P3D255: Congenital Lymphatic Dysplasia and Bone Disease in a Neonate with PIEZO1 Mutation

Introduction: The PIEZO1 gene encodes the largest known human transmembrane protein, PIEZO1. PIEZO1 channels are crucial during development of lymphatic vasculature, acting as baroreceptors in both the lymphatic and vascular systems, and sensing frictional force to determine vascular structure. Additionally, PIEZO1 has recently been hypothesized to be an important mechanotransducer in bone development, conferring mechanosensitivity to osteoblasts and promoting bone formation. While previous reports of pathologic variants in PIEZO1 have described lymphatic malformation resulting in nonimmune hydrops fetalis, lymphedema, and chylothoraces, there are no known reported cases of such variants conferring bone disease in humans.

Case Description: A female infant was born to a 28-year-old, gravida 4 now para 2 Pashtun mother at an estimated 39 weeks' gestation. The pregnancy was notable for parental consanguinity (first cousins). The infant was hydropic and hypotonic at birth. Diuretic-refractory edema worsened, specifically after initiation of enteral formula and breast milk feeds, with severe pitting edema, pleural effusions, and worsened respiratory distress. Enteral feeds were therefore discontinued; a thoracentesis was performed, and fluid analysis confirmed congenital chylothorax. The lymphedema and chylothoraces persisted and were refractory to octreotide, diuretics, albumin infusions, and thoracentesis. At approximately six weeks of age, an extubation attempt proved unsuccessful due to persistent facial and airway edema. Tracheostomy was ultimately necessary, and the patient remained on intermittent mechanical ventilation.
The patient’s course was later complicated by bilateral incidentally noted femur and humeri fractures with diffuse, abnormal bony mineralization; notably, laboratory/endocrinologic studies of bone health were normal. Bone biopsy of a distal femur fracture demonstrated abnormal endochondral ossification with absence of normal zonal maturation of cartilage into bone (Figure 1). Lymphoscintigraphy was also completed and demonstrated lack of tracer movement at 24 hours, consistent with severe lymphatic dysplasia (Figure 2). Gene-specific RNA sequencing analysis revealed a novel c.2991+7C>T homozygous PIEZO1 mutation resulting in aberrant splicing and premature termination of the PIEZO1 protein.

Discussion: We described a patient with severe congenital lymphatic dysplasia that resulted from a novel variant in PIEZO1. 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 and she ultimately succumbed to worsening pleural edema. This is the first reported case of pathologic bone fractures in a patient with a loss-of-function PIEZO1 variant, implicating this particular variant as a novel genetic predisposition for fractures.

Conclusion: This is the first known case of pathologic fractures associated with a PIEZO1 mutation and is the first report of PIEZO1 channel deficiency being associated with bone disease in humans. As our patient’s fractures were noted incidentally, this report may support evaluation for pathologic fractures in patients with known PIEZO1 mutations, further elucidating PIEZO1’s potential role as a critical regulator of bone mass and strength.