A case of PSMC5-associated neurodevelopmental proteasomopathy

A 7-year-old male was seen in consultation by a Clinical Genetics team for bone marrow failure and global developmental delay. He was born to non-consanguineous White parents of Western European descent. He was born at term by spontaneous vaginal delivery after an unremarkable pregnancy. He presented to care in the neonatal period with congenital thrombocytopenia, which evolved over time into unexplained bone marrow failure. Additional medical issues included childhood-onset seizures treated with levetiracetam, bilateral hearing loss requiring hearing aids, non-congenital scoliosis requiring bracing, joint instability requiring ankle foot orthoses, and multiple aspiration pneumonias leading to gastrostomy tube insertion for feeding. He had hypotonia and global developmental delay without stagnation or regression. Brain MRI in early childhood identified mild global hypomyelination. At age 7 years, his cognitive functioning had not yet been formally assessed. He had a diagnosis of autism spectrum disorder and was non-verbal. He was able to walk independently with an abnormal gait, and to climb stairs (not descend) with assistance. He could do some limited tracing with a pencil, but required someone to hold his hand to do so accurately. He had undergone extensive molecular and cytogenetic testing earlier in life for the bone marrow failure that was non-diagnostic. Chromosomal microarray analysis revealed normal male copy number. Trio exome sequencing identified a de novo missense variant in PSMC5 [NM_002805.5: c.973C>T;p.(Arg325Trp)]. On examination at age 7 years, his height z-score was -0.62, his weight z-score was -1.12, he was normocephalic, and he was noted to have distinctive facial features (see photo).