Introduction: Pathogenic variants in the PIEZO family member 2 (PIEZO2) gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5). Out of these, MWS has a recognizable phenotype that can be discerned easily, but the distinction between GS and DA5 is less evident. Few children with pathogenic PIEZO2 variants have been reported to show posterior fossa anomalies. Methods and Results: By candidate gene targeting guided by proper clinical evaluation and neuroimaging findings, a patient with classic MWS harboring a de novo novel variant (c.8237G>A, p.W2746*) in the C-terminal region of PIEZO2 was identified. In addition, another girl with the typical clinical features of GS is also described carrying the most prevalent reported variant (c.8057G>A, p.R2686H) in PIEZO2. The brain MRI of the 2 patients showed Dandy-Walker malformation (DWM). Diffusion tensor imaging visualized anteroposterior and downward aligned thin middle cerebellar peduncle. The association of DWM with arthrogryposis in the presence of PIEZO2 variants remains quite interesting and provides more evidence that PIEZO2 plays a role in the development of hindbrain although the underlying mechanism remains unclear. Moreover, the 2 girls had distinct foot patterning in the form of shortening of the first and fifth toes. Conclusion: Phenotype analysis and a comprehensive review of the literature strongly support the previously published data and corroborate the evidence that heterozygous PIEZO2- related disorders represent a continuum with overlapping phenotypic features.

PIEZO family member 2 (PIEZO2, OMIM 613629) and PIEZO family member 1 (PIEZO1, OMIM 611184) are large, transmembrane protein components of mechanically or stretch-activated ion channels found in many tissues [Coste et al., 2013]. PIEZO2 is a nonselective ion channel essential for mechanotransduction, which is the conversion of mechanical forces into biological signals [Coste et al., 2012], and is predominantly expressed in the sensory trigeminal ganglia, dorsal root ganglia, Merkel cells, lungs, and bladder [McMillin et al., 2014; Woo et al., 2014]. Therefore, gain-of-function of PIEZO2 causes dysregulation of these channels and could help to explain the pleiotropic effects on joints, ocular muscles, and bone development [Coste et al., 2013]. It was identified to cause Gordon syndrome (GS; OMIM #114300), distal arthrogryposis type 5 (DA5; OMIM #108145), and Marden-Walker syndrome (MWS; OMIM #248700) [McMillin et al., 2014]. Distal arthrogryposis is the main feature present in patients with GS, DA5, and MWS. In addition, patients with GS usually display cleft palate [Gordon et al., 1969], while patients with DA5 show deep-set eyes, ptosis, ophthalmoplegia, triangular facies, restrictive pulmonary function, and “firm” muscles. Blepharophimosis, immobile face, and micrognathia usually characterize MWS.

In comparison, biallelic loss-of-function variants of PIEZO2 (MIM 617146) result in either nonsense-mediated transcript decay or premature termination codons and consequently lead to a lack of PIEZO2 protein and a phenotype characterized by ataxia and dysmetria (secondary to sensitive loss of discriminative touch perception but normal pain, temperature, and vibration sensation), progressive muscular weakness, and different degrees of skeletal involvement (short stature, scoliosis, and camptodactyly) [Mahmud et al., 2017]. Heterozygous variants of PIEZO2 were mainly located in the C-terminal region, and most of them exhibit high evolutionary conservation among different species, whereas recessive variants were mainly localized in the N-terminal region and do not map to any hotspots [Ma et al., 2019].

The link between PIEZO2-related phenotypes and posterior fossa anomalies is poorly understood, especially considering the variability even between family members sharing the same pathogenic variant.

We refine the clinical phenotype of PIEZO2-associated arthrogryposis and complement the spectrum of variants. Given the observed overlapping clinical features among DA5, GS, and MWS patients, we propose that a clinical continuum exists within the heterozygous PIEZO2-associated disorders.

