Prolidase deficiency: case reports of two Argentinian brothers

Abstract

Case 1 A 28‐year‐old man presented with his first leg ulcer at the age of 10 years. With regard to the family history, there was no consanguinity between the parents, and the patient had a brother with similar findings. He had frequent infections in childhood, such as otitis media, tuberculosis, and septic arthritis. At the age of 11 years, he showed photosensitivity, malar erythema, and positive antinuclear antibody test (1 : 40), and systemic lupus erythematosus was diagnosed (Fig. 1). This disease was later ruled out because diagnostic criteria were not present. 1 Photosensitivity and malar erythema at the age of 11 years (Case 1) At the age of 12 years, the ulcers worsened and did not respond to different treatments (antimicrobials, prednisone), and a diagnosis of pyoderma gangrenosum was suggested. Nevertheless, histopathology rejected such a diagnosis. The disease progressed until the patient presented again to our department. On examination, the ulcers were located on both legs and thighs, had a polygonal form, elevated borders, and necrotic base (Fig. 2). They showed edema and induration with multiple scars. Dystrophic nails, saddle nose, hypertelorism, syndactyly, obesity, and deformity of the auricle were observed. Laboratory analysis revealed iron deficiency anemia (hematocrit, 30%), an erythrocyte sedimentation rate of 120 mm/h, an elevated gammaglobulin level (3.79 g%), and an elevated immunoglobulin E (IgE) (3285 U/L). Skin cultures were negative. The rest of the laboratory studies were normal (creatinine, glucose, C3, C4, negative HIV, and normal abdominal examination). The evaluation of cellular and humoral immunity showed normal results; chromosome studies disclosed no abnormalities. 2 Polygonal and deep ulcers on the left thigh (Case 1) A skin biopsy showed no specific abnormalities, except fibroblastic proliferation, inflammation, and ulcers that infiltrated the hypodermis. No signs of vasculitis were found. Multiple histologic analyses had been performed throughout the patient's life without any different findings. Aliquots of urine from the patient and controls were analyzed by capillary zone electrophoresis (CZE) according to the method proposed by Zanaboni et al. (Zanaboni G, Grimm KM, Dyne KM, et al. Use of capillary zone electrophoresis for analysis of iminodipeptides in urine of prolidase‐deficient patients. J Chromatogr B 1996; 683: 97–107.) The presence of a large amount of dipeptides, normally absent from control samples, was detected in the patient. There is no specific or effective treatment for prolidase deficiency, but the patient received oral and topical antimicrobials, oral prednisone, 1 mg/kg/day, and thalidomide, 200 mg/day, for 8 months in order to decrease the size of the ulcers and to improve his life quality. Unfortunately, treatment failed. Case 2 The 23‐year‐old younger brother showed his first lesion at the age of 8 years. He had smaller leg ulcers than his brother, but they were pruriginous (Fig. 3). The round ulcers of 2–3 cm in diameter were on the inner part ...

Topical tacrolimus therapy in the management of lower extremity ulcers due to prolidase deficiency

“…There are several distinct characteristics of PD ulcers. Specifically, they occur mostly on the lower extremities and have an onset before the age of 12, as was seen in this patient . The ulcers often have an irregular shape, purulent exudate, and prominent granulation tissue .…”

“…Prolidase deficiency is a rare autosomal recessive disease with an estimated incidence of 1‐2 per 1 million births . Prolidase is involved in protein catabolism throughout the body .…”

“…Clinically, this process leads to ulcer formation and impaired wound healing . The diagnosis of PD can be confirmed with elevated urinary iminodipeptide excretion or genetic studies showing pathogenic mutations in the PEPD gene …”

A nonsense mutation of PEPD in four Amish children with prolidase deficiency

“…The enzyme is a 493-amino acid peptide encoded by the peptidase D (PEPD) gene located at 19q12-q13.1 [Hechtman, 2000]; the gene spans 130 kb and has 15 exons [Tanoue et al, 1990]. Although more than 10 mutations in the PEPD gene have been documented since the first case was found in 1968 [Tanoue et al, 1990;Ledoux et al, 1994Ledoux et al, , 1996Kikuchi et al, 2000;Forlino et al, 2002;Lupi et al, 2004], prolidase deficiency (MIM 170100) remains a rare autosomal recessive disease with no more than 50 cases reported in the literature [Goodman et al, 1968;Powell et al, 1974;Sheffield et al, 1977;Freij et al, 1984;Lemieux et al, 1984;Leoni et al, 1987;Bissonnette et al, 1993;Shrinath et al, 1997;Hechtman, 2000;Mandel et al, 2000;Dyne et al, 2001;Kokturk et al, 2002;Lopes et al, 2002;Cabrera et al, 2004;Lupi et al, 2004].…”

The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts

“…It is evident that an absence of prolidase severely impedes the recycling of collagen‐derived proline. Some clinical symptoms related to collagen deficit can be attributed to prolidase deficiency . On the other hand, an increased activity of liver prolidase was found during the fibrotic process .…”