The most characteristic symptom of YNS is nail dystrophy. Patients present with regularly thickened, yellowishly discolored finger- or toe nails and report abnormally slow nail growth. Alterations may furthermore affect nail folds and bases and loss of cuticles, erythema and edema can often be noted here. The latter may also be provoked by paronychia, i.e., by concurrent inflammation of soft tissues surrounding the nails. In some cases, severe dystrophy results in separation of nails from nail beds and nails fall out. Roughening and loss of transparency are not usually observed in YNS. Nail dystrophy may precede other symptoms by years.

Other symptoms mainly refer to pleural effusion and peripheral lymphedema. The former manifests in dyspnea, cough and chest pain; the latter in considerable swelling of different parts of the body. Initially, lymphedema renders the skin of affected areas soft and puffy, but chronic lymphedema is associated with fibrotic changes and thus hardening of the skin. Lymphedema most frequently affects the lower limbs.

Many YNS patients suffer from refractory infections of the respiratory tract. Chronic or recurrent sinusitis, bronchitis and pneumonia are often observed. Bronchiectasis may be detected in computed tomography scans. Indeed, recurrent airway infections may be the very first indicator of YNS, but the latter cannot be diagnosed before onset of additional symptoms.

• Recurrent Pleural Effusion

  Initially he presented with recurrent pleural effusion, which developed into empyema within 3 years. This case serves to reinforce that recurrent pleural effusions should be initiated in the early stage of YNS to prevent the development of empyema. [ncbi.nlm.nih.gov]

• Nail Abnormality

  Although nail abnormalities were the first sign to be noticed, this syndrome is now known to involve multiple organ systems and its association with other diseases is well described. A review of the medical literature is provided. [ncbi.nlm.nih.gov]

  Fawcett RS, Linford S, Stulberg DL, Nail Abnormalities: Clues to Systemic Disease. [dermnet.org.nz]

  Ask your provider about medicines that help with abnormal-appearing nails. If you have a nail infection, you may be prescribed antifungal or antibacterial drugs. [nlm.nih.gov]

• Falling

  Nails grow very slowly and may even fall out. Inflammation of nail folds is sometimes reported. Pleural effusion and peripheral lymphedema form also part of the characteristic YNS symptom triad. [symptoma.com]

  Puliyel A 93-year-old lady presented following a fall causing public rami fractures. Clinical examination revealed yellow discolouration of the nails (Figure 1 a), which had been present for at least 2 years. [academic.oup.com]

  The nail can become loose and sometimes falls off. Pitting is associated with psoriasis and alopecia areata. Ridges are tiny, raised lines that develop across or up and down the nail. [nlm.nih.gov]

  Last fall I saw a Swedish medical study called "Titanium, Sinusitis, and the Yellow Nail Syndrome" that claims that titanium and/or titanium dioxide is the cause of YNS. [medhelp.org]

• Myxedema

  The common causes of a transudate (cardiac failure, hepatic cirrhosis, nephropathy, myxedema, or hypoproteinemia) or exudate (lymphoma, metastatic disease, connective tissue disease, infection) were excluded. [circ.ahajournals.org]

• Fatigue

  In the six months before admission he had an episodic productive cough associated with dyspnoea and pleural effusions, intense fatigue and weight loss of ∼7 kg. [erj.ersjournals.com]

  They all admit I have a chronic cough, a thick gel-like mucous, problems breathing, extreme fatigue,nodules in my lungs and bronchial tubes (with a hardening of the bronchial tubes), swelling of hands and feet. [medhelp.org]

• Pleural Effusion

  Top, Chest radiograph on admission, showing bilateral pleural effusions with normal heart and normal pulmonary vasculature. Bottom, Spontaneous reduction in both pleural effusions after 7 weeks. [circ.ahajournals.org]

  A chest roentgenogram revealed a large right pleural effusion and a small left pleural effusion. [ncbi.nlm.nih.gov]

  […] association with chronic pleural effusion was later described by Emerson (2). [caribbean.scielo.org]

• Cough

  Three years later she had normal nails and no cough, but her knee implant had loosened. She received a new titanium implant, and a year later she again had a productive cough and yellow nails with titanium (1.1 μg g −1 ). [doi.org]

  A case of yellow nail syndrome involving an eight-year-old girl with associated discoloured yellowish nails on the fingers and toes, lymphedema and chronic cough, and sputum production is reported. [ncbi.nlm.nih.gov]

• Productive Cough

  He also had a concurrent history of chronic sinusitis with persistent productive cough. [ncbi.nlm.nih.gov]