Patient I

She was the second child of healthy consanguineous parents. At the time of her birth, her mother and father were 25 and 32 years old, respectively. She was born at 38 weeks gestational age by cesarean section after an uncomplicated pregnancy. Her birth weight was 2,500 g (−1.5 SD). The birth length, OFC, and Apgar scores were not recorded. Bilateral congenital contracture deformities of the feet were noted at birth. We have first seen her when she was 4 months old. On examination, her weight, length, and OFC were 4,000 g (−3 SD), 52 cm (−4 SD), and 39.5 cm (−0.6 SD), respectively. The girl had a high forehead, deep-set eyes, bilateral ptosis, anteverted nares, long philtrum, and thin lips (Fig. 1). Camptodactyly, absent phalangeal creases, abnormal hand creases, and syndactyly of the third and fourth fingers were also noted. She had generalized hypotonia with normal deep tendon reflexes. The karyotype was 46,XX. Infancy was characterized by feeding problems associated with poor weight gain, and frequent upper respiratory infections.

Fig. 1.

a–e Patient I. a At the age of 4 months. b At the age of 9 months. Note the blepharophimosis, immobile face, and micrognathia of MWS. c Right hand showing absent finger creases and abnormal dermatoglyphics. d, e Right foot and its X-ray showing shortening of the first and fifth toes. f–j Patient II. f At the age of 12 months, showing deep-set eyes and micrognathia. g Cleft palate and uvula of GS. h Feet showing tip toe walking. i X-ray of the feet showing shortening of the first and fifth toes. j Forearm showing radio-ulnar synostosis.

Fig. 1.

a–e Patient I. a At the age of 4 months. b At the age of 9 months. Note the blepharophimosis, immobile face, and micrognathia of MWS. c Right hand showing absent finger creases and abnormal dermatoglyphics. d, e Right foot and its X-ray showing shortening of the first and fifth toes. f–j Patient II. f At the age of 12 months, showing deep-set eyes and micrognathia. g Cleft palate and uvula of GS. h Feet showing tip toe walking. i X-ray of the feet showing shortening of the first and fifth toes. j Forearm showing radio-ulnar synostosis.

Close modal

She had normal cognitive and language development with a slight delay in sitting and walking (10 months and 16 months of age, respectively). Brain magnetic resonance imaging (MRI) showed hypoplastic corpus callosum, wide fourth ventricle, hypoplastic vermis of cerebellum, cystic dilatation of posterior fossa and elevated torcula, at the posterior junction of the occipital lobe and the infratentorial space, upwardly rotated (Fig. 2). Echo heart and abdomino-pelvic ultrasound were normal. The hearing test did not reveal any abnormalities and ophthalmologic examination was normal (no pigmentary abnormalities). Intraoral examination revealed long philtrum, high arched palate, long uvula, and micrognathia.

Fig. 2.

a–c Patient I. Brain MRI showing hypoplastic corpus callosum, wide fourth ventricle, hypoplastic vermis, cystic dilatation of posterior fossa and elevated torcula, at the posterior junction of the occipital lobe and the infratentorial space, upwardly rotated. d–f Patient II. d, e Dandy-Walker malformation. f Diffusion tensor imaging tractography of the middle cerebellar peduncles (MCP) in axial projection shows MCP bilaterally as a large structure that extends from the rostral pons laterally to the cerebellar hemispheres. Note the normal antero-posterior direction (green color).

Fig. 2.

a–c Patient I. Brain MRI showing hypoplastic corpus callosum, wide fourth ventricle, hypoplastic vermis, cystic dilatation of posterior fossa and elevated torcula, at the posterior junction of the occipital lobe and the infratentorial space, upwardly rotated. d–f Patient II. d, e Dandy-Walker malformation. f Diffusion tensor imaging tractography of the middle cerebellar peduncles (MCP) in axial projection shows MCP bilaterally as a large structure that extends from the rostral pons laterally to the cerebellar hemispheres. Note the normal antero-posterior direction (green color).

