OTHER NMDs

Recessive mutations in PIEZO2 gene cause a distinctive phenotype with arthrogryposis and impaired proprioception. The clinical picture is fully disclosed in adults, but in infancy it is not readily recognizable, thus the differential diagnosis is wide. We describe 8 individuals from 2 unrelated families with recessive PIEZO2 mutations. Family 1 is a consanguineous Spanish Gipsy family with 6 members affected, first or second cousins between them. They are 3 males and 3 females. Pregnancies were uneventful, but from birth all showed neonatal hypotonia. Additional neonatal features were as follows: talipes (4), umbilical/inguinal hernia (4), hip dislocation (3) and respiratory insufficiency (3, one requiring tracheostomy). Two cases had hyperkinetic generalized movements, resembling chorea, in the first months of life. They resolved spontaneously before 6 months of age. All presented motor developmental delay. The boy with a tracheostomy died at 11 months due to respiratory problems. Four lost ambulation (mean age of 7 years). At present (age of last assessment is between 12 and 20 years) the 5 individuals show severe proprioception defects and musculoskeletal abnormalities, as "duck bill" deformity of the thumb and scoliosis (3 needed surgery). Distal muscle wasting is common. For years, they were suspected to have either a congenital myopathy or a collagen disease. CK levels were normal. Muscle biopsies performed in the first year of life in 5 patients were unremarkable, except for one case with multi-minicores. Finally, NGS disclosed the novel homozygous intronic variant c.1239+29T>G in PIEZO2 gene. Functional studies are ongoing, but an extensive segregation study supports its pathogenicity. Family 2 is a non-consanguineous Hispanic family with 2 male siblings affected aged 2.5 years and 5 months. Both had neonatal hypotonia, talipes, respiratory insufficiency, transitory hyperkinetic movements, and delayed motor development. The older brother has a tracheostomy, scoliosis, and cognitive involvement. His muscle biopsy was normal. NGS detected a homozygous variant in PIEZO2 gene, c.5053C>T, which has already been described as pathogenic. We provide additional genetic and clinical features of the disease. Hyperkinetic movements are a remarkable clue in hypotonic infants that has not previously been reported.