  A 54-year-old woman was referred for evaluation of possible cor pulmonale based on the presence of dyspnea, chronic productive cough, and bilateral leg edema for 8 years. [circ.ahajournals.org]

  Three years later she had normal nails and no cough, but her knee implant had loosened. She received a new titanium implant, and a year later she again had a productive cough and yellow nails with titanium (1.1 μg g −1 ). [doi.org]

• Rhinorrhea

  Clinical signs include daily mucopurulent rhinorrhea, nasal obstruction and frequent post-nasal drip. [ojrd.biomedcentral.com]

• Jaundice

  Jaundice (Hyperbilirubinemia) in Adults Jaundice (hyperbilirubinemia) in adults may be caused by a variety of medical diseases or conditions. Some cases of jaundice can... [medicinenet.com]

  Yellow nails are caused by various conditions, such as: Jaundice The presence of icterus causes yellowish discoloration of the nails when the bilirubin deposition is heavy. [news-medical.net]

  Other possible reasons why your nails can turn yellow include: bronchiectasis, or damaged airways lung infections, such as tuberculosis overusing nail polish without giving your nails a break jaundice certain medications, such as quinacrine (Atabrine) [healthline.com]

• Myalgia

  Anecdotal associations have also been described: anhydrosis, pectus excavatum, eosinophilia–myalgia syndrome, bullous stomatitis, sarcoidosis and Raynaud’s phenomenon, cerebral aneurysm and pancytopenia [ 6 ]. [ojrd.biomedcentral.com]

• Chemosis

  The other findings documented in patients with YNS may include chylous ascites and intestinal lymphangiectasia (16, 17), chronic chemosis and peri-orbital oedema (18), and severe recurrent pericardial effusion (19). [caribbean.scielo.org]

  Fig. 3 Sinus computed-tomography scan: note the subtotal opacity of the left maxillary sinus and ethmoidal sinusitis Other manifestations Very rare ocular involvement has been reported: chemosis, corneal micropannus (vascularized sheet of fibrous tissue [ojrd.biomedcentral.com]

  I have bronchiectasis and also " chemosis of conjuctiva “( whites of my eye’s are swollen, Painful ! ) And of course yellow nails, detached, malformed on hands and toes, no cuticles. [medhelp.org]

• Yellow Nails

  TY - JOUR T1 - Relapse of Yellow Nail Syndrome with Pulmonary Lymphedema. [unboundmedicine.com]

  We also did a short literature review of yellow nail syndrome. [caribbean.scielo.org]

  Therefore, yellow nail syndrome should be suspected in children having only typical nail changes. [casesjournal.biomedcentral.com]

  What is yellow nail syndrome ? Yellow nail syndrome is a rare disorder of the nail, which is usually accompanied by lymphoedema (swelling of parts of the body caused by blockage or damage to the drainage of the lymphatic system). [dermnet.org.nz]

  Yellow nail syndrome (YNS) is a rare clinical entity of unknown etiology that is characterized by a triad of yellow nails, respiratory manifestations, and lymphedema. [ncbi.nlm.nih.gov]

• Skin Disease

  American Family Physician 2004;69:1417-24 On DermNet NZ: Nail diseases Onycholysis Skin signs of rheumatic disease Other websites: Books about skin diseases: See the DermNet NZ bookstore [dermnet.org.nz]

  Psoriasis Psoriasis is a long-term skin condition that may cause large plaques of red, raised skin, flakes of dry skin, and skin scales.... [medicinenet.com]

• Nail Deformity

  […] disturbances and lymphedema; while the pincer nail deformity is characterized by thickening and excessive transverse curvature of the nail plate. [romj.org]

  A case of systemic lichen planus with nail deformity due to mercury in dental amalgam. Skin Res (1995) 37 :252–6. Google Scholar 11. Yokozeki H, Nuyama S, Nishioka K. [journal.frontiersin.org]

• Excessively Curved Nails

  Hypoalbuminemia and protein losing enteropathy are due to lymphatic leakage of protein and it is also associated with increased capillary permeability of the walls of villi.[ 5 ] Onycholysis, yellowish green, thickened, and excessively curved nails are [ncbi.nlm.nih.gov]

• Guillain-Barré Syndrome

  A Woollons, CR Darley : Yellow nail syndrome following Guillain-Barré syndrome Clin Exp Dermatol 22: 253 – 254, 1997 Crossref, Medline, Google Scholar 6. [jco.ascopubs.org]

  […] be a genetic abnormality with variable expression, this has been widely disputed. [4], [5] YNS is associated with several conditions including endocrine disorders such as diabetes and thyroid dysfunction, autoimmune diseases, immunodeficiency states, Guillain-Barré [jpgmonline.com]

