Yellow nail syndrome
Department of Dermatology, New York University
A 70-year-old man presented with a three-year history of thickened and slow growing, yellow-to-green, discolored fingernails and toenails with loss of lunulae and cuticles. He also had a concurrent history of chronic sinusitis with persistent productive cough. His presentation was consistent with the diagnosis of yellow nail syndrome (YNS), which is a rare disorder classically characterized by the triad of yellow dystrophic nails, lymphedema, and respiratory tract abnormalities but which more frequently manifests with only two of three features. The exact mechanism of YNS remains unknown; however, it is thought to reflect functional and/or anatomic defects in the lymphatic vasculature. Treatment options are limited and often unsuccessful, but spontaneous remission occurs in approximately 30 percent of affected patients.
A 70-year-old man presented to the Charles C. Harris Skin and Cancer Pavilion in February, 2008, with a three-year history of thick and slow growing, yellow-to-green fingernails and toenails, some of which had undergone periodic shedding. He had been treated empirically for presumed onychomycosis by his primary medical doctor with a three-month course of oral terbinafine without improvement or resolution. The patient had been evaluated elsewhere in August, 2006, at which time nail clippings from multiple digits submitted for periodic acid-Schiff staining failed to show fungal elements. No further treatment was pursued. Review of systems disclosed a concurrent three-to-four-year history of chronic sinusitis and bronchitis with persistent productive cough for which the patient was being evaluated by an otorhinolarygologist. He denied other cutaneous or systemic complaints.
Medical history includes hypertension and gastritis; he is being treated with verapamil, hydrochlorothiazide, aspirin, omeprazole, potassium chloride, and multivitamins. He denied a family history of nail dystrophy, but reported that his father had bronchiectasis and chronic obstructive pulmonary disease and that his mother died from lung cancer.
Fingernails and toenails exhibited thick, yellow and green nail plates with transverse and longitudinal over-curvature. Loss of lunulae and cuticles affected all of the digits. Nail plates of the first and third digits of the left hand were absent without scars of the nail bed. Mild pitting edema to mid-shin was observed in the lower extremities.
A complete blood count, comprehensive metabolic panel, hepatic function panel, and fasting lipid profile were normal. Fungal cultures from nail clippings and subungual debris resulted in no growth. A chest computed tomography scan in January, 2008, was normal, without evidence of pleural or pericardial effusions or interstitial changes. Skin prick tests in February, 2008, showed reactivity to dust mites and molds.
Yellow nail syndrome (YNS), which was first described by Samman and White in 1964 and by Emerson in 1966, is an uncommon disorder that is characterized by a classic triad of yellow dystrophic nails, lymphedema, and respiratory tract abnormalities [1, 2]. The diagnosis of YNS requires two of the three primary features, and the complete triad is observed in only 27 percent of cases . Over 150 cases of YNS have been published in the adult and pediatric literature, with roughly 89 percent of patients exhibiting yellow nails, 80 percent exhibiting lymphedema of varying severity, and 63 percent suffering from respiratory abnormalities [3, 4]. Nail changes include slow growth (0.1-0.25 mm/week, normal 0.5-2 mm/week), yellow and green discoloration, transverse and longitudinal over-curvature that results in a hyperconvex nail plate, onycholysis, shedding, and loss of lunulae and cuticles [3, 5]. Erythema and edema of the proximal nail fold or chronic paronychia may be present . Respiratory involvement may vary but most often manifests as chronic cough, sinusitis, bronchiectasis, and exudative pleural effusions. In a recent case series, approximately 45 percent of YNS patients demonstrated nail changes and bronchiectasis or sinusitis without any evidence of lymphedema, which is similar to our patient's presentation .
The median age at onset is 40 years but varies widely from birth to the eighth decade. Individual manifestations of the syndrome can appear at different times. While it arises sporadically in most adults, YNS has also been reported in conjunction with immunodeficiency syndromes and autoimmune diseases, such as thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, and Guillain-Barré syndrome. YNS also has been described as a paraneoplastic syndrome in association with a variety of malignant conditions, which include lymphoma and carcinoma of the breast, lung, larynx, endometrium, and gall bladder [7, 8]. There have been isolated reports of familial and congenital cases of YNS, which suggests a genetic basis with heterogeneous inheritance [9, 10, 11]. Recently, a mutation in the FOXC2 gene, a forkhead transcription factor, was identified in a family with YNS and has been implicated in the development of multiple phenotypically-diverse lymphedema syndromes . This mutation is predicted to disrupt the DNA binding domain and/or C-terminal α-helices essential for transcription activation by the forkhead transcription factor .
The specific etiology of YNS remains obscure; however, the pathogenesis is thought to reflect functional or anatomic defects in the lymphatic vasculature and flow. In a subset of YNS patients, lymphangiography demonstrated hypoplastic, deficient, or sclerotic lymphatic vessels. Such abnormal lymphatic ducts are hypothesized to result in reduced lymphatic drainage, which leads to peripheral edema, pleural effusions, and nail changes when affecting the nail bed [13, 14, 15]. Another subset of YNS patients had persistent hypoalbuminemia due to increased enteric loss of albumin, which suggested that increased microvascular permeability may contribute to pathogenesis of the syndrome . Histopathologic investigation of the nail bed and matrix has shown dense, fibrous tissue replacing subungual stroma with ectatic, endothelium-lined lymphatics .
Treatment of the disfiguring nail changes in YNS is often sought due to the psychosocial ramifications. Effective treatment is challenging and frequently unsuccessful. Anecdotal case reports and a few small case series suggest some improvement with the use of topical and oral vitamin E, oral zinc supplementation, oral anti-fungals, and intralesional triamcinolone injections [4, 18, 19, 20]. Spontaneous remission of the nail changes has been reported in up to 30 percent of patients [3, 6].
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