Close modal

Patient II

She was the second girl of nonconsanguineous parents. At her birth, the father was 26 years and the mother was 25 years old. The mother mentioned that the father had contracture of fingers and talipes equinovarus and tip toe-walking in early childhood. He exhibits no intellectual disability despite the fact that he had just completed the elementary education (no formal IQ test). He also had a history of very small cleft palate. Brain MRI and skeletal survey were declined by the father. In addition, a paternal uncle and grandfather had similar distal contracture deformities. The girl was born at term by vaginal delivery after an uneventful pregnancy period. Her birth weight was 3,000 g (−0.7 SD). At birth, multiple congenital contractures of the hands and feet were noted. She was operated on pes equinovarus when she was 4 months. Echocardiographic evaluation at the age of 3 months documented patent foramen ovale, which closed spontaneously thereafter. She was first presented to our clinic when she was 1 year old for genetic counseling. Her measurements at that time were weight 7 kg (−2.6 SD), length 71 cm (−1.1 SD), and OFC 44.5 cm (−0.6 SD). She did not have flexion creases, and movements were restricted in all her fingers. She began walking at the age of 2 years and developed tip toe-walking by the age of 3 years. Proximally implanted first and fifth toes were noted (Fig. 1). Examination at the age of 3 years revealed height 86 cm (−1.8 SD), weight 11 kg (−2.2 SD), and OFC 49 cm (mean). Impaired upward gaze was noted. She had no intention tremors or dysmetria. The girl could use her hands for self-feeding but restriction of supination was noted. No dysarthria but mild speech delay was apparent at that age showing better expressive than receptive language. Flexible nasopharyngolaryngoscopy showed active mobility of lateral pharyngeal walls, and a gap was seen at the level of the velopharyngeal valve. At that age, her developmental quotient was 80 (using Portage program). X-ray of the forearm showed radio-ulnar synostosis, while X-ray of feet showed proximally inserted first and fifth toes. Ophthalmologic examination revealed hypopigmentation of the retina. Brain MRI showed hypoplastic corpus callosum and DWM. Diffusion tensor imaging (DTI) was acquired on a Philips 1.5 T Magnet, b = 0 and 1,000 s/mm2 with 33 directions, seed region of interest placed in the bilateral middle cerebellar peduncle (MCP). The workstation software was used to fuse axial T1-WI with DTI acquisition. Tractography was obtained using a tensor deflection algorithm using directional colors for the fibers. DTI showed mildly thinner MCP but with normal anteroposterior direction (Fig. 2). Chromosomal analysis from peripheral blood lymphocytes showed a normal 46,XX female karyotype. Electromyography and sensory nerve conduction studies were normal. Intraoral examination revealed thick upper labial frenum and cleft palate involving the uvula, the soft and hard palate, prominent philtrum, and mandibular micrognathia.

Variant Analyses

Genomic DNA was extracted from peripheral blood lymphocytes of the patients and their parents using a standard procedure. The PIEZO2 gene was amplified using specific primers designed by Primer3 software. The coding regions and exon/intron boundaries of approximately 50 bp sequence were investigated to identify any splice site variants as well. Primers are available upon request from the corresponding author. The PCR products were purified using Exo-SAP PCR Clean-up kit (Fermentas, Germany) and sequenced in both directions using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA, USA) and analyzed on the ABI Prism 3500 Genetic Analyzer (Applied Biosystems) according to the manufacturer’s instructions. The sequence data of the PIEZO2 gene were compared with the reference genomic and cDNA sequence of the gene (NM_001378183.1). A previously identified missense variant (c.8057G>A, p.R2686H) in exon 52 was detected in patient II and her father, while a novel nonsense variant (c.8237G>A, p.W2746*) of the PIEZO2 gene was identified in patient I (Fig. 3). According to ACMG-AMP guidelines, the c.8057G>A (p.R2686H) is classified as pathogenic variant (PS1), while our new stop-gain variant c.8237G>A (p.W2746*) is classified as likely pathogenic (PS2). The parents of patient I were confirmed to have the reference allele of the variant. The pathogenicity and functional impact of the novel variant is supported by SIFT and Mutation Taster software analyses. The paternal uncle and grandfather of patient II declined genetic testing.

Fig. 3.

