Dominant PIEZO2-associated disorders:
DA3 (Gordon syndrome)
Number of patients,prevalence & ethnic background
- 18 patients were reported to have PIEZO2-associated DA3.
- In a cohort of 12 families (15 affected individuals) with a suspected DA3, a heterozygous PIEZO2 mutation was identified in 10 families. Nine of 10 families had the same missense mutation (c.8057G>A, p.Arg2686His) (McMillin, 2014). Three further patients with DA3 from one family have been reported to have the same missense (c.8057G>A) variant (Alisch, 2017).
- All mutations locate in Exon 52 of PIEZO2.
- No data regarding the ethnic background of the individuals were provided.
Prenatal signs, early complications
- No specific prenatal sign or early complications were reported. Prenatally, arthrogryposis multiplex congenita and intrauterine growth retardation were reported in one patient. The affected sibling of this individual had a mild respiratory distress short after birth, although the growth parameters at birth were normal (Alisch, 2017).
Pathognomic features/hallmarks
- All individuals (100%) had cleft palate (n=13) or bifid uvula (n=13).
- Short stature was reported in 12 individuals (66%).
- Micrognathia was reported in 12 individuals (66%).
- Additional features were present less frequently, such as ptosis in 7 (39%), scoliosis in 7 (39%), mild cognitive dysfunction in 4 (22%), Chiari type I malformation in 3 (16%), and ophthalmoplegia in 2 (11%) individuals.
Frequency of features in an age-dependant representation
- In two individuals, for whom the prenatal history was available; arthrogryposis was already present in intrauterine life (Alisch, 2017). Cleft palate, camptodactyly and clubfeet were congenital as well as micrognathia when present. Short stature, if not present at birth, may develop postnatally and be accentuated by scoliosis in childhood.
Clinical course/prognosis
- PIEZO2-related Gordon syndrome is almost exclusively caused by c.8057G>A mutation. All of the individuals with GS and a c.8057G>A mutation had either cleft palate of a bifid uvula. Ocular manifestations were not commonly seen in Gordon syndrome. Neurodevelopmental problems were not a common manifestation in patients with GS. Four individuals from three families developed cognitive delay, and a Chiari I malformation is described in three unrelated individuals with GS (McMillin, 2014; Alisch, 2017). This could be mere coincidence or a low penetrant feature of GS.
DA5 (oculomelic amyoplasia)
Number of patients, prevalence & ethnic background
- 62 individuals from 30 families were reported to have PIEZO2-related DA5.
- Of 30 families affected by PIEZO2-related DA5, 11 (37%) families showed the same recurrent 3bp deletion (c.8181_8183delAGA, p.Glu2727del) (McMillin, 2014, Coste, 2012).
- 17 different mutations were identified. Among them, 13 missense (76%), two in-frame deletions (12%), one single bp deletion and one 8 bp deletion were reported.
- No data regarding the ethnic background of the individuals were provided.
Prenatal signs, early complications
- All individuals with available prenatal history (n=7) were born with congenital contractures. Contractures were mild to severe, and mostly located in fingers and feet (talipes equinovarus).
- The individuals with congenital contractures at feet developed toe walking in the early childhood.
Pathognomic features/hallmarks
- All patients with PIEZO2-related DA5 had normal intelligence.
- All patients from Okubo’s cohort (n=4) and Coste’s cohort (n=3) had ophthalmoplegia and ptosis. Among these seven individuals, five had deep-set eyes and five had blepharophimosis. Further oculopathologies were defined in fewer cases, such as hypermetropia (n=3), abnormal retinal pigmentation (n=1), macular retinal folds (n=1), and excavation of optic nerve head (n=1).
- Within McMillin’s cohort with largest number of affected individuals (n=52) in the literature, 69% (n=36) of individuals had ophthalmoplegia, and 67% (n=35) had ptosis. Five individuals did not show any ophthalmoplegia, and no ptosis was detected in 10 individuals. The remaining individuals were not tested or no data were available from those individuals.
- Short stature was reported in 24 individuals (34%). However, McMillin’s cohort did not provide any data on height in seven individuals and Harris et al. did not specify the DA5 phenotype of their patient (n=1).
- Among the individuals for whom detailed information on contractures was available, camptodactyly and absent phalangeal crease were present in all (n=7) individuals. All patients from Coste’s cohort (n=3) had reduced ability to open mouth, decreased facial expression and limited wrist extension. Knee contractures (n=2), clubfeet (n=2) and elbow contractures (n=1) were also present less frequently.
- Scoliosis was reported in 14 (20%) individuals. In particular, spine stiffness developed in 14 (20%) individuals.
- Frequency of features in an age-dependant representation
- Individuals with information on natural history generally showed AMC and ocular manifestations in the prenatal and neonatal period. These individuals developed toe-walking in early childhood.
- Short stature may manifest in early childhood until early adulthood.
