Arthrogryposis, Cleft Palate, Craniosynostosis, And Impaired Intellectual Development

A number sign (#) is used with this entry because of evidence that arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ACCIID) is caused by heterozygous mutation in the PPP3CA gene (114105) on chromosome 4q24.

Heterozygous mutation in the PPP3CA gene can also cause infantile or early childhood epileptic encephalopathy-1 (IECEE1; 617711).

Description

ACCIID is characterized by arthrogryposis, cleft palate, craniosynostosis, micrognathia, short stature, and impaired intellectual development. Seizures and bony abnormalities (severe slenderness of the ribs and tubular bones and perinatal fractures) have been observed (Mizuguchi et al., 2018).

Clinical Features

Mizuguchi et al. (2018) reported 2 unrelated patients with arthrogryposis, cleft palate, craniosynostosis, micrognathia, short stature, and impaired intellectual development. One patient (patient 5) was a 5-year-old female who had severe hydrops fetalis with ascites and right hydronephrosis on fetal ultrasonography. She had severe feeding difficulties and respiratory distress requiring tube feedings and mechanical ventilation. She had coronal craniosynostosis, hypertelorism, short nose, cleft palate, micrognathia, and arthrogryposis with bilateral talipes equinovalgus. Radiologic examination showed severe slenderness of tubular bones and ribs (gracile bones) with bowing of the radii and delayed calvarial ossification. She also developed several fractures during the neonatal period. She had a hypoplastic left kidney with severe vesicoureteral reflux and severe developmental delay. No seizures were observed. The other patient (patient 6) was a 7-year-old boy who had pedal edema at birth, as well as trigonocephaly, cleft palate, micrognathia, retrognathia, ptosis, arthrogryposis, and brachydactyly. He had significant developmental delay and developed generalized seizures with fever in infancy, which were mild and responsive to treatment. Brain MRI showed periventricular white matter changes with asymmetric ventriculomegaly.

Molecular Genetics

In 2 patients with ACCIID, Mizuguchi et al. (2018) identified de novo heterozygous mutations in the autoinhibitory domain of the PPP3CA gene (114105.0007-114105.0008). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Using a yeast model, the mutations were found to be constitutively activating.