Hereditärer Prolidasemangel Beitrag zur Differentialdiagnose therapieresistenter Beingeschwüre

Leg ulcers may be caused by many different diseases. Most frequently, they are due to vasculopathies, to a lesser extent to metabolic, neuropathic or hematologic diseases. Neoplasms, connective tissue diseases, infections, trauma, and panniculitis should also be included in the differential diagnosis. A 38-year-old Caucasian female patient with hereditary prolidase deficiency developed progressive and very painful leg ulcers. The ulcers first appeared in childhood and did not respond to various treatments. Additional features of prolidase deficiency included mental retardation, short stature, extensive dental caries, and multiple malar teleangiectases. Hereditary prolidase deficiency is a very rare autosomal recessive disease. It is caused by heterogeneous mutations of the prolidase gene and affects many aspects of protein metabolism. Ion exchange chromatography and high voltage electrophoresis of urine can prove the suspected diagnosis. So far, there is no efficient therapy for hereditary prolidase deficiency. All reported treatment attempts have ended in failure.     

Prolidase deficiency: the use of topical proline for treatment of leg ulcers

A 41-year-old man with prolidase deficiency has had chronic leg ulcers and recurrent cellulitis for most of his life. Until recently he had been hospitalized at least annually for this and suffered significant morbidity as a result. Since commencing topical 5% proline in white soft paraffin ointment to treat the leg ulcers, there has been marked improvement in the ulcers and decreased frequency of hospitalizations for cellulitis. This lends further support to the use of topical proline in the treatment of patients with skin ulcers secondary to prolidase deficiency.     

Transient beneficial effect of GH replacement therapy and topical GH application on skin ulcers in a boy with prolidase deficiency

A diagnostic examination for short stature in a boy with chronic ulcers of the feet due to prolidase deficiency, a rare disorder associated with intractable ulcers of the skin, led to the diagnosis of growth hormone (GH) deficiency. Replacement treatment with r-hGH associated with the topical application of a GH-containing ointment when the boy was 13 years old resulted in complete but transitory healing of the ulcers, which can probably be attributed to the growth-promoting effects of GH on dermal connective tissue.     

Hereditary prolidase deficiency in 2 sisters with therapy-resistant leg ulcers

Two sisters with hereditary prolidase deficiency are presented. Recurrent and painful leg ulcers are the predominant feature.     

Topical Treatment of Skin Ulcers in Prolidase Deficiency

Prolidase deficiency is a hereditary enzyme deficiency characterized dermatologically by chronic recurrent ulcers and scarring due to increased skin fragility. It has been speculated that the enzyme deficiency causes a relative deficiency of proline in the wounds of these patients and negatively affects clinical healing. Two ulcers in a 17-year-old girl with established prolidase deficiency were treated for 12 weeks with ointments containing amino acids in an open study comparing the effects of 5% proline and a combination of 5% proline plus 5% glycine. Both ointments caused significant reduction of the ulcer size (p < 0.02), but the 5% proline-5% glycine mixture caused a more rapid reduction (0.01 < p < 0.02). The results confirm previous findings in this rare inborn error of metabolism.     

Prolidase deficiency: a case report and literature review

We describe a patient in whom chronic leg ulceration was due to prolidase deficiency. The clinical features of this condition are described and we discuss the metabolic abnormality and the treatment regimes which have been employed. We also report the further finding of erosive cystitis, which we consider should be added to the list of clinical features of prolidase deficiency.     

Leukocyte Adhesion Deficiency Type 1 Presenting with Recurrent Pyoderma Gangrenosum and Flaccid Scarring

Abstract: We report an 11‐year‐old boy with a longstanding history of recurrent pyoderma gangrenosum and abnormal wound healing who eventually developed a fatal invasive fungal infection. This article emphasizes the importance to consider leukocyte adhesion deficiency type 1 in the differential diagnosis of patients with recurrent skin ulcers.     