- Individuals with spine stiffness developed exertional dyspnea and restrictive pulmonary disease depending on the severity of the stiff/rigid spine deformity.
Clinical course/prognosis
- The clinical course and the prognosis of the disease depended on the severity of the contractures, oculomotor limitation and spine stiffness.
- The contractures may respond to physiotherapy, but severe contractures persisted despite the therapy. Affected individuals may need multiple orthopaedic procedures to preserve the function of the affected limbs/fingers.
- Restrictive pulmonary function is caused by the impaired expansion of the thoracic wall due to scoliosis and/or stiff spine. Forced vital capacity (FVC) as low as 26-50% have been documented.
Marden-Walker Syndrome
Number of patients, prevalence & ethnic background
- To date, only one patient is reported as PIEZO2-related Marden-Walker Syndrome with a de novo mutation (c.8056C>T, p.Arg2686Cys).
- The c.8057G>A (p.Arg2686His) mutation, which is adjacent to nucleotide position of MWS-causative mutation, is present in most of patients with Gordon syndrome and in two DA5 families. Therefore, Gordon syndrome, Marden Walker Syndrome and DA5 are suspected to be allelic conditions (McMillin, 2014).
- Prenatal signs, early complications
- In MWS, prenatal findings may be polyhydramnios and fetal akinesia with distal arthrogryposis. Hindbrain malformations, especially Dandy-Walker malformation can be detected by detailed ultrasound examination or prenatal MRI.
Pathognomic features/hallmarks
- As PIEZO2-related MWS was described in only one patient, the hallmarks of this phenotype per se cannot be designated. However, the described phenotype by McMillin had the characteristic features of MWS, such as joint contractures including camptodactyly, cleft palate, blepharophimosis, “immobile facies”, diminished muscular bulk, developmental delay, and hindbrain malformations, most commonly Dandy-Walker malformation.
- Frequency of features in an age-dependant representation
- The clinical features described in PIEZO2-related MWS were manifest in the neonatal and/or infantile period.
Clinical course/prognosis
- The clinical course and the prognosis of the disease depend on the severity of the contractures, and hindbrain malformations. Currently, the data on the natural history of PIEZO2-related MWS is scarce. Postnatal failure to thrive partly due to feeding difficulties may be frequent, and the overall life expectancy is probably reduced owing to complications like aspiration pneumonia.
Recessive PIEZO2-associated disorder:
Arthrogryposis, distal, with impaired proprioception and touch (DAIPT)
Number of affected individuals, prevalence & ethnic background
- 16 affected individuals from 8 different families:
- 2 Bangladeshi (Mahmud, 2017; Chesler, 2016);
- 1 mixed European and Japanese (Chesler, 2016);
- 2 Turkish (Delle Vedove, 2016; Haliloglu, 2016);
- 1 Indian (Delle Vedove, 2016);
- 1 Libyan (Delle Vedove, 2016);
- 1 Pakistani (Delle Vedove, 2016).
Prenatal signs, early complications
- 1 affected individual showed reduced intrauterine movements. All the affected individuals, in whom a prenatal US was performed (n=3), showed bilateral talipes equinovarus (TEV).
Pathognomic features/hallmarks
- At birth 7/8 examined affected individuals presented AMC (bilateral TEV). Hypotonia was described in all the affected individuals whose perinatal history was reconstructed (n=10). Five required O2 administration. Five patients experienced feeding problems due to poor sucking/swallowing.
Frequency of features in an age-dependant representation
- All affected individuals assessed for stature (n=12) had short stature. Their motor development was delayed, but they were usually able to walk independently or with orthesis. Their muscular tone and strength were reduced and the DTRs were absent. 12 out of 14 examined individuals developed scoliosis. 11 showed camptodactyly, while in 9 affected individuals’ hands displayed a characteristic combination of the abduction of the I metacarpal bone with the flexion of the first metacarpo-phalangeal joint. With age fingers often appeared to be long and slender. 11 out of 12 examined affected individuals presented everted feet and in 8 of them there was a marked sandal gap. In 5 patients joint laxity was noticed too. 4 out of 8 examined affected individuals had high arched palate.
- When specifically assessed, pain (n=5) and temperature (n=3) sensation were conserved. Vibration sensation (3/4) and proprioception (5/5) were reduced. Light-touch sensation and two-point discrimination showed discordant results.
- In 8/10 affected individuals cognition was generally not affected. Dysarthria was present in 6 out of 7 assessed patients.
- CK levels were usually within the normal range, but may be increased. In 4 out of 6 affected individuals, nerve conduction studies showed a sensory axonal neuropathy.
- Muscle biopsy results were unspecific.
Clinical course/prognosis
- In 2 affected individuals gastro-oesophageal reflux was reported and 3 suffered from respiratory tract infections, which sometimes required hospitalization. Affected individuals reached adulthood. Skeletal deformities (TEV, scoliosis) usually require ortheses and even surgery.