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Prolidase Deficiency Causing Recalcitrant Leg Ulcerations in Siblings

Hajjar, Nancy MD; Kabbani, Mariam MD; Tannous, Rim MD; Lebre, Anne-Sophie PhD, PharmD; Megarbane, Andre MD, PhD; Minari, Afaf MD; El Sayed, Fouad MD

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Advances in Skin & Wound Care: November 2021 - Volume 34 - Issue 11 - p 1-4
doi: 10.1097/01.ASW.0000792912.44120.64
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Prolidase deficiency (PD) is an autosomal recessive disorder with approximately only 100 cases reported worldwide.1–3 The peptidase-D (PEPD) gene located on chromosome 19q13.11 encodes prolidase, an important enzyme in collagen catabolism, whose deficiency results in various clinical manifestations including chronic leg ulcerations, facial dysmorphism, intellectual disability, and recurrent skin and pulmonary infections. The diagnosis can be confirmed either by decreased prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts combined with imidodipeptiduria or by the identification of a pathogenic PEPD gene variant.4 There exists neither cure nor consensus about treatment for this disorder.1,5,6

Herein, the authors report the case of two siblings born from healthy consanguineous parents where the diagnosis of PD was suspected and confirmed genetically. Informed consent was obtained from the patients to publish their photographs and report the case details.


Two patients, a brother and sister from consanguineous parents, presented to a dermatology clinic in Beirut, Lebanon, with recalcitrant leg ulcerations of several years’ duration.

Patient 1 was a 35-year-old man who, at the age of 15 years, started developing leg ulcerations resistant to standard wound care. His medical history spanned many years of frequent hospitalizations for repeated ulcer infections, with cultures revealing different types of organisms including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus.

On examination, he had multiple erosions and ulcerations on the dorsolateral aspect of the feet and the extensor surfaces of both legs. Providers also noted hypopigmented and hyperpigmented areas healing with radial scars (Figure 1).

Figure 1
Figure 1:
PATIENT 1 MULTIPLE LOWER LIMB ULCERSImage printed with patient consent.

Extensive workups were performed with noteworthy results including hypochromic microcytic anemia, thrombocytopenia, iron deficiency, and increased erythrocyte sedimentation rate. The patient’s metabolic panel was normal, as were his thyroid function tests and antinuclear antibody and antineutrophil cytoplasmic antibody levels. A serum protein electrophoresis showed mild hypoalbuminemia, a mild increase in the acute phase reactants in the α region, and a mild increase in γ globulins. A bone marrow aspirate revealed hypocellular bone marrow. A perilesional skin biopsy showed nonspecific findings consisting of dermal and epidermal necrosis with neutrophilic infiltrate (Figure 2). Based on these findings, providers prescribed oral corticosteroids and administered two 1-week courses of IV immunoglobulin therapy 8 months apart for suspected pyoderma gangrenosum without significant improvement.

Figure 2
Figure 2:
LEG SKIN BIOPSYHematoxylin-eosin stain (high power) showing focal superficial epidermal and dermal necrosis and dense neutrophilic deep infiltrate.

Doppler ultrasound during the first hospital admission showed no evidence of venous thrombosis but revealed diffuse atherosclerotic changes in both lower limbs. Arteriography confirmed the presence of mild to moderate stenosis (<50%) in the anterior tibial artery. In addition, an abdominal ultrasound revealed a moderately enlarged liver and an increase in spleen size. Moreover, a full body X-ray showed congenital C2 to C3 fusion of vertebral bodies, Schmorl’s nodes in the vertebral endplates of L2 and L3, and right acetabular dysplasia. Chest X-ray was normal.

Patient 2 was a 30-year-old woman whose clinical history parallels that of patient 1 but with a relatively later onset of ulcerations at 20 years. Her examination revealed similar ulcerations, scarring, and dyspigmentation to patient 1 but restricted to the dorsum of both feet. Her laboratory findings were similar to her brother. Arteriography showed the presence of a mild to moderate stenosis (<50%) in the proximal and distal portions of right and left superficial femoral arteries.

Both patients shared similar dysmorphic features, although these were more prominent in patient 1. They both had oval heads with prominent foreheads, low-set ears, depressed nasal bridges, proptosis, hypertelorism, everted lower lips, and micrognathia (Figure 3). They also suffered from mild intellectual disability.

Figure 3
Figure 3:
PATIENT 1 FACIAL DYSMORPHIC APPEARANCEImage printed with patient consent.

The painful, recalcitrant ulcerations combined with dysmorphic features and cognitive impairment in siblings with consanguineous parents prompted the authors to consider a PD diagnosis. Sanger sequencing of the PEPD gene was performed for patient 1. A known pathogenic variant in intron 7, c.549-1G > A, was found at the homozygous state.7

As a targeted approach, an ointment with 5% proline and 5% glycine was compounded, and the patients were instructed to apply it to the ulcers once daily. A follow-up visit after 8 months revealed partial improvement of the ulcerations starting from the 3rd month of treatment.


