Expanding the clinical and immunological phenotype of prolidase deficiency: A case report.

Prolidase deficiency (PD) is a rare autosomal recessive disorder associated with recurrent infections, immune dysregulation, and autoimmunity. PD is characterized by persistent dermatitis, skin fragility, and non-healing ulcerations on the lower limbs as its main dermatologic characteristics. Herein, we report a boy with PD due to a novel variant in PEPD who had abnormal facies, cognitive impairment, corneal opacity, recurrent infections, and persistent non-healing leg ulcers. Th17 lymphocyte counts and phosphorylated-STAT5 expression following IL-2 stimulation were reduced in our patient as compared to healthy control.

Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD.

Prolidase deficiency (PD) is a rare autosomal recessive inborn error of immunity caused by biallelic homozygous or compound heterozygous loss-of-function mutations in PEPD, the gene that encodes prolidase. PD typically manifests with variable dysmorphic features, chronic cutaneous ulcers, recurrent infections and autoimmune features, including systemic lupus erythematosus. So far, there is no consensus regarding treatment of PD and its autoimmune manifestations. Here, we present a 28-year-old female patient with PD due to a novel homozygous intragenic deletion in PEPD, diagnosed at the age of 6 years and 7 months with an undifferentiated connective tissue disease that, apart from its very early onset, would be consistent with the diagnosis of Sjögren's syndrome. Steroids and diverse conventional synthetic disease-modifying antirheumatic drugs failed to control PD-associated vasculitis and mucocutaneous ulcerations and led to infectious complications, including cytomegalovirus colitis. Introduction of rituximab (RTX) treatment in this patient led to sustained recession of mucocutaneous ulceration, enabling tapering of steroids. High interleukin-1ß (IL-1ß) production by this patient's monocytes, together with the detection of both IL-1ß and interleukin-18 (IL-18) in her serum, suggest enhanced inflammasome activation in PD, whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD.

Establishment of a human induced pluripotent stem cell line, KMUGMCi007-A, from a patient with prolidase deficiency (PD) bearing homozygous in-frame mutation in the PEPD gene.

Prolidase deficiency (PD) is a rare autosomal recessive disorder characterized mainly by skin lesions of the legs and feet, respiratory infections and mental retardation, and impaired immune system. To date, no effective PD treatment has been developed. The PD case are caused by homozygous mutation in PEPD gene. The peripheral blood mononuclear cells from a patient carrying homozygous in-frame mutation of the PEPD gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. The homozygous in-frame mutation in PEPD will cause the abnormal protein variant. The established human induced pluripotent cell line will enable proper in vitro disease modelling of PD.

Prolidase deficiency: A novel PEPD missense variant in exon 2.

Prolidase deficiency is an autosomal recessive disease that causes impaired collagen degradation. Altered collagen homeostasis results in the intracellular accumulation of imidodipeptides, which contain proline and hydroxyproline. The many clinical manifestations of prolidase deficiency include dysmorphic facial features, skeletal deformities, hepatosplenomegaly, necrotizing skin ulcers, and recurrent infections. Current clinical knowledge of this genetic disease relies upon few case reports due to its extreme rarity. Diagnosis is dependent on the detection of a pathologic gene variant. Additional diagnostic confirmation may be provided by urine amino acid quantification or reduced in vitro prolidase activity. We present a case of prolidase deficiency caused by a novel variant manifested by skeletal malformations and lifelong multisystemic infections. Genetic testing revealed a homozygous missense variant in the PEPD gene at nucleotide position 200, whereby adenine was replaced by guanine (c.200A > G). The corresponding amino acid change replaced glutamine with arginine at codon 67 (p.Gln67Arg). After boiling the urine sample for hydrolysis, quantitative urine amino acids demonstrated a markedly elevated proline level, confirming the diagnosis. We also provide a discussion of the pathophysiology, clinical manifestations, diagnostic testing, and clinical management of this disease.

Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity.

