DISCUSSION
We described a patient with severe congenital lymphatic dysplasia that resulted from a novel variant in the PIEZO1 gene that caused aberrant splicing and resulted in premature termination of the protein. In our patient’s case, the most pronounced feature of her disorder remains the generalized congenital lymphedema. Our patient’s lymphedema was refractory to medical management. She remained tracheostomy-dependent, despite overall healthy lung tissue, and succumbed to worsening pleural edema in the setting of the family’s decision to provide palliative care. In most reported cases, if edema persisted, it was limited to a few body segments. Our patient, however, experienced persistent anasarca upon facility transfer at 4 months of age. Furthermore, our patient’s lymphoscintigraphy showed no evidence of radiotracer movement after 24 hours. These findings may suggest our patient’s PIEZO1 variant leads to a more severe form of lymphatic malformation than has been previously reported. Our patient’sPIEZO1 variant has not previously been reported in the literature. This case is also the first reported case of pathologic bone fractures in a patient with a loss-of-function PIEZO1 variant, implicating this variant as a novel genetic predisposition for fractures.
Significant research identified PIEZO1 as an important mechanotransducer implicated in bone growth and maintenance. In a recent study, Wanget al. evaluated the role of PIEZO1 in the formation and remodeling of bone.8 The work postulated that osteoblasts use PIEZO1 to sense mechanical loading and promote bone resorption by osteoclasts. In PIEZO1 knockout mice, their study demonstrated that trabecular bone mass was significantly reduced compared to the wildtype.8 Notably, they observed multiple bone fractures in weight-bearing appendicular bones postnatally. Likely, these fractures are only noted postnatally because the amniotic environment does not provide enough mechanical loading to cause pathological fractures. This theory supports the hypothesis that the PIEZO1 protein acts in the osteoblastic lineage cells to regulate bone remodeling by mechanical sensing. Furthermore, some studies have shown single nucleotide polymorphisms in PIEZO1 in patients who develop osteoporosis, suggesting another link to the importance of PIEZO1 ion channels on bone development and remodeling.8
Lab studies have shown that repeated small strains help to guide the modeling and remodeling phases of bone healing in patients who have undergone trauma. In contrast, in settings of complete non-weightbearing during the remodeling phase after a fracture, callus formation may be diminished, and healing can slow or fail all together. Excessive strain can result in a similar pattern of disordered formation.6,8 While research has recently expanded significantly regarding the function of the PIEZO1 family of mechanoreceptors, there is still very little known about the role this protein plays in fetal development or the implications this may have on treatment for a variety of bone diseases.
PIEZO1 mechanotransduction is a critical process in bone growth and maintenance. Research demonstrates the expression and function of the PIEZO1 protein is impacted by PIEZO1 variants both acutely, as detailed in this case presentation, and chronically, as it is under-expressed in individuals who develop osteoporosis.7 Importantly, the expression and function are also affected by the environment, as it is suppressed in microgravity situations.6 This case presentation, in concert with the recent literature on PIEZO1’s role as a major skeletal mechanosensor impacting bone homeostasis, could result in wide-ranging implications on the treatment and prevention of bone disease with potential applications in military/civilian trauma, space travel, rehabilitation, and even osteopenia of prematurity, among many others.