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Fabien Maldonado, MD; Jay H. Ryu, MD, FCCP
Author and Funding Information

Mayo Clinic Rochester, MN

Correspondence to: Fabien Maldonado, MD, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905; e-mail: maldonado.fabien@mayo.edu


The authors have no conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2008;134(6):1353-1354. doi:10.1378/chest.08-2181
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To the Editor:

Zarogiannis and colleagues raise several important issues. As they correctly point out, a defect in lymphatic function, either acquired or hereditary in nature, seems the most likely culprit in explaining the diverse manifestations of yellow nail syndrome (YNS). Indeed, the first description of YNS included lymphangiographic studies in 13 patients with evidence of anatomic lymphatic abnormalities in 4 patients.1 Other authors2,3 have described hypoplastic or ectatic lymphatic vessels on histopathologic specimens. Functional lymphatic impairment has been suggested on the basis of reduced pleural lymphatic outflow using radioiodinated albumin.

Analysis of the histopathologic specimens available in our study failed to identify any obvious anatomic defect of the lymphatics, thus leading us to hypothesize that the underlying pathogenic mechanism for the YNS may be a functional defect in the majority of cases.4 However, it is possible that multiple mechanisms give rise to the manifestations that we recognize as YNS. As Zarogiannis et al point out, mutation in the transcription factor FOXC2 is a potential candidate in the pathogenesis of YNS because it has been closely linked to diseases of the lymphatics including lymphedema-distichiasis syndrome. We would also like to highlight the importance of the vascular endothelial growth factor (VEGF) family of proteins in lymphatic diseases and particularly VEGF receptor 3, which serves as the cognate receptor for VEGF-C and VEGF-D. This receptor plays a key role not only in lymphatic development but also function, both in relationship to lymphatic endothelial cells and paracrine interactions with pericytes. It is well established now that mutations in the VEGF receptor 3 gene are associated with a number of hereditary lymphatic diseases including primary lymphedema.5

Although entirely speculative, it is possible that the YNS may represent a phenotype common to diseases characterized by lymphatic-associated genetic mutations or in which an inherited abnormal lymphatic system may decompensate when certain triggering events, such as respiratory infections, occur (in a second-hit type phenomenon). This would account for the variety of clinical manifestations, age of presentation, and histopathologic characteristics commonly observed. Additional laboratory investigations (focusing specifically on the genes or gene products mentioned) on specimens isolated from patients with YNS would be likely to shed some light on this intriguing disorder.

Samman PD, White WF. The “yellow nail” syndrome. Br J Dermatol. 1964;76:153-157. [PubMed] [CrossRef]
 
Solal-Céligny P, Cormier Y, Fournier M. The yellow nail syndrome. Light and electron microscopic aspects of the pleura. Arch Pathol Lab Med. 1983;67:183-185
 
Wells GC. Yellow nail syndrome: with familiar primary hypoplasia of lymphatics, manifest late in life. Proc R Soc Med. 1966;59:447. [PubMed]
 
Maldonado F, Tazelaar HD, Wang CW, et al. Yellow nail syndrome: analysis of 41 consecutive patients. Chest. 2008;134:375-381. [PubMed]
 
Ghalamkarpour A, Morlot S, Raas-Rothschild A, et al. Hereditary lymphedema type I associated with VEGFR3 mutation: the firstde novocase and atypical presentations. Clin Genet. 2006;70:330-335. [PubMed]
 

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References

Samman PD, White WF. The “yellow nail” syndrome. Br J Dermatol. 1964;76:153-157. [PubMed] [CrossRef]
 
Solal-Céligny P, Cormier Y, Fournier M. The yellow nail syndrome. Light and electron microscopic aspects of the pleura. Arch Pathol Lab Med. 1983;67:183-185
 
Wells GC. Yellow nail syndrome: with familiar primary hypoplasia of lymphatics, manifest late in life. Proc R Soc Med. 1966;59:447. [PubMed]
 
Maldonado F, Tazelaar HD, Wang CW, et al. Yellow nail syndrome: analysis of 41 consecutive patients. Chest. 2008;134:375-381. [PubMed]
 
Ghalamkarpour A, Morlot S, Raas-Rothschild A, et al. Hereditary lymphedema type I associated with VEGFR3 mutation: the firstde novocase and atypical presentations. Clin Genet. 2006;70:330-335. [PubMed]
 
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