Prolidase deficiency, natural history and identification of a rare variant c.1409G>A (p.(Arg470His)) in PEPD gene. Case report
2Centro de Genética Preditiva e Preventiva, Instituto de Biologia Molecular e Celular, i3S, Portugal
Background: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin lesions, facial dysmorphism, intellectual disability, splenomegaly and recurrent infections. Knowledge of its natural history and genetic basis is increasingly important.
Case Study: We present a 27 years old male, son of non-consanguineous parents, with unremarkable family history, admitted at 4 years old with chronic recalcitrant skin lesions. He presented high forehead, hypertrichosis, psychomotor developmental delay, splenomegaly, thrombocytopenia and hyperimmunoglobulinemia G and E, as well as imidodipeptiduria which established the diagnosis. The patient is now 27 years old and presents hypertelorism, proptosis, prognathism, low hair implantation, mild microcephaly, hypertrichosis and chronic, non-painful, superficially ulcerated, scaly skin lesions. His intelligence quotient (IQ) is 74-83. Over the years, the patient maintained thrombocytopenia, splenomegaly, hyper IgG and IgE, without other immunological anomalies nor recurrent or severe infections. He also presents mild paraseptal emphysema.
Results: Whole-exome sequencing based PEPD gene analysis identified two homozygous variants: c.692_694del(p.(Tyr231del)); c.1409G>A(p.(Arg470His)). The first is a previously described likely pathogenic variant. The second is a rare variant of unknown significance. Parents testing confirmed homozygous state for both variants.
Discussion/Conclusion: Patients with prolidase deficiency wait an average of 11.6 years before diagnosis. Considering that half develop symptoms by age 4, we can say that there was no diagnostic delay. Biochemical diagnosis can be challenging, since imidodipeptide elevations can not be detected in routine plasma amino acids if not specifically screened for. The wide variability in clinical presentation and the low disease awareness delay the diagnosis. Molecular diagnosis can be challenging, although very useful, namely for genetic counseling purposes.
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