Prolidase deficiency in two siblings with chronic leg ulcerations. Clinical, biochemical, and morphologic aspects

Prolidase deficiency occurred in two sisters suffering from recurrent leg ulcers that appeared in early childhood. The patients presented the typical clinical symptoms of the disease, including characteristic facies, dermatologic manifestations of the lower extremities, splenomegaly, and hematologic anomalies. Large amounts of iminodipeptides were excreted into the urine, and prolidase activity in their erythrocytes was virtually absent. Changes associated with a connective-tissue disorder were demonstrated by light and electron microscopic studies of the patients' apparently normal skin. Collagen fibers were smaller than in controls and were irregularly packed; the fibrils had normal aspect but were significantly smaller than in one age-matched control. Elastin fibers appeared altered both in size and structure.     

Wound healing and current dermatologic dressings

Dressings should not be relied upon to heal ulcers. They are ancillary when conditions are otherwise optimal for healing. Thus, before relying on a dressing, wherever possible, causes of ulcers should be eliminated. Arterial, venous, and lymphatic flow should be encouraged and edema controlled. Dressings may, however, modify the etiologic factors contributing to ulceration by protecting against further trauma and counteracting infection. There are now a number of agents which can be applied to ulcers that can modify the capillary bed, either by encouraging the angiogenesis of granulation tissue or promoting capillary flow by discouraging blood cell aggregation, promoting fibrinolysis, or simply by means of support and compression, allowing the venous and lymphatic system to respond to underlying muscle and joint movement. It should be remembered that dressings cannot restore to normal congenital defects such as the absence of valves, nor repair damaged veins, nor provide the necessary agents in diseases of malnutrition, such as scurvy and diabetes mellitus, or in biochemical defects, such as prolidase deficiency. They are unlikely to modify the consequence of circulating immune complexes or neoplasia.     

Corticosteroid treatment of prolidase deficiency skin lesions by inhibiting iminodipeptide-primed neutrophil superoxide generation

We studied the pathogenetic role of iminodipeptides, and the effects of corticosteroids on the skin lesions of two adult female siblings with prolidase deficiency. The elder sister had had severe skin ulcers and mental retardation since childhood, while the younger sister had shown milder clinical manifestations since late adolescence. The ulcers showed vascular wall thickening and neutrophil infiltration. Oral prednisolone at moderate doses was not effective, but corticosteroid pulse therapy followed by a moderate dose of prednisolone improved the preulcerative indurated lesions and ulcers. A 2-year follow-up of the younger patient indicated that N-formyl methionyl leucyl phenylalanine-induced neutrophil superoxide generation was elevated, in parallel with an increase in the serum iminodipeptide level, when the skin ulcers and preulcerative indurated lesions were most active. Corticosteroid pulse therapy downregulated the superoxide generation by neutrophils. The serum iminodipeptide level, however, did not decrease during 25 days after pulse therapy. These findings suggest that iminodipeptides may play an important part in aggravating the skin lesions by priming neutrophil superoxide generation, and that high-dose corticosteroids improve the skin lesions, probably by inhibiting the infiltration, and superoxide generation by, neutrophils. Neutrophil superoxide generation was more prominent in the elder sister, suggesting that clinical severity may depend on the response of neutrophils to the iminodipeptides. Chronic stimulation by superoxide may cause thickening of cerebral blood vessels and eventual mental retardation.     

A homozygous missense mutation in PEPD encoding peptidase D causes prolidase deficiency associated with hyper-IgE syndrome

BACKGROUND: Prolidase deficiency is a complex disease characterized by various skin manifestations accompanied by mental retardation, facial dysmorphism and susceptibility to pyogenic infections. METHODS: We assessed a patient presenting a peculiar phenotype combining manifestations of prolidase deficiency with features typical of hyper-IgE syndrome. Mutation analysis was performed using direct PCR amplification and PCR restriction fragment length polymorphism analysis. RESULTS: We identified a novel homozygous recessive mutation in the PEPD gene, which was found to segregate in the family of the patient with the disease and was not found in a panel of DNA samples representative of all major Druze families living in northern Israel. DISCUSSION: Our results suggest that prolidase deficiency associated with hyper-IgE syndrome, a rare disorder, can be caused by mutations in PEPD.     

