknown aetiology, usually sporadic and affecting adults over 50 years worldwide, with no gender predominance [1] The completed triad is present only in 27-60% of cases, with nail chromonychia being the main clinical manifestation, as shown in Table 1. The diagnosis is clinical, particularly based on nail abnormalities, pulmonary manifestations, lymphedema and sinusitis. Chromonychia (nail discoloration), together with xantonychia (yellow nail coloration), progressive thickening and hardening of the nail plate and a slow growth (reduced by half), are the main characteristics of the YNS [1]. Respiratory manifestations occur in 60-70% of patients, with chronic cough as the most frequent symptom [3, 4]. Pleural effusion presents in up to 46% of cases, usually bilateral with a lattescent appearance (chylothorax); bronchiectasis in 44% [1, 4]. Both chronic and acute rhinosinusitis are common, presenting in 14-83% of cases with daily mucopurulent rhinorrhea and nasal obstruction [1]. Lower limbs lymphedema is present in 29-80% of cases, usually bilateral [1]. A lymphatic disorder with defective lymphatic drainage has been hypothesised as a possible cause of lymphedema, pleural effusion and subungual tissue sclerosis with nail alterations [1]. Another hypothesis considers microvasculopathy and protein leakage [3, 5]. YNS may present as a paraneoplastic syndrome, associated with malignant diseases, such as lung and breast cancer or non-Hodgkin lymphoma [1]. The paraneoplastic presentation could be due to lymphatic micro-obstruction, possibly correlated with circulating tumour microemboli [6], or due to cancer histopathology. Other diseases described associated with YNS are autoimmune and immunodeficiency [1]. Differential diagnosis is broad and involves: asbestos-related disease, heart failure, connective tissue diseases, malignancies and onychomycosis are the main ones [4]. To date there is not a specific treatment for YNS. Resolution has been observed in up to 30% of patients, either spontaneously, or after cancer treatments in case of a paraneoplastic condition [1]. Oral α-tocopherol (vitamin E) at 1000-1200 IU/day, is considered the only partially effective agent nail alterations [1]. Regular antifungal treatment (itraconazole or fluconazole) and oral zinc sulphate were also tried, with scarce evidence [1]. A randomised study using topic vitamin E preparation showed no difference versus placebo [7]. Acute exacerbations of bronchiectasis and sinusitis can be treated with antibiotics and symptomatic drugs, whereas for recurrent flares up or poor symptom control, low dose oral azithromycin (250 mg 3 times/week), and a physiotherapy program should be prescribed. Flu and pneumococcal vaccinations are recommended [1]. Surgical intervention for recurrent or large pleural effusions can be useful, while somatostatin analogues as octreotide for chylothorax can be tried [1]. Complete decongestive therapy is an option for lymphedema volume reduction [1].