Distal arthrogryposis type 5 and PIEZO2 novel variant in a Canadian family

Abstract

The group of distal arthrogryposis (DA) disorders is characterized by congenital contractures of the distal joints. In most instances, these are genetic disorders are inherited in an autosomal dominant fashion; however, there is wide genetic and phenotypic spectrum. Distal arthrogryposis type 5 (DA5) is clinically characterized by short stature, deep‐set eyes, ptosis, ophthalmoplegia, triangular facies, restrictive pulmonary function, and “firm” muscles. DA5 is produced by a gain‐of‐function mutations in PIEZO2 gene, encoding for an ion‐channel required to convert mechanical stimulus to biological signals in mammals essential to proprioception. Heterozygous mutations in PIEZO2 may lead to other phenotypes like Gordon Syndrome and Marden Walker syndrome. In this report, we present a 3‐generation family affected with DA5, who all carry a variant of unknown clinical significance c.8068A>C (p.Ser2690Arg) in the PIEZO2 gene. DA5 is a very rare condition with less than 20 cases previously reported. Our report expands the phenotype and contributes to evidence of this variant's pathogenicity.

Distal Arthrogryposis type 5 in an Italian family due to an autosomal dominant gain-of-function mutation of the PIEZO2 gene

“…To date, PIEZO2 missense, and frameshift (as the one here described, rsID 587,777,077, Ensembl transcript ENST00000503781.7, and reported in literature by some Authors [5,7,10]) pathogenic variants, account for the vast majority of variants. They have highly pleomorphic effects and different pathophysiological consequences [15,16]. The clinical manifestations of PIEZO2-associated diseases display a great variation, as well [10].…”

“…Indeed, gain-of-function mutations of PIEZO2 have been also linked with DA3 (also known as Gordon Syndrome, GS, MIM#114300), Marden-Walker Syndrome (MWS, MIM#248700) and other related diseases [12,17]. GS is commonly mistaken with DA5, but it may be distinguished by the presence of cleft palate and bifid uvula, whereas ophthalmological, muscle, and respiratory problems are primarily observed in DA5 [15]. Other less frequent signs and symptoms seen in DA5 patients are pectus excavatum (33%, observed also in our patient), trismus (26%), metacarpal and metatarsal synostosis (25%), toe syndactyly (18%), neck webbing (8%, found in the mother of our newborn), and sensorineural hearing loss (6%, and also present in the proband) [15].…”

“…GS is commonly mistaken with DA5, but it may be distinguished by the presence of cleft palate and bifid uvula, whereas ophthalmological, muscle, and respiratory problems are primarily observed in DA5 [15]. Other less frequent signs and symptoms seen in DA5 patients are pectus excavatum (33%, observed also in our patient), trismus (26%), metacarpal and metatarsal synostosis (25%), toe syndactyly (18%), neck webbing (8%, found in the mother of our newborn), and sensorineural hearing loss (6%, and also present in the proband) [15]. Differential diagnosis of DA5 also includes Aase-Smith Syndrome (MIM#147800), and Marden-Walker Syndrome (characterized by joint contractures, cleft palate, blepharophimosis, "immobile" facies, diminished muscular bulk, developmental delay and hindbrain malformations) [15].…”

“…Periodic ophthalmological examinations are recommended to rule out keratoconus, refraction problems or abnormalities of the retina, which may require correction, while hearing screening is able to early detect sensorineural hearing loss (as in our proband). Moreover, pulmonary function testing and echocardiography should be performed for the early diagnosis of restrictive pulmonary disease [15].…”

PIEZO2‐related distal arthrogryposis type 5: Longitudinal follow‐up of a three‐generation family broadens phenotypic spectrum, complications, and health surveillance recommendations for this patient group

“…PIEZO component 2 (PIEZO2) has been identified as an ion channel sensitive to mechanical forces. Gain of function (GoF) mutations in PIEZO2 have been previously described in DA type 3, DA3, DA5, and Marden–Walker syndrome (Alisch et al, 2017; Coste et al, 2013; McMillin et al, 2014; Okubo et al, 2015; Seidahmed et al, 2021; Zapata‐Aldana, Al‐Mobarak, Karp, & Campbell, 2021) and DA 1 (Li et al, 2018). Previous reports have focused on young patients or large groups with limited information on the long‐term features that may develop.…”