The disorder caused by bi-allelic variants in RPS6KC1is characterized by a broad spectrum of severity, ranging from prenatal lethality to a complex neurodevelopmental syndrome.
The clinical manifestations of this disorder involve multiple systems, with a primary focus on neurological development, motor function, and craniofacial features.
• Nearly all affected individuals exhibit developmental delay and intellectual disability, which ranges from mild to severe. In some instances, a loss of previously acquired skills (regression) has been noted later in childhood.
• Motor signs: neonatal hypotonia often evolving into progressive spastic paraparesis or tetraparesis, hyperreflexia. Axonal neuropathy and mild distal weakness can also be present.
• Behavioral issues are prevalent. These include autistic traits, anxiety disorders, repetitive behaviors, ADHD, and occasionally aggressive or depressive symptoms.
• Movement Disorders: Some patients present with gait ataxia, tremors, dystonia, or myoclonus.
• Seizures are reported in more than half of the affected individuals.
• Many individuals display facial features that overlap with Coffin-Lowry syndrome. Long face, prominent forehead, downslanted palpebral fissures, ptosis, and hypotelorism, anteverted nares, a prominent nose, a long philtrum, a thin upper lip, and dental anomalies such as prominent maxillary incisors or a single median maxillary incisor, retrognathia and low-set, posteriorly rotated ears have been reported.
• Musculoskeletal manifestations: scoliosis, lumbar hyperlordosis, pes cavus, asthenic body habitus.
• Other manifestations: strabismus, ocular apraxia, cardiovascular issues like mitral valve prolapse.
• Prenatal Lethality: The condition is associated with a high incidence of miscarriages, stillbirths, and hydrops fetalis.
Neuroimaging findings:
• White matter volume loss is a consistent finding in all available brain MRI scans.
• Delayed myelination during infancy.
• Thinning or hypoplastic corpus callosum, sometimes with a dysplastic appearance.
• Colpocephaly.
• Cerebral atrophy.
• Vermis hypoplasia or atrophy, brainstem hypoplasia. Megacisterna magna.
RPS6KC1