Prolidase deficiency (PD) is a multisystem disorder caused by mutations in the PEPD gene, which encodes a ubiquitously expressed metallopeptidase essential for the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. PD typically presents in childhood with developmental delay, skin ulcers, recurrent infections, and, in some patients, autoimmune features that can mimic systemic lupus erythematosus. The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden. In this study, we address the question of causation and show that Pepd-null mice have increased antinuclear autoantibodies and raised serum IgA, accompanied by kidney immune complex deposition, consistent with a systemic lupus erythematosus-like disease. These features are associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver. Pepd deficiency leads to spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of Ag receptor specificity or antigenic stimulation. However, an increase in KLRG1+ effector CD8 cells is not observed in mixed chimeras, in which the autoimmune phenotype is also absent. Our findings link autoimmune susceptibility in PD to spontaneous T cell dysfunction, likely to be acting in combination with immune activators that lie outside the hemopoietic system but result from the abnormal metabolism or loss of nonenzymatic prolidase function. This knowledge provides insight into the role of prolidase in the maintenance of self-tolerance and highlights the importance of treatment to control T cell activation.

Obstinate leg ulceration secondary to prolidase deficiency, treated with 5% topical proline.

Prolidase deficiency is a rare cause of chronic ulceration with less than 100 reported cases in the literature. This article highlights to clinicians the features of this uncommon genodermatosis, the challenge of diagnosis, and treatment options.

A case of prolidase deficiency in a male patient.

Prolidase deficiency is an extremely rare, autosomal recessive disorder resulting in defective collagen formation. We report a case of prolidase deficiency in a male child, highlighting the dermatologic features. Early diagnosis is important as these patients encounter significant multisystem comorbidities requiring multispecialty care.

Prolidase deficiency in an infant with an incidental finding of methaemoglobinaemia.

A 4-week-old boy presented to the hospital with symptoms of diarrhoea and vomiting initially thought to be due to cow's milk allergy. He was discharged with extensively hydrolysed formula. The patient represented with worsening of symptoms with metabolic acidosis and was screened and treated for sepsis. However, his condition deteriorated further and he developed methaemoglobinaemia. He was transferred to the high dependency unit and was given two doses of methylene blue. Further investigations were carried out, including rapid trio exome sequencing, which identified a homozygous pathogenic Peptidase D (PEPD) variant (c.978G>A, p.(Trp326*)). This was consistent with a diagnosis of prolidase deficiency.

Prolidase Deficiency Causing Recalcitrant Leg Ulcerations in Siblings.

ABSTRACT: Prolidase deficiency (PD) is a rare autosomal recessive genodermatosis with variable clinical manifestations. It results from a mutation in the peptidase-D gene that leads to abnormal activity of the prolidase enzyme, an important player in collagen catabolism. The authors report the case of two siblings presenting with dysmorphic features, disturbed blood panel, and recalcitrant leg ulcerations of several years' duration. Sequencing of the 15 exons and of the intron/exon junction regions of the peptidase-D gene revealed the presence of a homozygous pathogenic variant c.549-1G > A. An ointment with 5% proline and 5% glycine was compounded, and the patients were instructed to apply it once daily. A follow-up visit after 8 months revealed partial improvement of the ulcerations starting from the third month of treatment. These authors hope this case report sheds light on this disease and recommend it be incorporated into the differential diagnoses of chronic leg ulcerations, particularly those starting at a young age.

Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases.

PURPOSE: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature. METHODS: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival. RESULTS: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old. CONCLUSION: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.

Prolidase - A protein with many faces.

Prolidase is a metal-dependent peptidase specialized in the cleavage of dipeptides containing proline or hydroxyproline on their C-termini. Prolidase homologues are found in all kingdoms of life. The importance of prolidase in human health is underlined by a rare hereditary syndrome referred to as Prolidase Deficiency. A growing number of studies highlight the importance of prolidase in various other human conditions, including cancer. Some recent studies link prolidase's activity-independent regulatory role to tumorigenesis. Furthermore, the enzyme or engineered variants have some applications in biotechnology. In this short review, we aim to highlight different aspects of the protein the importance of which is increasingly recognized over the last years.

Prolidase deficiency in two dermatological patients in western Sicily.

Prolidase deficiency is a rare disorder inherited through an autosomal recessive gene. The hallmark of the disorder are iminodipeptiduria, chronic skin ulcers, recurring infections, mental retardation and characteristic facial appearance, although prolidase deficiency can occur with no clinical manifestation. The primary biological function of the enzyme involves the metabolism of collagen degradation products and the recycling of proline for collagen resynthesis. We describe two patients with prolidase deficiency and review the different clinical manifestations suggesting the pathogenetic mechanism through few hypotheses.