RFC4 Deficiency: Journey of Uncertainty to Diagnosis and Early Compassionate Care

Introduction: Diagnosing rare genetic diseases in the pediatric ICU (PICU) often involves a complex and emotional “diagnostic odyssey.” RFC4-related multisystem disorder is an ultra-rare autosomal recessive condition, with only nine reported cases as of 2024. It presents with progressive neurologic dysfunction, including sensorineural deafness, hypotonia, motor incoordination, weakness, and developmental delay. Early palliative care is essential for families facing life-limiting diagnoses.


Description: We report a 5-month-old male with global hypotonia, bilateral sensorineural hearing loss (B/L SNHL), poor weight gain, cyanotic episodes, and hypoxia. Diagnosed with B/L SNHL at birth, he also showed failure to thrive (FTT).
Four years earlier, a sibling with similar features (B/L SNHL, FTT, developmental delay) died of apparent SIDS at 7 months. Autopsy revealed mild cardiac fibroelastosis. Trio whole exome sequencing (WES) of the sibling and parents had been non-diagnostic.
Our patient displayed choreoathetoid movements, hyporeflexia, and poor responsiveness not explained by SNHL alone. EEG showed subtle temporal lobe seizures initially responsive to anti-seizure medications. Brain MRI was normal. CSF revealed elevated protein (105 mg/dL) without infection or other potentially treatable etiology. Given the family history, trio WES was repeated (proband, both parents).
Seizures became refractory, requiring multiple agents without improvement. WES revealed compound heterozygous variants of uncertain significance in RFC4 [maternal c.882+4_882+5del p.? and paternal c.827_835del (p.G276_F278del)]. Retrospective testing confirmed the deceased sibling had the same variants, though RFC4 had not yet been associated with disease at that time. RFC4, involved in DNA replication and repair, is now linked to Morimoto-Ryu-Malicdan neuromuscular syndrome (MRMNS; MIM #621010, PMID:16980295).
After diagnosis during a two-week hospitalization, care goals were aligned with the family. The patient was transitioned to comfort care and discharged with hospice support. He expired within two months.


Discussion: This case highlights the value of repeated family-based genetic testing. Timely PICU diagnosis using WES supports informed decisions and compassionate care in rare, life-limiting conditions like RFC4 deficiency.