  The syndrome may be idiopathic, familiar, or related to acquired immune deficiency syndrome (AIDS), collagen diseases, drug-effect, Guillain-Barré syndrome, hypoalbuminemia, hypogammaglobulinemia, malignancy, nephritic syndrome, thyroid disorders, tuberculosis [romj.org]

  Yellow nail syndrome following Guillain–Barré syndrome. Clin Exp Dermatol. 1997;22:253–4. doi: 10.1111/j.1365-2230.1997.tb01084.x. PubMed View Article Google Scholar Cockram CS, Richards P. Yellow nails and nephrotic syndrome. [ojrd.biomedcentral.com]

  Darley, Yellow nail syndrome following Guillain‐Barré syndrome, Clinical and Experimental Dermatology, 22, 5, (253-253), (2006). A. Hershko, B. Hirshberg, M. Nahir and G. [doi.org]

Diagnosis of YNS is based on physical examination. Patients may or may not present nail dystrophy, pleural effusion and peripheral lymphedema - diagnosis of YNS does not require the whole triad. Thus, patients may be diagnosed with YNS even though nail changes cannot be detected.

Further workup mainly aims at ruling out differential diagnoses and identifying possibly underlying disorders. A patient's medical history may be of great value to this end. An apparent susceptibility for airway infections is often reported, but additional complaints may hint at a primary disease.

With regards to laboratory analyses of blood samples, hypoalbuminemia is a very common finding in YNS patients. Inflammatory parameters may be altered due to concurrent respiratory infection.

Diagnostic imaging is carried out to assess the extent of pleural effusion. Lymphangiography may be realized to evaluate lymphatic system function and to locate the origin of lymphedema, but is associated with considerable risks of aggravation of damage. Therefore, lymphoscintigraphy is often preferred over lymphangiography.

• Pseudomonas

  There was a similar prevalence of Pseudomonas aeruginosa infection and mild lung function abnormalities. [ncbi.nlm.nih.gov]

  Codes ICD10CM: L60.5 – Yellow nail syndrome SNOMEDCT: 45342007 – Yellow nails Look For Subscription Required Diagnostic Pearls Subscription Required Differential Diagnosis & Pitfalls Onychomycosis Chronic paronychia Pseudomonas nail infection Drug-induced [visualdx.com]

  Pseudomonas is a type of bacteria that infects the nail bed and results in a greenish color to the nails. [medicinenet.com]

  Her sputurm cultures grew at various times Pseudomonas aeruginosa, Burkholderia cepacia, Streptococcus pneumoniae, Achromobacter xylosoxidans, Alcaligenes faecalis, and Moraxella catarhalis. [caribbean.scielo.org]

  Since the onset of nail changes, the patient's course has been complicated by Pseudomonas aeruginosa bronchitis and sinusitis. She did not have any features of lymphedema. Treatment with vitamin E 1,600 IU/day was started. [karger.com]

• Trichophyton Rubrum

  Fungal Nails Fungal nails (onychomycosis) may be caused by many species of fungi, but the most common is Trichophyton rubrum. Distal subungal... [medicinenet.com]

• Pleural Effusion

  Top, Chest radiograph on admission, showing bilateral pleural effusions with normal heart and normal pulmonary vasculature. Bottom, Spontaneous reduction in both pleural effusions after 7 weeks. [circ.ahajournals.org]

  A chest roentgenogram revealed a large right pleural effusion and a small left pleural effusion. [ncbi.nlm.nih.gov]

  […] association with chronic pleural effusion was later described by Emerson (2). [caribbean.scielo.org]

While there is no causative treatment for congenital YNS, acquired YNS may spontaneously resolve if the underlying disease can be identified and adequately treated. Further therapy aims at relieving symptoms and has to be adjusted to the individual complaints of each patient.

Nail dystrophy has been treated by topic and systemic administration of vitamin E, although its effectivity remains questionable and placebo oil has been stated to achieve similar results [11]. Of note, nail changes have also been reported to remit spontaneously.

Standard therapies are applied to treat pleural effusion, lymphedema and airway infections. Such therapies may comprise:

• For pleural effusion: thoracocentesis, pleurodesis, pleurectomy, implantation of a pleurovenous or pleuroperitoneal shunt and decortication [12].
• For lymphedema: compression, physiotherapy, general exercise as well as administration of supplementary zinc.
• For respiratory infections: expectorants, antitussives, antibiotics and anti-inflammatory drugs.

Families affected by inheritable forms of YNS may benefit from genetic counseling.

