sions, improvement in pulmonary function tests, and symptoms in a KLA patient with a CBL mutation treated with trametinib [48, 49].

Thoracic duct embolization has been reported to be effective for controlling chylous complications when there appears to be a component of CCLA [59].

Course/Prognosis

KLA is an aggressive disease with variable response to treatment and often poor outcomes [59]. In the original study of 20 patients describing KLA, the 5-year survival was 51% with an overall survival of 34% [43]. The most common cause of death is cardiorespiratory failure and disseminated intravascular coagulation (DIC). A second study with six patients and a mean follow-up of 4.5 years reported 4 failures of treatment with 2 deaths [45]. Although KLA has continued to carry a poor prognosis, the ability to identify a causative mutation and choose a targeted therapy may change outcomes for these patients in the future [49]. It is important to note that these data were derived from pediatric cohorts, and that response to treatment, outcomes, and survival for adult populations is not clear [2].

Gorham Stout Disease

Gorham Stout disease (GSD) is a rare condition that was rst described in 1838 by Jackson [60], and further characterized in a review of 16 cases by Drs. Gorham and Stout in 1954 [61]. It is a disease of young adults and children with no gender predilection. Approximately 400 cases have been reported to date [32, 62]. A hallmark feature that differentiates GSD from GLA is progressive destruction of fat and/or long bones, a feature that has spawned the alternative designation of “vanishing bone disease” [63]. The most common sites affected include ribs, scapula, vertebrae, humerus, femur, skull, and maxillofacial bones.

Etiopathogenesis

No genetic mutations that are de nitely responsible for the clinical manifestations of GSD have been identi ed to date. Recently, two groups identi ed KRAS mutations at known hotspots (G12D, Q61R) within GSD lesions [27, 64]. Their work has suggested that either increased PI3K signaling in lymphatic endothelial cells or overexpression of VEGF-C by

bone cells can stimulate aberrant formation of lymphatics in bone. These lymphatics recruited from regional networks in l- trate the periosteum and eventually invade bone [65]. Increased VEGF-A levels in local tissues may play a role in angiogenesis and bone resorption through RANK-mediated osteoclastic activity [66, 67]. Increased IL-6 levels have also been noted.

Histology demonstrates progressive osteolysis of the cortex or lytic lesions in the bone characterized by thin reactive bony trabeculae with increased osteoclast activity. Intraosseous lymphatic malformations characterized by thin, irregular, occasionally dilated vascular channels stain that positive for PROX-1 and D2–40 replace the marrow cavity.

It can be challenging to differentiate from GSD from GLA histologically. GSD typically produces contiguous lesions in the ribs, cranium, clavicle, and cervical spine, and can be associated with pleural/pericardiac effusions and CSF leak [1, 25, 28, 32, 33, 42, 68].

Clinical Presentation and Diagnosis

GSD usually presents in the third decade of life although onset in younger and older patients has been reported [32, 62]. Two types of GSD include focal/progressive type with spontaneous stabilization and arrest after years of bony destruction, and diffuse involvement that includes pleura or/ and visceral organs.

Symptoms vary, but pain, weakness, and functional impairment are common, with speci c manifestations depending on the location of lesion. Pathologic fractures are often among the presenting manifestations. Spinal involvement can result in CSF leak, and cervical spine involvement is particularly worrisome given high risk for severe morbidity or even mortality with pathologic fracture. Pulmonary parenchymal disease and pleural or pericardial effusions can present with respiratory symptoms. Chylothorax occurs in up to 17% of patients, thought to be due to lymphatic leak from affected bone.

There is no single diagnostic test for GSD, although imaging and/or biopsy demonstrating evidence of cortical bone destruction is commonly used. It is important to avoid biopsy of an affected rib if at all possible, as this could introduce leak of chyle into the chest resulting in new pleural effusion. Cortical bone destruction is often present in contiguous lesions with a predilection for the axial skeleton. On MRI, soft tissue masses of GSD usually generate low T1 and high T2 signals. When there is a suspicion for GSD, imaging should cover the axial skeleton which is more commonly involved compared to GLA.