NORD gratefully acknowledges Fabien Maldonado, MD, Professor of Medicine, Thoracic Surgery and Mechanical Engineering, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, for assistance in the preparation of this report.
Yellow nail syndrome is an extremely rare disorder characterized by malformations affecting the fingernails and toenails, abnormalities affecting the lungs and the airways (respiratory tract) and swelling or puffiness in different parts of the body because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the skin (lymphedema). Yellow nail syndrome usually affects older adults. The exact cause of yellow nail syndrome is not known. Occasionally, yellow nail syndrome has been reported to run in families suggesting that genetic factors may play a role in the development of the disorder in some patients.
The characteristic finding associated with yellow nail syndrome is the development of yellow, thickened, and excessively curved nails with almost complete stoppage of nail growth. Loss of the strip of hardened skin at the base and sides of a fingernail (cuticles) may also occur. Separation of the nails from the nail bed (onycholysis) may cause the nails to fall out. Some individuals may develop infection of the soft tissue around edge of the nails (paronychia). Any nail (both toenails and fingernails) may be affected. Unlike the nails in similar, related disorders, the nails of individuals with yellow nail syndrome generally remain clear (translucent) and smooth as opposed to not transparent (opaque) and rough.
Yellow nail syndrome is occasionally associated with the accumulation of fluid in the membranes surrounding the lungs and lining the chest cavity (pleural effusion). Pleural effusions can cause shortness of breath, chest pain and a cough. Additional respiratory problems may occur in yellow nail syndrome such as chronic infection and inflammation of the main air passages (bronchial tubes) out of the lungs (bronchitis), destruction and widening of the small air passages out of the lung (bronchiectasis), ongoing inflammation of the membranes that line the sinus cavities (sinusitis) and/or chronic inflammation or infection of the lungs (recurrent pneumonias). Individuals with yellow nail syndrome may have a history of respiratory problems before developing characteristic nail findings.
Individuals with yellow nail syndrome often have swelling of the arms and legs due to the accumulation of a fluid known as lymph (peripheral lymphedema). The legs are especially affected in yellow nail syndrome. The onset of lymphedema may occur around puberty. Areas affected by lymphedema may feel heavy or tight. Decreased flexibility may develop in the hands, feet, wrists or ankles if lymphedema is present in the corresponding arm or leg. The skin on areas affected by lymphedema may become hardened or thickened.
The exact cause of yellow nail syndrome is not known. Most cases seem to occur randomly, for no apparent reason (sporadically). Some researchers believe that yellow nail syndrome is a sporadic, acquired condition. However, some sources in the medical literature currently classify yellow nail syndrome as a primary genetic disorder.
Some cases of yellow nail syndrome have run in families suggesting that, in these cases, genetic factors may play a role in the development of the disorder. Some researchers have speculated that yellow nail syndrome is inherited in an autosomal dominant pattern, although the evidence for this remains scarce. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
Some reports in the medical literature have linked some cases of yellow nail syndrome to changes (called mutations or variants) of the FOXC2 gene. This gene is known to cause a similar disorder called lymphedema-distichiasis syndrome. Some researchers believe that the only primary lymphedema disorder caused by mutation of this gene is lymphedema-distichiasis syndrome and that individuals with yellow nail syndrome linked to this gene may have been misdiagnosed.
Yellow nail syndrome has occurred with greater frequency than would be expected in individuals with certain forms of cancer, immunodeficiency syndromes, nephrotic syndrome, thyroid disease, and rheumatoid arthritis. In individuals with rheumatoid arthritis and yellow nail syndrome, researchers believe certain drugs used to treat the arthritis (thiol drugs) play a role in the development of yellow nail syndrome. Recent reports have suggested the possibility of titanium toxicity as a potential cause of the syndrome, prompting some physicians to recommend removal of titanium prostheses or dental implants on occasions. It should be emphasized that due to the rarity of the syndrome, this association remains entirely speculative. In addition, symptoms do not seem to improve significantly after removal. Accordingly, removal of titanium-based medical devices cannot be recommended.
Many of the symptoms of yellow nail syndrome are commonly associated with malfunction of the lymphatic system including yellow nails, lymphedema, and breathing (respiratory abnormalities). The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. Researchers believe that in yellow nail syndrome, lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. Researchers have also speculated that abnormal of leakage of fluid through very tiny vessels (microvascular permeability) may also contribute to the development of lymphedema in yellow nail syndrome.
Yellow nail syndrome affects males and females in equal numbers. More than 100 cases have been reported in the medical literature. Yellow nail syndrome usually occurs in older adults with most cases occurring in individuals over 50 years of age. Although uncommon, yellow nail syndrome can occur in children.
Yellow nail syndrome was first described in the medical literature in 1964.
A diagnosis of yellow nail syndrome is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. The nail changes in yellow nail syndrome are distinct from the nail changes that occur in most other lymphedema syndromes.
The treatment of yellow nail syndrome is geared toward the symptoms present in each individual. Treatment may include antibiotic therapy for repeated respiratory infections. The yellowed, malformed nails may improve without therapy. In some cases, the changes may be permanent. Vitamin E has been used to treat nail changes. Corticosteroids have also been used to treat individuals with yellow nail syndrome. Surgical management of respiratory problems such as pleural effusions has been used in some cases. Removal of titanium prostheses or dental implants is not recommended, as the evidence for a causal relationship between titanium and yellow nail syndrome is at best speculative, and symptoms do not appear dramatically improved after these interventions.
Genetic counseling may be helpful for affected individuals and their families. Other treatment is symptomatic and supportive.
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Maldonado F, Tazelaar HD, Wang CW, Ryu JH. Yellow nail syndrome: analysis of 41 consecutive patients. Chest. 2008;[Epub ahead of print].
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;56:1230-1234.
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;23:390-295.
Razi E. Familial yellow nail syndrome. Dermatol Online J. 2006;12:15.
Berry FB, Tamimi Y, Carle MV, Lehmann OJ, Walter MA. The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Hum Mol Genet. 2005;14:2619-27.
Lehuede G, Toussirot E, Despaux J, Michel F, Wendling D. Yellow nail syndrome associated with thiol compound therapy for rheumatoid arthritis. Two case reports. Joint Bone Spine. 2002;69:406-408.
D’Alessandro A, Muzi G, Monaco A, Filiberto S, Barboni A, Abritti G. Yellow nail syndrome: does protein leakage play a role? Eur Respir J. 2001;17:149-152.
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