Although there is no specific treatment for YNS, the disease usually follows a benign course. Respiratory tract complications are managed with medication and possibly surgery and life expectancy of YNS patients is only modestly reduced when compared with the general population [10].

Etiological factors triggering or contributing to YNS are largely unknown.

YNS has been proposed to be a genetic disorder associated with congenital lymphatic hypoplasia and inherited with an autosomal dominant trait. This assumption is based on isolated case reports describing YNS in young children and increased prevalence in some families [3] [4]. In this context, FOXC2 gene mutations have been associated with non-congenital primary lymphedema . This gene encodes for forkhead box protein C2, a transcription factor expressed in a variety of tissues even before birth and required for cell differentiation and organ development. However, FOXC2 mutations have only been confirmed for specific types of lymphedema and any relation to YNS is still mere speculation [5]. In fact, most cases reported to day are sporadic and middle-aged and elder adults seem to be affected more often than children. Thus, the hypothesis of YNS being a primarily genetic disorder requires additional evidence before being accepted. The possibility of polygenic etiology should also be considered.

Most likely, gene variants predispose for YNS and environmental factors or comorbidities trigger symptom onset. Recently, chronic exposure to titanium has been proposed as a cause of YNS. The authors of that study state YNS to remit after interrupting release of titanium ions from titanium implants and to recur upon reexposure [6]. With regards to the latter, increased prevalence of YNS has been observed among those patients suffering from rheumatoid arthritis, thyroid disorder, immunodeficiency and malignancies like lymphoma and cancer of bronchial tubes, lungs, breast, gall bladder and kidneys. To date, it can only be speculated about the causal relation between each of those diseases and YNS. In some cases, medication prescribed to treat those disorders seems to trigger YNS rather than the disease itself. However, relations described between a specific disease and YNS are often anecdotal because of the small overall number of YNS cases reported so far.

While genetic disorders may lead to anatomical anomalies of the lymphatic system, acquired forms of YNS seem to be related to functional impairment of lymphatic vessels. Hypoplasia and malformation may be the result of the former; occlusion, dissection as well as an increased vascular permeability may account for the latter.

YNS is a very rare disease and less than 200 cases have been described so far. Thus, any epidemiological assessment is based on this restricted number of patients.

No predilection regarding race has been reported. An analysis of 97 YNS cases revealed a male-to-female ratio of 1 to 1.6 [7], but later retrospective studies found less differences regarding gender [8]. Most patients diagnosed with YNS are older than 50 years, but the disease has also been described in children. Possibly, acquired lymphatic disorders and congenital malformations or hypoplasia account for cases diagnosed in both age groups, respectively.

Most experts assume impaired function of lymphatic vessels to account for most YNS symptoms. YNS patients typically present with a symptom triad of nail dystrophy, pleural effusion and peripheral lymphedema - the latter two may be directly related to lymphatic vessel malfunction. Lymphangiography has been conducted in several patients diagnosed with YNS and lymphatic hypoplasia has been detected in a considerable share of patients examined. Minor morphologic anomalies may still be related to significant loss of function, but are not necessarily recognizable by means of lymphangiography. Also, interpretation of lymphangiographic images may be a very challenging task. Histopathological analyses of tissue samples obtained from YNS patients would be of much help to determine if lymphatic vessel structure is altered or not in those individuals that weren't diagnosed with hypoplasia. Malformations of lymphatic vessels may provoke an increase of lymphatic capillary permeability and a reduction of lymphatic drainage [9]. Presumably, both contribute to pleural effusion and peripheral lymphedema. These conditions may cause dyspnea and lymphatic fibrosis, respectively.

Pleural effusion fluid samples have been analyzed in order to distinguish between lymph, transudate and exudate. However, criteria for neither of these classic categories are fully met: This fluid is very rich in proteins, a property corresponding to exudate, but does contain very limited amounts of leucocytes, which is more typical for lymph and transudate. Lymphocytes predominate [8]. Contrary to lymph drained from other tissues, physiological pleural fluid is rather poor in proteins. These findings argue for the above stated theory of considerable elevation of vascular permeability and insufficient drainage adding to pleural effusion. Thus, according to current knowledge, pleural fluid formation is augmented and removal is decreased.

No specific measures can be recommended to prevent YNS.

Yellow nail syndrome (YNS) is a very rare disease typically involving nail dystrophy and discoloration, pleural effusion, recurrent infections of the respiratory tract and peripheral lymphedema.

