Distal Arthrogryposis with Impaired Proprioception and Touch: Description of an Early Phenotype in a Boy with Compound Heterozygosity of PIEZO2 Mutations and Review of the Literature

Abstract

The recessive PIEZO2-associated disease, distal arthrogryposis with impaired proprioception and touch (DAIPT), is characterized by hypotonia, perinatal respiratory distress, significantly delayed motor milestones, and progressive symptoms of distal arthrogryposis and scoliosis. Here, we describe the youngest patient with DAIPT to date, who, at the age of 3.5 years, did not show a single clinical sign of distal arthrogryposis or contractures, but had a history of bilateral clubfoot operations. On the contrary, he presented with some features, not described thus far, such as syringohydromyelia, a small cyst of the spinal cord, moderate microcephaly with premature closure of anterior fontanelle, and spontaneous unilateral patella dislocation at the age of 32 months. Using whole exome sequencing, we identified 2 new different loss-of-function mutations in the PIEZO2 gene in our patient. We also review the phenotypes of all 16 previously published patients with DAIPT, summarize the distinctive clinical features of this rare genetic disorder, and recommend that DAIPT be included in the differential diagnosis of floppy infant. PIEZO2 is a unique ion channel that converts mechanical impulses into cellular signals and is involved in various mechanotransduction pathways. In addition to DAIPT, mutations in PIEZO2 have been described to cause 3 more distinct phenotypes of distal arthrogryposis, which are dominant and associated with gain-of-function mutations. On the contrary, recessive DAIPT is associated with loss-of-function PIEZO2 mutations.

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

“…Recently, a new family of nonselective cation channels in mammalian cells, known as "Piezo" (including Piezo1 and Piezo2), has been described in various mechanosensitive tissues and cells, including brain, heart, lung, liver, and kidney (3)(4)(5)(6). Although Piezo2 is a principal sensor for light touch and proprioception in mammals (7,8), Piezo1 is involved in the regulation of vascular development and blood pressure, lung growth, and injury (9)(10)(11)(12). Previous research showed that endothelial Piezo1 is required for the proper development of blood vessels (12)(13)(14)(15) by increasing phosphorylation of AKT or ERK and causing cell alignment through stretch-mediated Ca 2 þ influx and calpain activation or upregulation (10,(15)(16)(17)(18).…”

Muscle spindle function in healthy and diseased muscle

“…Since proprioception is vital for motor and body control, patients with a loss of proprioception either due to an autoimmune disease [5] or due to a lossof-function mutation in a protein essential for proprioception [6] have prominent sensory and motor deficits, generally leading to ataxia and dysmetria. Patients with a congenital absence of proprioception show delayed development of head control and walking, an early impairment of fine motor skills, sensory ataxia with unsteady gait, increased stride-to-stride variability in force and step length, an inability to maintain balance with eyes closed (Romberg's sign), a severely reduced ability to identify the direction of joint movements, and an absence of tendon reflexes [6][7][8][9][10][11][12]. The motor problems are so severe that without the compensatory activity of other senses, including the vestibular and the visual systems, the patients are unable to maintain their posture, walk or perform coordinated voluntary movements.…”

Case Report: Further Delineation of Neurological Symptoms in Young Children Caused by Compound Heterozygous Mutation in the PIEZO2 Gene

“…Biallelic loss-of-function pathogenic variants in PIEZO2 cause a specific DAIPT ( distal arthrogryposis with impaired proprioception and touch ) phenotype, including severe hypotonia with significant delay of motor milestones, transient respiratory distress and feeding problems in early infancy in addition to symptoms of severe progressive scoliosis and progressive contracture deformities of the hands and feet (Behunova et al, 2018 ). Congenital contractures of the feet are present in nearly all patients, whereas congenital contractures of the wrist or hands (including duck bill deformity) are present in most (Alper, 2017 ).…”

“…In the same year Haliloglu et al described an 18-year-old boy. The heterozygous carriers (parents and siblings) were healthy (Behunova et al, 2018 ). In 2018, Behunova et al reported a three and a half year old boy, the youngest patient with DAIPT till that time.…”