A Novel PEPD Mutation (Prolidase Deficiency) Presenting as Refractory HLH Treated with Bone Marrow Transplant

Prolidase deficiency (PD) is a rare inborn error of immunity due to autosomal recessive pathogenic variants in the PEPD gene. Clinical presentation of this condition is highly variable, making diagnosis difficult. The most common presentations of PD are cutaneous (ulcers) followed by dysmorphism, developmental delay, and frequent infections. Genetic testing can be helpful in the diagnosis of PD and other inborn errors of immunity. The limitations of genetic testing lie in the interpretation of genomic results for rare or ultra-rare disorders, particularly variants of unknown significance (VUS). Clinical correlation is still vital in the era of genomic medicine. We present a case of a two-year-old female who presented with recurrent episodes of hemophagocytic lymphohistiocytosis (HLH). HLH episodes were triggered by multiple organisms, including EBV. HLH was managed with systemic steroids and anakinra while stem cell transplant workup was being performed. While on therapy, type 1 and 2 IFN signaling were normal, but CXCL9 and IL-18 were elevated. Genetic testing identified a pathogenic variant in PEPD (deletion in exon 7) and a VUS c.79C>T p.(Arg27Trp). Other VUSs were found in NFAT5, POLD2, and POLE. HLH is reported in at least one patient with PD, making the diagnosis a consideration. Familial genetic study confirmed the pathogenic mutation was paternally inherited and VUS maternally inherited. The proband’s sister carried only the paternal pathogenic mutation. Urine amino acid studies showed marked proline elevation in the proband (similar to another known affected individual) and was normal in all other family members. Confirmation of two PEPD variants in trans, markedly elevated urine proline, and a phenotype compatible with PD allowed for reclassification of the VUS to likely pathogenic variant. The patient underwent matched HSCT from her sister. The patient so far has not had recurrence of her HLH. This case is the second known case of PD treated with HSCT. The first case resulted in fatality within the first 100 days of transplant due to invasive fungal infection. It is unclear if HSCT will correct the entirety of PD complications, but we are hopeful early intervention will reduce sequalae and improve quality of life.