Nail changes are often the most striking symptom, but some YNS patients may only suffer from respiratory and lymphatic disorders. On the other hand, nail dystrophy may be the only manifestation of the disease. Both fingernails and toe nails may be affected by retarded growth, thickening, yellowish discoloration, infection or even nail loss. Nail dystrophy presumably results from impaired lymphatic drainage due to lymph vessel malfunction. Lymphatic hypoplasia is generally assumed to account for the latter, whereas the role of vessel occlusion or dissection remains elusive. Similarly, pleural effusion and peripheral lymphedema are provoked by insufficient lymphatic drainage. However, recurrent sinusitis, bronchitis and pneumonia as well as bronchiectasis may not be explained by lymphatic hypoplasia.

Most YNS cases - not even 200 have been reported to date - occur sporadically. Familial accumulation has only been observed in isolated cases and the hypothesis of YNS being an inheritable form of lymphedema is not generally accepted [1]. A number of theories regarding alternative causes has been published. In this context, YNS has been reported to be drug-induced, has been related to rheumatoid arthritis, thyroid disorder and malignant neoplasms. Spontaneous remission after successful treatment of the underlying disease has been described [2].

Yellow nail syndrome (YNS) is a very rare disease characterized by nail changes, fluid accumulation around the lungs, recurrent infection of the respiratory tract and peripheral lymphedema. Less than 200 cases have been reported to date.

Causes

The precise causes of YNS are largely unknown. Although the disease is typically diagnosed in middle-aged adults, congenital forms have been described. This fact implies genetic defects to account for YNS. However, YNS has also been related to other diseases, e.g., to rheumatoid arthritis, thyroid disorder and cancer, and these may trigger symptom onset in elder individuals. Presumably, genetic predisposition and environmental factors both contribute to YNS.

Functional impairment of the lymphatic system may lead to fluid accumulation in the pleural cavity, i.e., in the small space between lungs and rips, and in peripheral tissues. It may be caused by developmental defects of lymphatic vessels or acquired malfunction. Little is known about the pathophysiology of nail changes and airway infections.

Symptoms

YNS is named after one of its most common symptoms: a yellow discoloration of finger- and/or toe nails. Nails are thicker than usual but don't lose their transparency. Nails grow very slowly and may even fall out. Inflammation of nail folds is sometimes reported.

Pleural effusion and peripheral lymphedema form also part of the characteristic YNS symptom triad. The former is the medical term for the accumulation of fluid around the lungs; this condition may cause breathing difficulties. Peripheral lymphedema manifests as swollen, puffy skin.

Additionally, YNS patients may experience recurrent infections of the respiratory tract.

Diagnosis

Diagnosis is based on clinical examination. Of note, YNS patients don't necessarily present all three signs of the above described symptom triad.

Further diagnostic measures may be carried out to assess the extent of lesions and to rule out differential diagnoses. To this end, laboratory analysis of blood samples, plain radiography and computed tomography scans may be realized.

Treatment

Therapy is largely symptomatic. However, if an underlying disease can be identified and cured, YNS-associated symptoms may resolve spontaneously.

Nail changes may be treated by local administration of vitamin E or systemic supplementation of that compound. A variety of drugs and surgical procedures may be applied to treat pathologies of the respiratory tract and peripheral lymphedema. Therapeutic approaches as distinct as administration of antibiotics, physiotherapy and surgical drainage of pleural fluid may be carried out to this end.

While nail changes sometimes remit spontaneously, YNS patients often suffer from chronic malfunction of their lymphatic system and require regular follow-ups.

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2. Iqbal M, Rossoff LJ, Marzouk KA, Steinberg HN. Yellow nail syndrome: resolution of yellow nails after successful treatment of breast cancer. Chest. 2000; 117(5):1516-1518.
3. Nanda A, Al-Essa FH, El-Shafei WM, Alsaleh QA. Congenital yellow nail syndrome: a case report and its relationship to nonimmune fetal hydrops. Pediatr Dermatol. 2010; 27(5):533-534.
4. Razi E. Familial yellow nail syndrome. Dermatol Online J. 2006; 12(2):15.
5. Rezaie T, Ghoroghchian R, Bell R, et al. Primary non-syndromic lymphoedema (Meige disease) is not caused by mutations in FOXC2. Eur J Hum Genet. 2008; 16(3):300-304.
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10. Maldonado F, Ryu JH. Yellow nail syndrome. Curr Opin Pulm Med. 2009; 15(4):371-375.
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12. Tanaka E, Matsumoto K, Shindo T, Taguchi Y. Implantation of a pleurovenous shunt for massive chylothorax in a patient with yellow nail syndrome. Thorax. 2005; 60(3):254-255.