Ulcus cruris associated with prolidase deficiency

Prolidase deficiency is an autosomal recessive disorder that is associated with chronic cutaneous ulcers, mental retardation, unusual facial appearance, skeletal deformities, joint dislocations, hematological anomalies, splenomegaly, and chronic infections. The most typical finding is chronic, recurrent leg ulcers appearing in early childhood. Prolidase (peptidase-D) is necessary for collagen biosynthesis and its deficiency leads to impairment in connective tissue of the skin, capillaries, and lymphatic vessels. We report a 33-year-old woman who had a 15-year history of nonhealing ulcer on left pretibial region accompanied by splenomegaly, hypochromic microcytic anemia, and thrombocytopenia. Prolidase deficiency is a rare genodermatosis and must be considered in the differential diagnosis of leg ulcers that develop at an early age.     

Use of Becaplermin for nondiabetic ulcers: pyoderma gangrenosum and calciphylaxis

Large difficult to heal ulcers of various etiologies carry a high morbidity and mortality rate. Becaplermin is a recombinant platelet‐derived growth factor approved for treatment of diabetic ulcers. In this two‐case series, we report the use of becaplermin in the treatment of ulcers due to (i) calciphylaxis, an often fatal condition resulting from systemic calcification and thrombosis of vessels and (ii) pyoderma gangrenosum (PG), a neutrophilic dermatosis. We also report that topical collagenase worsened PG ulcers, consistent with pathergy. Becaplermin can be used to help treat ulcers resulting from calciphylaxis and PG. These encouraging results lend support for the utilization of becaplermin in the treatment of nondiabetic chronic ulcers of various etiologies.     

Alpha‐1‐antitrypsin deficiency‐related panniculitis: two cases with diverse clinical courses

Alpha‐1‐antitrypsin deficiency (AATD)‐related panniculitis is an extremely rare and underdiagnosed entity, and there is a paucity of data on its treatment. We report two cases of AATD‐related panniculitis. The first was a 24‐year‐old woman with known AATD who presented with painful leg ulcers refractory to treatment with corticosteroids and colchicine. She had a good response to α1‐antitrypsin infusions but required dose adjustment due to flares in disease activity. The second case was a 38‐year‐old woman who presented with painful nodules on the legs refractory to corticosteroid therapy. Laboratory investigations revealed severe AATD. She had an excellent response to colchicine therapy. In both these cases of AATD, panniculitis was the first clinical manifestation of the disease. AATD‐related panniculitis may have none of the typical clinical clues for AATD, such as a family history, cirrhosis or emphysema. Early identification may help prevent these complications from developing.     

A case of primary cutaneous peripheral T‐cell lymphoma,not otherwise specified,with cytotoxic phenotype showing multiple ulcers on the entire body

Primary cutaneous peripheral T‐cell lymphoma, not otherwise specified (pcPTCL‐NOS), is a rare, aggressive, fatal type of cutaneous T‐cell lymphoma. The clinical presentation of pcPTCL‐NOS is characterized by generalized plaques, nodules or tumors but ulcers are uncommon. We report an atypical case of pcPTCL‐NOS with cytotoxic protein expression, presenting as multiple ulcers on the entire body. A 48‐year‐old man first presented with pruritic papules on the trunk. The papules gradually increased in number and became ulcerated. We finally diagnosed pcPTCL‐NOS because of diffuse dermal infiltration of medium‐ to large‐sized pleomorphic CD4 positive lymphoid cells. Ulceration suggests infiltration of lymphoid cells expressing cytotoxic proteins, which can induce apoptosis in the epidermis and dermis. Our patient died of bacterial sepsis that invaded from the uncontrollable ulcers. A suspicion of pcPTCL‐NOS is needed when encountering clinical pictures of refractory multiple ulcers and a biopsy should always be performed, because treatment delay may lead to a very poor prognosis.     

