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.

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.

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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