Left Pedigree of family I and part of the sequencing electrophoregram showing the novel variant c.8237G>A (p.Trp2746Ter) in patient I compared with the wild type in her father and mother. Right Pedigree of family II and part of the sequencing electrophoregram showing the previously identified variant c.8057G>A (p.Arg2686His) in patient II and her father compared with the wild type in her mother. The arrows indicate the sites of the variants.

Fig. 3.

Left Pedigree of family I and part of the sequencing electrophoregram showing the novel variant c.8237G>A (p.Trp2746Ter) in patient I compared with the wild type in her father and mother. Right Pedigree of family II and part of the sequencing electrophoregram showing the previously identified variant c.8057G>A (p.Arg2686His) in patient II and her father compared with the wild type in her mother. The arrows indicate the sites of the variants.

Close modal

We report 2 new cases diagnosed with both arthrogryposis and DWM. The facial gestalt (including blepharophimosis, immobile face/mask face, and micrognathia) of patient I matched what had been described in previous patients with MWS [McMillin et al., 2014; Seidahmed et al., 2021], while patient II showed cleft palate consistent with the clinical diagnosis of GS. The constellation of these features prompted targeted sequencing that identified a novel nonsense variant (c.8237G>A, p.W2746*) of PIEZO2 in patient I who showed the classic MWS phenotype but without microcephaly and cleft palate. Previous reports of patients with molecularly confirmed MWS are limited to only 2 individuals with missense variants (one with c.8056C>T, p.R2686C; and the other with c.7251G>C, p.Y2417C). These 2 patients reached the far end of the spectrum for MWS disorder since they showed cleft palate in addition to blepharophimosis, DWM, and distal arthrogryposis [McMillin et al., 2014; Seidahmed et al., 2021]. Interestingly, McMillin et al. [2014] reported a patient diagnosed clinically as GS who showed a frameshift variant (c.8238_8245delGACTAGAG) that led to the same truncating protein (p.W2746*fs) as in our patient I, supporting the overlap between GS and MWS (Table 1).

Table 1.

Clinical findings and variants identified in patients with dominant PIEZO2 continuum and posterior fossa malformations

Clinical findings and variants identified in patients with dominant PIEZO2 continuum and posterior fossa malformations
Clinical findings and variants identified in patients with dominant PIEZO2 continuum and posterior fossa malformations

Patient II had the variant c.8057G>A, previously reported in approximately 94.4% of individuals with classic GS showing either cleft palate or a bifid uvula [McMillin et al., 2014; Alisch et al., 2017]. These findings substantiate the suggestion that this variant (c.8057G>A) points to the diagnosis of GS [McMillin et al., 2014].

To date, 19 different pathogenic variants have been reported in the PIEZO2 gene (Fig. 4), most of them are missense variants (15/19; 78.9%), whereas deletion variants were described in 4 families (21.1%). They are clustered mainly in highly conserved residues at the C-terminus of the protein [Coste et al., 2013; McMillin et al., 2014; Okubo et al., 2015; Alisch et al., 2017; Zapata-Aldana et al., 2019; Seidahmed et al., 2021]. As such, the novel variant identified in patient I is the first nonsense variant in PIEZO2.

Fig. 4.

Schematic diagram of PIEZO2 protein showing 2 Pfam domains with reported variants associated with dominant PIEZO2 continuum and posterior fossa malformations. Variants in red were described in patients with posterior fossa malformations.

Fig. 4.

Schematic diagram of PIEZO2 protein showing 2 Pfam domains with reported variants associated with dominant PIEZO2 continuum and posterior fossa malformations. Variants in red were described in patients with posterior fossa malformations.

Close modal

DWM is an interesting feature that was documented in patient I with MWS and patient II with GS. Indeed, out of the 66 affected patients with PIEZO2 variants, only 24 patients performed brain MRI of whom 3 patients (3/24) had DWM [McMillin et al., 2014; Seidahmed et al., 2021] while Chiari I malformation was detected in another 3 patients (3/24) (Table 1). Thus, the prevalence of posterior fossa anomalies in PIEZO2 is 25%. DWM has not been recorded in previous GS reports but was well recognized in MWS and reported once with DA5. In contrast, Chiari I malformation has been described in 3 patients with GS. Thus, this is the first report of DWM in a patient molecularly diagnosed as GS.

