INTRODUCTION
The PIEZO1 gene is located on chromosome 16 (16q24.3) and encodes
the largest known human transmembrane protein, PIEZO1. The PIEZO1
protein has low tissue specificity, showing expression in at least 27
different tissue types.1 This mechanoreceptor is
activated by mechanical force and controls potassium and calcium flow in
multiple cell types, most prominently lung, bladder, skin, and red blood
cells.1,2 Studies have shown that in fetal tissue the
highest expression of this protein is in the liver, spleen, and
lymphatic vessels.1,2 PIEZO1 channels are crucial
during development of lymphatic vasculature, acting as baroreceptors in
the lymphatic and vascular systems, and sensing frictional force to
determine vascular structure.3 Pathogenic variants inPIEZO1 have therefore been phenotypically associated with
lymphatic malformation, perinatal edema, and non-immune fetal hydrops,
as well as hemolytic anemia and pseudohyperkalemia.2,4PIEZO1 -related disorders include autosomal recessive lymphatic
malformation 6 (LMPHM6, OMIM 616843) due to biallelic loss-of-function
variants and autosomal dominant dehydrated hereditary stomatocytosis
(OMIM 194380) due to heterozygous gain-of-function
variants.5 Despite significant phenotypic
heterogeneity, both disorders may present with perinatal edema and
non-immune hydrops fetalis.5
Congenital lymphatic dysplasia is the hallmark feature of LMPHM6,
resulting in severe impairment of vascular development, and commonly
causing in utero demise. The associated primary lymphedema
affects all body segments, causing pleural effusions, pulmonary and
intestinal lymphangiectasia, facial and neck swelling, chylothoraces,
and pericardial effusion. In some cases, hydrops fetalis has resolved
postnatally with concomitant recurrence of peripheral edema during
childhood, typically in the lower limbs. Most reported cases of LMPHM6
have resultant pleural effusions that become chylous with the
introduction of enteral feeds.5
More recently, PIEZO1 has been implicated as a potential
mechanotransducer in osteoblastic bone formation. Osteoblasts respond to
mechanical loading and bone growth and maintenance is known to be
impaired in microgravity environments and non-weight bearing patients.
However, the mechanism by which this occurs has previously been
uncertain.6 Recent research found that knockout mice
with PIEZO1-deficient osteoblasts sustain spontaneous fractures in the
setting of impaired bone density and strength. Patients with
osteoporosis have been found to have reduced expression of the PIEZO1
protein.6 Likewise, simulated microgravity
environments result in decreased osteoblastic function via suppression
of PIEZO1 activity.7 Here, we present a patient with
LMPH6 due to likely pathogenic homozygous loss-of-function PIEZO1variants who has unexplained bone disease, the first reported case of
significant bone disease in this phenotype.