Leg Ulcers Secondary to Prolidase Deficiency

Advances in Skin & Wound Care, Nov/Dec 2004 by Trent, Jennifer T, Kirsner, Robert S

First described by Goodman in 1968, prolidase deficiency (PD) is a rare, autosomal recessive inborn error of collagen metabolism.1,2 It is caused by a defect in the PEPD gene on chromosome 19.3,4 As of 2004, approximately 40 cases of PD had been reported.5 In addition to its clinical features, some patients with PD develop systemic lupus erythematosus later in life, suggesting that PD may also be a risk factor for this disease.5,6

Although patients may exhibit a variety of signs and symptoms (Table 1), PD is most commonly characterized by recurrent chronic leg ulcers, typical facies, splenomegaly, and mental handicaps.1,2,5,7 Patients initially display signs of PD anytime from birth to 22 years of age, with most presenting prior to puberty.6,8,9 Ninety percent of patients manifest some dermatologie features of PD, with more than 50% suffering from chronic leg ulcers.2 Although most ulcers occur on the lower extremities, ulcerations on the upper extremities have been reported in some cases.7 Wounds related to PD are difficult to heal and frequently recur.10 They are characterized by irregular borders with prominent granulation tissue and purulent exudate. Surrounding atrophy, scarring, and lack of hair are usually present. secondaiy infection is the most common complication; however, squamous cell carcinoma develops within a long-standing leg ulcer in rare cases.10,11

Pathogenesis

Collagen is degraded to iminodipeptides, which are then broken down into amino acids that can be resynthesized to form collagen.12 One of the enzymes that degrades iminodipeptides is prolidase. Specifically, it cleaves dipeptides with proline or hydroxyproline at the C-terminus end.1,11 Decreased activity of prolidase causes a concomitant increase in urinary excretion of dipeptides (iminodipeptiduria). This iminodipeptiduria represents a deficient recycling of proline and leads to impaired collagen synthesis and wound healing.1,7,13,14

In patients with PD, amyloid deposits have been found within the vessels of the skin and internal organs, including the spleen.6 Splenic amyloid deposits lead to splenomegaly and subsequent splenic dysfunction. This may be the cause of the characteristic increased risk of infection in patients with PD.

Neutrophils have also been found to play a role in clinical manifestations of PD. Increased iminodipeptide levels lead to proliferation of neutrophils, which, in turn, generate Superoxide molecules that mediate inflammation and tissue destruction.15 In addition, neutrophils release collagenases and, along with histamine from mast cells, mediate further tissue inflammation and subsequent tissue destruction.16

Diagnosis

PD can be diagnosed based on decreased prolidase activity in the blood and increased levels of urinary iminodipeptides.1 Prolidase is a ubiquitous enzyme; however, it exerts its greatest activity in the red blood cells and kidney.11 To determine the prolidase level, an enzyme assay of prolidase can be done using red blood cells and fibroblasts.1,11 To establish the presence of iminodipeptiduria, the patient's urine may be analyzed using urine electrophoresis on paper or thin-layer cellulose acetate and column chromatography; direct chemical ionization mass spectrometry can also detect iminodipeptiduria.2,5,11 In addition, PD can be diagnosed in utero by using chorionic villus sampling or amniocentesis.5 Laboratory abnormalities associated with PD include iron-deficiency anemia, thrombocytopenia, and hypergammaglobulinemia.6'7 However, these are neither diagnostic of nor pathognomonic for PD.

Skin histopathology is almost normal in patients with PD,2 although there may be a decrease in the size of collagen fibers or fragmentation of collagen fibers with impaired aggregation.8 Elastic fibers are normal,8 but dense bodies have been found in capillary endothelium.17 Angiopathy, perivascular neutrophilic infiltrate, dermal sclerosis, occlusion of capillary and arteriole walls with thrombi, and fibrosis of vessels walls have been demonstrated in patients with PD.17,18 Congo red staining has confirmed the presence of amyloid, which can occlude the vessels.6,15,17

Treatment

Various topical, systemic, and surgical treatments for leg ulcers secondary to PD have been reported in the literature (Table 2); however, none has been shown to be effective in randomized, controlled trials. Topical antibiotics, such as gentamicin, polymyxin, and colistin, are suggested to be effective in controlling infection.12 When infection develops, oral or intravenous antibiotics become necessary.17 Topical 5% proline and 5% glycine combined in an ointment base have been shown to be more effective in healing ulcers from PD than topical 5% proline in ointment alone.13 In addition, a combination of topical and systemic growth hormone healed recalcitrant leg ulcers in 1 patient.4

Various systemic therapies that have shown efficacy in a handful of patients with leg ulcers from PD include a combination of vitamin C and manganese, with or without proline; a combination of zinc sulfate and vitamin C; and growth hormone.1-6,7,12,13,19 Periodic red blood cell transfusions and apheresis erythrocyte exchanges have also proven to be effective in healing chronic leg ulcers.6,20 Dapsone was used to heal 1 patient's recalcitrant leg ulcers.17