The genotype/phenotype relationship in PIEZO2 variants currently remains elusive. The posterior fossa anomalies appear to be associated with variants localized to the Pfam domain at the C-terminus (Fig. 4), though generally, variants are distributed throughout the protein. Interestingly, the 2 patients carrying truncating (Table 2) variants in the Pfam domain at the C-terminus of PIEZO2 gene, c.8208delA (p.Y2737Ifs*7) and c.8238_8245delGACTAGAG (p.W2746*fs) [McMillin et al., 2014], had no posterior fossa anomalies unlike our patient with c.8237G>A. In contrast, patients with missense variants c.8057G>A, c.7251G>C, c.8056C>T and in-frame deletion variant c.8181_8183delAGA displayed posterior fossa malformations. It is worthy to mention that c.8057G>A and c.8181_8183delAGA were also reported in another 10 and 9 patients, respectively without posterior fossa malformations. Moreover, patients with posterior fossa anomalies [McMillin et al., 2014] had family members carrying the same PIEZO2 variant but without posterior fossa anomalies, suggesting the presence of modifying factors. The bioinformatics analyses found the p.E2727del (c.8181_8183delAGA) and p.R2686H (c.8057G>A) variants affected the transmembrane region of PIEZO2, and the former modifies the secondary structure of PIEZO2 protein in addition [Ma et al., 2019]. We recommend that brain MRI should be arranged for all children with PIEZO2-related disorders to investigate this feature.

Table 2.

The clinical and radiological findings in patients with truncating dominant PIEZO2 variants

The clinical and radiological findings in patients with truncating dominant PIEZO2 variants
The clinical and radiological findings in patients with truncating dominant PIEZO2 variants

Despite the DWM, the 2 girls had a favorable outcome showing no cerebellar symptoms. This was similarly observed by Seidahmed et al. [2021]. Therefore, DTI was arranged to detect possible white matter tract anomalies secondary to disrupted or altered axonal pathway. It is noteworthy to mention that no published reports describe DTI findings in DWM, but one showed an abnormal more transverse orientation of the MCP [Chokshi et al., 2011] although normal orientation and decussation of superior cerebellar peduncle [Chokshi et al., 2011]. In our patient, a mildly thinner MCP but with normal anteroposterior direction was observed. The favorable outcome could be explained by the preservation of the white matter tracts detected by the DTI.

The unique feature of shortening of the first and fifth toes noticed in our patients was similarly described in 4 affected individuals with DA5 harboring c.4456G>C (p.A1486P) of PIEZO2 [Okubo et al., 2015]. Moreover, a patient was presented with GS who also showed this unique foot pattern, although it was not commented in the figure or text [McMillin et al., 2014]. We think that this anomaly might be underreported, and further reports are needed to substantiate our observation.

Retinal pigmentation and metatarsal/metacarpal synostosis observed in patient II with GS were reported in 2 unrelated patients with DA5 [Coste et al., 2013; Okubo et al., 2015] giving more evidence for the phenotypic overlap between DA5 and GS.

In conclusion, given the common genetic etiology and the overlapping clinical features and sometimes even indistinguishable phenotype [McMillin et al., 2014], we suggest that MWS, GS, and DA5 are fitting to be termed as dominant PIEZO2 continuum, and the diagnosis should rely on molecular findings instead of clinical discrimination because of the overlapping clinical features.

The cooperation of the families is much appreciated.

The study was approved by the Medical Research Ethics Committee of the NRC (approval reference No. 20068) and followed standard Helsinki declarations. Patients were enrolled with written parental consent for participation in the study, publication of case reports, and photographs.

The authors declare no conflict of interest.

There are no funding sources to report.

