A rare cause of cutaneous ulceration: Prolidase deficiency

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1.

Prolidase deficiency (PD) is a rare hereditary disease characterised by skin lesions including ulcerations, frequent infections, characteristic facies, mental retardation, and splenomegaly. Diagnosis of prolidase activity is made by sequence analysis of the peptidase D (PEPD) gene in erythrocytes, leukocytes, or fibroblasts.1 Here, we report a case with associating immunological abnormalities and PD.

A 20‐year‐old boy was admitted to the dermatology clinic for severe ulceration on lower extremities, which were persistent for the past 6 months. Family history indicated that his parents were first‐degree relatives. On dermatological examination, there were several geographic ulcers on the thighs and soles with irregular borders (Figures 1 and 2). Atrophic depressed scars on the cheeks were also noted. Laboratory studies showed an elevated erythrocyte sedimentation rate (31 mm/h), elevated IgG level (2100 mg/dL; 750‐1560 mg/dL), and elevated total IgE level (379 UI/mL; 1.3‐165 UI/mL). Antinuclear antibodies (ANA) were positive at a titre of 1:320 (homogenous and granular pattern). Complement components (C3‐C4) were within normal levels, and antibodies to double‐stranded DNA, cardiolipin, rheumatoid factor, cryoprotein precipitates, and direct Coombs test were negative. Abdominal ultrasonography showed splenomegaly with a 16 cm vertical length of spleen. Multiple skin biopsies from the edge of the ulcers demonstrated thrombus formation, fibrin, and perivascular neutrophilic infiltrate in the dermis and subcutaneous tissue, and there were also vasculitis findings in small vessel walls. Diagnosis of PD was confirmed by peripheral blood cell DNA mutation analysis of the PEPD gene, demonstrating a c.611dupAGGCCCACCGTGA homozygous mutation. The patient was treated with oral ascorbic acid (2 g/d) and topical 5% prolin plus 5% glycine ointment (twice a day).

Figure 1.

Crusted ulcers with irregular borders on the posterior thighs

Figure 2.

Shallow and deep ulcers on the lateral aspect of the sole

PD is a rare autosomal‐recessive disorder caused by mutations in the PEPD gene. Prolidase is a metallo‐enzyme in all cells whose co‐factor is magnesium. Enzymes hydrolyse dipeptides, which are C‐terminal proline and either hydroxyproline; thus, it plays a role in endogenous and diet proteins, especially in the late stages of collagen degradation.1 PD leads to the systemic accumulation of proline or hydroxyproline‐containing iminopeptides at the C‐terminal and then to extreme amounts of urine, which leads to a decrease in the amount of total proline in the body. This defect in the pathway of proline reuse leads to an abnormality in collagen production and deterioration of skin healing.2 Prolidase is located in the 19q12‐q13.2 region of the genomic chromosome. At least 19 different mutations have been identified in the PEPD gene so far.3 Significant phenotypic variability has been reported. One of the siblings with the same PEPD homozygous mutation in a familial case had clinical findings of typical PD, while the other brother was found to be totally asymptomatic.1 High amounts of proline in the neuropeptides demonstrate common mental retardation in prolidase enzyme deficiency.3 PD is also associated with abnormal laboratory findings such as iron deficiency anaemia, thrombocytopenia, high liver function tests, hypergammaglobulinemia, and hypocomplementemia.4 Systemic lupus erythematosus (SLE), hyper IgE syndrome, and chronic pulmonary disease are other associated diseases.5, 6, 7 Cases reported with SLE may implicate an aspect of PD causing immunological abnormalities, including hypergammaglobulinemia, splenomegaly, and ANA positivity; vasculitis may accompany PD as well.4, 5, 6, 7

In a study by Aviel et al, the SLE patient ratio selected among patients diagnosed with PD was 13%, concluding that this relationship can not be coincidental and that patients with PD have an increased incidence of SLE compared with the normal population.8 A pathomechanism was suggested: dipeptide residues that accumulate in the small vessel wall initiate necrosis‐like cell death. Another hypothesis is that C1q levels with high proline content alter the immune response and predispose to autoimmune diseases.

Treatment options include compression covers, prophylactic antibiotic use, and topical 5% proline to control lymphoedema.9 Combined therapy with topical proline and proline‐glycine has limited benefit.10 Oral Mn2 + and ascorbic acid supplementation are important in collagen synthesis, but the results are inconsistent. Oral proline therapy has not been clinically beneficial, and data on erythrocyte suspension, corticosteroid pulse therapy, and combined oral‐topical growth hormone have been limited.11, 12

In conclusion, PD is a rare cause of cutaneous ulceration that can accompany SLE, which may implicate an aspect of PD causing immunological abnormalities, including hypergammaglobulinemia, splenomegaly, and ANA positivity; vasculitis may accompany PD as well.