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Yellow Nail Syndrome

YNS

Yellow nail syndrome is a very rare disease of largely unknown etiology that is characterized by nail dystrophy, pleural effusion, peripheral lymphedema and recurrent airway infection.


Presentation

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
  • Yellow nail syndrome is characterized by primary lymphoedema, recurrent pleural effusion and yellow discoloration of the nails.[ncbi.nlm.nih.gov]
  • 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]
  • Two cases of yellow nail syndrome (a triad of yellow dystrophic nails, chronic lymphedema and pleural effusion) are described which demonstrate long-term control of recurrent pleural effusions by tetracycline pleurodesis.[ncbi.nlm.nih.gov]
  • We report two cases of recurrent pleural effusions in YNS, the first case with bilateral effusions and the second with right-sided effusions treated 2 months apart from bilateral long-term tunnelled catheters and thoracoscopic pleurectomy and compare[ncbi.nlm.nih.gov]
  • A 61 year old male, with a bilateral persistent and recurrent pleural effusion, had undergone frequent tapping over a period of eight months, prior to the referral.[ncbi.nlm.nih.gov]
Nail Abnormality
  • The patient reported that her grandmother had similar nail abnormality and lower extremity edema. Other family members and patient's grandchildren were healthy. This report demonstrates a case of familial yellow-nail syndrome.[ncbi.nlm.nih.gov]
  • 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]
  • These nail abnormalities may also change over time.Most people with yellow nail syndrome (four fifths) have lymphedema; it is symmetrical and typically affects both legs. It is the first symptom of the condition in about a third.[en.wikipedia.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]
Multiple Congenital Anomalies
  • Winter and Michael Baraitser, A catalogue of multiple congenital anomaly syndromes, Multiple Congenital Anomalies, 10.1007/978-1-4899-3109-2_1, (1-672), (1991). D.A. Fenton, R. Bull, J. Gane and P.S.[doi.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]
  • The patient was diagnosed as having the yellow nail syndrome based on the triad of yellow nails, lymphedema, and pleural effusions. The patient's intractable bilateral pleural effusion was treated with pleurodesis using OK-432.[ncbi.nlm.nih.gov]
  • A chest roentgenogram revealed a large right pleural effusion and a small left pleural effusion.[ncbi.nlm.nih.gov]
  • Yellow nail syndrome, also known as "primary lymphedema associated with yellow nails and pleural effusion", is a very rare medical syndrome that includes pleural effusions, lymphedema (due to under development of the lymphatic vessels) and yellow dystrophic[en.wikipedia.org]
  • The pleural effusions often require pleurodesis. The pathogenesis is probably a dysfunction of the lymphatic system (1, 2).[ncbi.nlm.nih.gov]
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]
  • He presented at birth with congenital lymphoedema and was referred at 6 months of age for investigation of recurrent cough and wheeze. He had clinical and radiological evidence of bilateral pleural effusions and a pericardial effusion.[ncbi.nlm.nih.gov]
  • At 12 months after successful LT, the patient has good graft function, but findings of YNS including chronic cough, lymphedema and yellow nails are still present. To the best of our knowledge, this is the first case of YNS who underwent LRLT for FHF.[ncbi.nlm.nih.gov]
  • The patient had experienced several episodes of nonproductive cough during the previous few years. Each episode had lasted 2–3 months before subsiding spontaneously.[doi.org]
  • A 38-year-old woman was referred to the emergency complaining of chronic cough and increasing dyspnea within last 2 weeks. She had given birth 1 month ago.[ncbi.nlm.nih.gov]
Productive Cough
  • He also had a concurrent history of chronic sinusitis with persistent productive cough.[ncbi.nlm.nih.gov]
  • Respiratory manifestations included chronic productive cough (100%), chronic rhinosinusitis (88%), pleural effusions (20%) and lymphoedema (12%). Chest symptoms preceded yellow nails in the majority (68%).[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]
  • Half a year later, she developed viscous postnasal drip and a productive cough. Later, her nails became yellow and thickened. She shed the nails on both thumbs and on her right middle finger. She had gold in many of her teeth.[doi.org]
Purulent Sputum
  • The patient underwent cultures of purulent sputum for Streptococcus pneumoniae and Haemophilus influenzae, bronchial washings for H. influenzae, and nail scrapings for fungi.[ncbi.nlm.nih.gov]
Yellow Nails
  • ., YELLOW NAILS AND LYMPHCEDEMA, The Lancet, 283, 7346, (1313), (1964).[doi.org]
  • We report the second case of post-operative yellow nail syndrome.[ncbi.nlm.nih.gov]
  • Yellow nail syndrome What are the signs and symptoms? Yellow nail syndrome most often starts in middle age, although a similar condition has been described in younger children.[dermnet.org.nz]
  • Abstract Yellow nail syndrome (YNS) is triad of yellow nails, lymphedema, and respiratory tract involvement. The exact pathogenesis of nail changes in YNS is unknown.[ncbi.nlm.nih.gov]
  • 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]
Nail Deformity
  • deformity is characterized by thickening and excessive transverse curvature of the nail plate.[romj.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]
Adnexal Mass
  • Physical examination showed yellow thickened nails and lower limb oedema, and a painless huge adnexal mass. Diverse tumours have been described associated with yellow nail syndrome; however, associations can also occur by chance.[ncbi.nlm.nih.gov]
Neglect
  • We present a case of a 55-years-old woman that had an insidious onset of respiratory disorders and chronic sinusitis, suspected to be infectious throughout the hospitalizations, associated with therapeutically neglected autoimmune thyroiditis.[ncbi.nlm.nih.gov]

