Clinical and biochemical characterization of a patient with prolidase deficiency, a rare disorder of collagen metabolism

Prolidase deficiency (PD) is an autosomal recessive inborn error of metabolism, with an estimated incidence of 1 per 1.25 million births. Prolidase is critical for the turnover of proline and hydroxyproline-rich proteins, such as collagen. Collagen metabolism is essential for matrix regeneration during cellular proliferation and complex bodily functions such as wound healing and immunological cell differentiation. PD clinical manifestations include persistent skin ulcerations and poor wound healing, hypertelorism, high arched palate, depressed nasal bridge, micrognathia, splenomegaly, intellectual disability, recurring infections, and hematological abnormalities. Biochemically, a diagnosis of PD is supported by increased urinary excretion of glycyl-proline and other proline-containing iminopeptides detected by amino acid analysis. There are no current targeted therapies, but suggested interventions have included topical proline-glycine ointment, manganese supplementation, topical and oral steroids, and immunomodulation with monoclonal antibodies. Here, we describe a 30-year-old patient with PD whose clinical course has been characterized by recurrent skin ulcerations/cysts with secondary scarring, recurrent infections, anemia, thrombocytopenia, lymphopenia, elevated liver enzymes, hirsutism, and seemingly unrelated papillary thyroid cancer. Skin manifestations were particularly severe due to the added complication of a diagnosis of hidradenitis suppurativa. Quantitative analysis of amino acids and related compounds revealed markedly elevated glycyl-proline in urine and plasma. To further characterize the biochemical phenotype, untargeted metabolomic analysis was sent on both plasma and urine. An increase was noted in several metabolites from the prolidase-dependent dipeptide recycling pathways. A better understanding of the pathophysiological mechanisms involved in prolidase deficiency may prove useful as different therapeutic approaches are being considered.