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.

Keywords: DAIPT; Distal arthrogryposis; Floppy infant; Hypotonia; PIEZO2; Proprioception.

Fig. 1

Phenotype of the patient (age 3.5 years). a, b Whole body and extremities. Hypotonia, inability to stand or walk alone, and a dislocated left patella are shown. c, d Face and upper body. Slightly short palpebral fissures, pointed asymmetric chin, mild pectus excavatum, inverted nipples, and pronounced vascular drawing at the upper chest as well as loose skin at the lower chest are noticeable. e-h Hands and feet without contractures. Surgical correction of bilateral clubfeet at the age of 6 months was performed.

Fig. 2

Sequences of the patient's PIEZO2 mutations. a Mutation c.76C>T (p.Arg26Ter) in exon 2. b Mutation c.1528-1G>T in intron 12.