Workup

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.

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]
  • The patient was diagnosed as having the yellow nail syndrome based on the triad of yellow nails, lymphedema, and pleural effusions. The patient's intractable bilateral pleural effusion was treated with pleurodesis using OK-432.[ncbi.nlm.nih.gov]
  • A chest roentgenogram revealed a large right pleural effusion and a small left pleural effusion.[ncbi.nlm.nih.gov]
  • Yellow nail syndrome, also known as "primary lymphedema associated with yellow nails and pleural effusion", is a very rare medical syndrome that includes pleural effusions, lymphedema (due to under development of the lymphatic vessels) and yellow dystrophic[en.wikipedia.org]
  • The pleural effusions often require pleurodesis. The pathogenesis is probably a dysfunction of the lymphatic system (1, 2).[ncbi.nlm.nih.gov]

Treatment

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:

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

Prognosis

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].

Etiology

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.

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

No specific measures can be recommended to prevent YNS.

Summary

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].

Patient Information

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.

References

Article

  1. Hoque SR, Mansour S, Mortimer PS. Yellow nail syndrome: not a genetic disorder? Eleven new cases and a review of the literature. Br J Dermatol. 2007; 156(6):1230-1234.
  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.
  6. Berglund F, Carlmark B. Titanium, sinusitis, and the yellow nail syndrome. Biol Trace Elem Res. 2011; 143(1):1-7.
  7. Nordkild P, Kromann-Andersen H, Struve-Christensen E. Yellow nail syndrome--the triad of yellow nails, lymphedema and pleural effusions. A review of the literature and a case report. Acta Med Scand. 1986; 219(2):221-227.
  8. Valdés L, Huggins JT, Gude F, et al. Characteristics of patients with yellow nail syndrome and pleural effusion. Respirology. 2014; 19(7):985-992.
  9. D'Alessandro A, Muzi G, Monaco A, Filiberto S, Barboni A, Abbritti G. Yellow nail syndrome: does protein leakage play a role? Eur Respir J. 2001; 17(1):149-152.
  10. Maldonado F, Ryu JH. Yellow nail syndrome. Curr Opin Pulm Med. 2009; 15(4):371-375.
  11. Lambert EM, Dziura J, Kauls L, Mercurio M, Antaya RJ. Yellow nail syndrome in three siblings: a randomized double-blind trial of topical vitamin E. Pediatr Dermatol. 2006; 23(4):390-395.
  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.

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Last updated: 2019-07-11 21:04