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.