Prolidase deficiency is an inborn error of collagen synthesis.6 During collagen turnover, prolidase cleaves the imidodipeptides containing proline and hydroxyproline.3,4,6 Accordingly, PD leads to high levels of circulating imidodipeptides that interfere with collagen synthesis.3,4,6 Moreover, PD may be accompanied by vasculopathy and thrombus formation.7 Although the underlying mechanisms are not fully elucidated, the occasional association with hypergammaglobulinemia and antinuclear antibodies may prove a valid explanation.7 Further, and in addition to the abnormal collagen synthesis in small vessels, reported elevated levels of fibrinogen and proinflammatory markers may be responsible for thrombophilia.7

Clinically, PD is a heterogeneous disorder with an autosomal recessive transmission, which explains the increased risk of this genodermatosis as a result of consanguinity. It has variable penetrance and expressivity ranging from lack of symptoms to leg amputations and even death from skin and pulmonary infections, and this likely accounted for the differences in disease presentation between siblings in this case report.1,5 The most common dermatologic finding is chronic painful ulcerations usually appearing at a young age (6 months to 30 years).5 They are located primarily on the feet with lesser involvement of the upper extremities.5 These ulcers are typically resistant to standard wound care and take months to years to heal.5,6 Other skin findings may include telangiectasia of the face and hands, eczema-like lesions, lymphedema, premature graying of hair, and phototoxicity.3,5 Several cases of systemic lupus erythematosus have been reported in association with PD.5,8,9 Dysmorphic facial features, although not a constant finding, are frequently reported.3–5

Neurologic manifestations include intellectual disability in 75%, developmental delays, and white matter microthrombi on brain MRI.5 In terms of pulmonary findings, recurrent pneumonia, asthma-like manifestations, and bronchiectasis can be found.5 Bone anomalies were also reported in a patient with suspicion of PD but without molecular diagnosis.5

Laboratory findings are not universal, but a characteristic of this disease is massive imidodipeptiduria (10-30 mmol/d).5 Other disturbances may include mild thrombocytopenia, elevated liver enzymes, hypocomplementemia, elevated immunoglobulin E levels,5,8,9 and mild anemia, which can be either microcytic or normocytic with reports of hemolysis.5,8,9

There are two possible ways to confirm the diagnosis of PD.4,5 The first depends on the combination of elevated imidodipeptides in the urine and a low prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts (ranges from none to less than 10% in affected individuals).4,5 The second method is detecting biallelic pathogenic variants of the PEPD gene on chromosome 19.4,5

There is no cure for PD.5,9 Attempted treatments reported in the literature vary, as do their results. Topical proline and glycine ointments, with concentrations ranging from 2.5% to 5%, have been used with differing results.3,4,9 Given the relative lack of adverse reactions to topical treatment compared with other systemic medications, along with the positive results seen in some reports, the authors opted to use an ointment with 5% proline and 5% glycine. In contrast, oral intake of proline does not appear to be beneficial, whereas supplementation with oral manganese and ascorbic acid has inconsistent results.3,9 As for immunosuppressive therapy, data on pulse systemic corticosteroids are limited; topical tacrolimus was successful in one report.3,6 Hyperbaric oxygen also showed potential benefits.6 Another case associated with antiphospholipid syndrome was successfully treated with a combination of aspirin, oral vitamin C, and hydroxychloroquine, supporting a potential role of vasculopathy in the pathogenesis of PD.8 Recently, anticoagulant treatment with enoxaparin yielded promising results, which the authors attributed to the inhibition of prolidase proteolysis by enoxaparin.7


Prolidase deficiency is an autosomal recessive disorder with variable clinical manifestations. Although rare, it is underdiagnosed and seldom considered when addressing the cause of leg ulcerations. In fact, the Quebec Newborn Urine Screening Program estimates an incidence of 1:1,235,000; this statistic stands in stark contrast to the few cases reported.5 Accordingly, 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.


1. Spodenkiewicz M, Spodenkiewicz M, Cleary M, et al. Clinical genetics of prolidase deficiency: an updated review. Biology (Basel) 2020;9:108.
2. Wilk P, Wątor E, Weiss MS. Prolidase—a protein with many faces. Biochimie 2020;S0300-9084(20):30223–6.
3. Adışen E, Erduran FB, Ezgü FS, et al. A rare cause of lower extremity ulcers: prolidase deficiency. Int J Low Extrem Wounds 2016;15:86–91.
4. Koechel A, Fink C, Schäkel K. Prolidase deficiency in two sisters with recurrent ulcerations of the lower extremities. J Dtsch Dermatol Ges 2017;15:1142–3.
5. Ferreira C, Wang H. Prolidase deficiency. GeneReviews 2015. Last accessed August 9, 2021.
6. Good AJ, Nielson CB, Schoch JJ. Topical tacrolimus therapy in the management of lower extremity ulcers due to prolidase deficiency. Pediatr Dermatol 2019;36:926–8.
7. Süßmuth K, Metze D, Muresan AM, et al. Ulceration in prolidase deficiency: successful treatment with anticoagulants. Acta Derm Venereol 2020;100:adv00002.
8. Razmi TM, Jindal AK, Arora K, Joshi V, Suri D, De D. Refractory leg ulcers in prolidase deficiency with antiphospholipid antibody positivity responding to aspirin-hydroxychloroquine-vitamin C combination therapy. Dermatol Ther 2020:e14156.
9. Lsazade A, Elçin G, Doğan S, et al. A rare cause of cutaneous ulceration: prolidase deficiency. Int Wound J 2019;16:1057–8.

collagen; genes; leg; prolidase deficiency; mutation; siblings; ulcers; wound care

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