tends to be slowly progressive, but in some cases it can spontaneously remit.

Etiopathogenesis

The exact etiology of YNS is unknown; however, impaired lymphatic transport has been implicated in several studies [80]. Lymphoscintigraphy has demonstrated impaired functional lymphatic activity in patients with YNS rather than hypoplasia or aplasia [81]. There have reports of infants born with non-immune hydrops fetalis as well as a familial form of YNS affecting siblings suggesting an inheritable cause in some cases [82] [83, 84]. YNS has been reported in patients with autoimmune diseases [85– 87], malignancies [88], and immunode ciencies [89, 90]. Reports of onset of YNS after major surgery have also been reported, such as after mitral valve replacement or coronary bypass [91–95].

Exposure to titanium has been implicated as a possible cause, supported by high titanium levels in the nails of YNS patients [84, 96]. Sources of titanium are thought to include implants and food.

Clinical Presentation and Diagnosis

YNS is a clinical diagnosis, usually based on documentation of two of the three classical symptoms (yellow nails, lymphedema, and pleural effusion). Ruling out other common causes of lymphedema is important, however. While a diagnosis can be made without nail discoloration, it is challenging to do so due to overlap with other lymphedema syndromes. Nail discoloration varies from pale yellow to dark green and is associated with markedly thickened, hard and excessively curved nails (side to side) that grow very slowly [97]. There is also loss of the lunula and cuticles with detachment from the nail bed [98].

Pulmonary manifestations occur in 50–70% percent of patients, with chronic cough being the most common, followed by pleural effusions [99, 100]. The effusions tend to be recurrent, bilateral, lymphocytic exudates. A common misconception in YNS is that chylothorax is the most common type of effusion, although only 20% have triglyceride levels consistent with that diagnosis [100]. Bronchiectasis is present in 44% of cases, typically with a bilateral lower lobe distribution [101] (Fig. 21.7). Pulmonary symptoms often precede nail discoloration.

Lymphedema occurs in 30–80% of the cases and is usually bilateral and below the knee, but can also occur in other distributions, such as the face or result in ascites or chylopericardium. Acute or chronic rhinosinusitis is common and is reported in up to 83% of the patients and may precede nail changes by up to a few years [102]. Hard ear wax and keratosis obturans have been reported in YNS as well [103, 104].

Although YNS is not known to be due to genetic mutations, some cases of YNS have been reported in individuals with mutations in the FOXC2 gene, which also causes a similar disorder called lymphedema-distichiasis syndrome [105].

Management

Pleural effusions may require symptomatic management with drainage; however, they tend to re-occur. Pleurodesis and decortication are effective treatments for recurrent clinically signi cant effusions. Octreotide has been used in some cases and appears to be more ef cacious in patients with chylous effusions [106]. Spontaneous remission of nail changes is noted in up to 30% of the cases. Oral antifungals have also been used, sometimes in conjunction with Vitamin E, with inconsistent bene t [107–109]. It is important to exclude fungal infection with Wood’s lamp testing and other means in patients withYNS since onychomycoses can mimic the disorder. Lymphedema can be treated with compressive stockings or wraps, elevation of the extremities, manual lymphatic drainage, or a comprehensive approach called Complete Decompressive Physiotherapy.

In a few isolated case reports, major surgery or use of bucillamine have been found to be associated with YNS [110], while sinus surgery [102], removal of titanium implants [96], or other sources of exposure have occasionally been reported to result in clinical improvement. It is admittedly dif-cult to distinguish spontaneous remission from a clinical effect of the intervention in these cases, however.

Course/Prognosis

There is no cure for YNS at this time and current treatment is focused on relieving symptoms. Prognosis varies depending on the severity of manifestations, but the disease has a relatively benign course in most patients. Recurrent thoracenteses are sometimes required, with risk of procedural complications and can sometimes lead to hypoalbuminemia.

Summary

Thoracic lymphatic disorders are uncommon conditions that can present with protean manifestations in adults. A high index of suspicion should be maintained in patients with chylous effusion, plastic bronchitis, or low density mediastinal masses or lymphatic parenchymal patterns on CT, such as interlobular septal thickening. Submission of tissue for genetic analysis and referral to specialized centers is strongly advised, as many of these conditions have been shown to be driven by targetable mutations in cell growth and proliferation pathways.

Clinical Vignette

A 50-year-old non-smoking South American woman presented with a 20-year history of recurrent cough productive of milky fuid, intermittent hemoptysis, and pleuritic chest pain. She carried a diagnosis of LAM based on a lung biopsy obtained 6 years earlier. She had no history of pneumothorax, tuberous sclerosis, or exercise limitation. Laboratory evaluation demonstrated normal hemoglobin and prothrombin time (PT), a low normal platelet count (109,000/mL (100,000–400,000/mL)), elevated d-dimer (10.10 mg/ mL (0.01–0.49 mg/mL)), normal brinogen (250 mg/ dL (150–425 mg/dL)), and elevated brin split products (FSPs) at more than 20 mg/mL (>5 mg/mL). A chest radiograph showed a prominent right hilum with a perihilar interstitial in ltrate. Chest computerized tomography (CT) imaging showed multiple enlarged hypodense lymph nodes in the mediastinum and both hila, and prominent peribronchovascular and interlobular septal thickening, especially in the right lower lobe (Fig. 21.12). There were no cystic parenchymal lesions suggestive of LAM or no bony or splenic involvement. MRI of the chest showed a cystic, septated appearance of the mediastinal lymph nodes with heterogeneously increased T2 and decreased T1 signal intensity. Pulmonary function tests were normal. The right lower-lobe lung biopsy specimen from 6 years earlier was reviewed, and revealed mature lung parenchyma with dilated, malformed lymphatic vascular channels within the pulmonary septa, bronchoalveolar bundles, and brotic pleura that stained with anti-CD4. There were foci of PROX-1-positive intralymphatic and perilymphatic spindle cells, hemosiderin deposits, and extravasated blood cells. There was no evidence of pulmonary cysts or smooth muscle cell in ltrates suggestive of LAM, and immunostains for Human Melanoma Black (HMB-45), estrogen receptor, and progesterone receptor were negative. The clinical and pathological ndings were felt to be most consistent with KLA. The patient presented before genetic testing was widely available for KLA, but treatment with sirolimus was recommended.

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