Ghada M.H. Abdel-Salam and Hanan H. Afifi recruited the subjects into the study, performed the deep clinical characterization, and drafted the initial manuscript. Manar A. El-Serafy participated in clinical characterization and collection of samples. Mohamed I. Gadelhak performed the nasopharyngolaryngoscope examination and language assessment. Mohamed S. Abdel-Hamid performed the targeted sequencing and segregation analysis. Sahar N. Saleem performed the brain MRI and DTI and designed the figure. Inas S.M. Sayed performed the oro-dental examination. Ghada M.H. Abdel-Salam, Hanan H. Afifi, and Mohamed S. Abdel-Hamid designed and supervised the study and critically revised the manuscript. All authors reviewed and approved the final version of the manuscript.

The data supporting the findings of this study are available from the corresponding author upon request.

1.
Alisch
F
,
Weichert
A
,
Kalache
K
,
Paradiso
V
,
Longardt
AC
,
Dame
C
,
Familial Gordon syndrome associated with a PIEZO2 mutation
.
Am J Med Genet A
.
2017
;
173
(
1
):
254
9
.
2.
Chokshi
FH
,
Poretti
A
,
Meoded
A
,
Huisman
TA
.
Normal and abnormal development of the cerebellum and brainstem as depicted by diffusion tensor imaging
.
Semin Ultrasound CT MR
.
2011
;
32
(
6
):
539
54
.
3.
Coste
B
,
Houge
G
,
Murray
MF
,
Stitziel
N
,
Bandell
M
,
Giovanni
MA
,
Gain-of-function variants in the mechanically activated ion channel PIEZO2 cause a subtype of distal arthrogryposis
.
Proc Natl Acad Sci U S A
.
2013
;
110
(
12
):
4667
72
.
4.
Gordon
H
,
Davies
D
,
Berman
M
.
Camptodactyly, cleft palate, and club foot. A syndrome showing the autosomal-dominant pattern of inheritance
.
J Med Genet
.
1969
;
6
(
3
):
266
74
.
5.
Ma
Y
,
Zhao
Y
,
Cai
Z
,
Hao
X
.
Variants in PIEZO2 contribute to Gordon syndrome, Marden-Walker syndrome and distal arthrogryposis: A bioinformatics analysis of mechanisms
.
Exp Ther Med
.
2019
;
17
(
5
):
3518
24
.
6.
Mahmud
AA
,
Nahid
NA
,
Nassif
C
,
Sayeed
MS
,
Ahmed
MU
,
Parveen
M
,
Loss of the proprioception and touch sensation channel PIEZO2 in siblings with a progressive form of contractures
.
Clin Genet
.
2017
;
91
(
3
):
470
5
.
7.
McMillin
MJ
,
Beck
AE
,
Chong
JX
,
Shively
KM
,
Buckingham
KJ
,
Gildersleeve
HI
,
Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5
.
Am J Hum Genet
.
2014
;
94
(
5
):
734
44
.
8.
Okubo
M
,
Fujita
A
,
Saito
Y
,
Komaki
H
,
Ishiyama
A
,
Takeshita
E
,
A family of distal arthrogryposis type 5 due to a novel PIEZO2 mutation
.
Am J Med Genet A
.
2015
;
167A
(
5
):
1100
6
.
9.
Seidahmed
MZ
,
Maddirevula
S
,
Miqdad
AM
,
Al Faifi
A
,
Al Samadi
A
,
Alkuraya
FS
.
Confirming the involvement of PIEZO2 in the etiology of Marden-Walker syndrome
.
Am J Med Genet A
.
2021
;
185
(
3
):
945
8
.
10.
Woo
SH
,
Ranade
S
,
Weyer
AD
,
Dubin
AE
,
Baba
Y
,
Qiu
Z
,
Piezo2 is required for Merkel-cell mechanotransduction
.
Nature
.
2014
;
509
(
7502
):
622
6
.
11.
Zapata-Aldana
E
,
Al-Mobarak
SB
,
Karp
N
,
Campbell
C
.
Distal arthrogryposis type 5 and PIEZO2 novel variant in a Canadian family
.
Am J Med Genet A
.
2019
;
179
(
6
):
1034
41
.
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