Association between venous leg ulcers and sex chromosome anomalies in men

We report here two cases of men, aged 46 and 23 years, with refractory chronic venous leg ulcers in association with sex chromosome aberrations: one with a 47,XXY/48,XXXY karyotype (Klinefelter syndrome) and the other with a 47,XYY karyotype (Jacob syndrome). In both patients, the occurrence of leg ulcers was the reason for seeking medical care; their medical history was other-wise unremarkable. Chromosomal analyses were performed due to the unusually young age for development of venous leg ulcers. The pathophysiology behind the occurrence of venous leg ulcers in patients with numerical aberrations of the sex chromosomes is incompletely understood. Involvement of elevated plasminogen activator inhibitor-1 levels in the pathogenesis of venous leg ulcers has been reported in patients with Klinefelter syndrome. Notably, our patient with 47,XXY/48,XXXY presented with androgen deficiency but normal plasminogen activator inhibitor-1 activity.     

Pressure ulcers induced by drug administration: A new concept and report of four cases in elderly patients

Drug‐induced akinesia is a potential cause of pressure ulcers. However, pressure ulcers that are caused by drug‐induced akinesia are not considered an adverse drug reaction (ADR). We propose that drug‐induced pressure ulcers (DIPU) are pressure ulcers that are caused by an external force that is experienced after drug administration, and we considered resolution of these ulcers after drug discontinuation to be a supportive finding. In this report, we reviewed the medical records of pressure ulcer cases from a 300‐bed hospital. Among 148 patients, four patients with pressure ulcers met the criterion for DIPU. In these cases, the suspected DIPU were related to treatment with olanzapine, fluvoxamine, valproic acid, clotiazepam, triazolam and rilmazafone. These drugs were administrated to manage the patients' behavioral and psychological symptoms that accompanied dementia. The DIPU in these patients were categorized as stage IV according to the National Pressure Ulcer Advisory Panel criteria. Discontinuation of the causal drugs led to significant improvements or complete healing of the pressure ulcers, and the patients subsequently recovered their mobility. Therefore, we propose that DIPU are potential ADR that have been overlooked in clinical practice. Thus, recognition of DIPU as an ADR may be important in preventing and appropriately managing pressure ulcers among elderly patients.     

Blood transfusions in the therapy of a case of prolidase deficiency

A case is reported of a 15-year-old boy with prolidase deficiency and marked urinary excretion of the iminodipeptide gly-pro. Prolidase activity of erythrocytes against substrate glycyl-proline was deficient, but after blood transfusions this was increased to 15.7% of donor activity and declined to 12% and 3.4% of normal activity after 8 and 45 days, respectively. Urinary iminodipeptide levels following transfusion remained unaltered.     

Bullous pyoderma gangrenosum of the bilateral dorsal hands

Pyoderma gangrenosum (PG) shows characteristic non‐infectious ulcers that are commonly associated with systemic diseases such as inflammatory bowel diseases, myeloproliferative disorders or aortitis syndrome. The typical clinical appearance is undermining ulcers with reddish and irregular borders on the legs. As PG has these notable signs, the diagnosis is relatively easy and its treatment depends on the severity of underlying complications. We report a case of a 60‐year‐old Japanese man, diagnosed with bullous PG, who also had been suffering from myeloperoxidase antineutrophil cytoplasmic antibody‐positive microscopic polyangiitis and pulmonary aspergillosis. This case displayed soft whitish ulcers that existed on the rough ulcer base, with irregular borders, on his bilateral dorsal hands. Initially, it seemed to be cutaneous secondary aspergillosis because the host was already infected with pulmonary aspergillosis in both lungs. The differential diagnosis of PG from aspergillosis was from the sterile bullae or neutrophilic bullae on his right forearm, which evolved into ulcers in a few days. This case was finally diagnosed as bullous PG and a topical glucocorticoid was very effective to epithelize the ulcers in 2–3 weeks.