Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases

Abstract

Purpose: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature.

Methods: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival.

Results: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old.

Conclusion: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.

Figure 1:

Flow diagram of the systematic review of the literature.

Figure 2:. Clinical characteristics of prolidase deficiency.

A-G: Facial features of patients 7, 8, 10, 11, 12 (E & F) and 14, respectively, including in some a high and/or prominent forehead, hypertelorism, epicanthal folds, ptosis, a low nasal root and/or hypoplastic alae nasi. H-J: Evolution of a typical ulcer, from onset (H) to final stages (J) (patient 12). K-R: Dermatologic manifestations, including pityriasis rubra pilaris (K, patient 14), pigmentary changes (L, patient 8), ulcers of variable severity (M, patient 9; N-O, patient 5), hyperkeratosis and distal erythema (P, patient 5), hirsutism with folliculitis (Q, patient 5) and telangiectasias (R, patient 14).

Figure 3:. Clinical manifestations (A-B), age of onset (C) and survival (D-G) analyses.

A-B: Main clinical manifestations reported at onset (A) and overall (B). C: Linear regression model, including the observed slope (solid line) and the theoretical slope (dashed line) of diagnostic delay. D-G: Overall survival (D), symptom-free survival (E), and ulcer-free survival for the entire cohort (F) and for missense and loss-of-function variants (G).