IntroductionWhile Systemic Lupus Erythematosus (SLE) typically presents with a multifactorial etiology, rare monogenic forms exist, usually diagnosed during childhood with a severe clinical course. This study aims to identify monogenic causes of SLE within the pediatric population of Northern Israel and to suggest criteria for genetic evaluation in patients with childhood-onset SLE.MethodsClinical and genetic data were collected from a single tertiary pediatric medical center in Israel, between 2010 and 2021. Patients diagnosed with SLE before the age of 18 years were enrolled in the study. Monogenic SLE was suspected in patients with any of the following criteria: (1) family history of SLE, (2) consanguinity, (3) early onset of symptoms (under 10 years), (4), atypical clinical course, (5) male gender, (6) syndromic features. Genetic evaluations were performed for these patients.ResultsSeventy-five patients were diagnosed with SLE, of whom 18 (24%) met the criteria for suspected monogenic SLE. Genetic evaluations were conducted for 13 out of the 18 patients (72%) leading to a diagnosis of a monogenic form of SLE in 6 of the 13 patients (46%), and total of 8% from the entire cohort. Four patients were diagnosed with prolidase deficiency, one patient with Aicardi-Goutières syndrome (AGS) and one patient with Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) syndrome. Additionally, candidate variants in C4B and ITPR3 genes were detected in an additional pedigree.ConclusionsMonogenic SLE was identified in 46% of the children within this selected cohort. A genetic diagnosis can yield direct clinical implications and enhance our understanding of the mechanisms involved in the more common sporadic forms of SLE.

Prolidase deficiency (PD) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the PEPD gene, which is responsible for making prolidase and collagen resynthesize. It leads to a wide range of clinical symptoms, including skin ulcers, intellectual disability, and recurrent infections. Diagnostics are based on the presence of dipeptides in the urine and prolidase activity in various cells, as well as the detection of the pathogenic variant in the PEPD gene; however, no standard method is currently known for its diagnosis nor for its treatment. Case 1 presents a 17-year-old male with dyspnea, cyanosis, and pulmonary arteriovenous malformations (AVMs), an atypical presentation for PD. Case 2, a one-year-old female with fever, seizures, productive coughs, erythematous ulcers, and developmental delays, highlights the disease's broad symptoms. This study widens our understanding of PD, especially for lesser-known populations, such as the population in Iran. It indicates considering PD in the differential diagnosis of various diseases and also a global collaboration for managing PD. The study also recommends a standard approach to diagnosing PD and a personal management system due to its broad manifestations. In addition, it indicates the need to consider different ethnic and geographical groups in future PD studies to further enhance our understanding of this rare disease.

Objective: Prolidase deficiency is a metabolic and immunological disorder that is inherited in an autosomal recessive manner. In prolidase deficiency, a broad spectrum of differences is observed in patients, ranging from asymptomatic to multisystem involvement. There is scarce information in the literature on the atypical features and immunophenotypes of this disease. Aim of this study is to present 4 new cases to provide information on the rare features of the disease and to raise awareness. Materials and Methods: This study included 4 female patients with prolidase deficiency. Their demographic, clinical, and immunologic characteristics were obtained from their medical records. Results: There were 4 female patients (P1-P4), with a mean age of 18.5 years (min-max: 10-29) and a mean age of symptom onset of 6.9 years (min-max: 0.04-27). The main presenting complaints of the patients were skin lesions (100%), dysmorphic features (100%), neurodevelopmental delay (100%), frequent infections (100%), and prolonged diarrhea (50%). P2 had diffuse large B-cell lymphoma, resulting in early death. Interestingly, P1 and P2 experienced opportunistic infections such as cytomegalovirus, Epstein-Barr virus, and Pneumocystis jirovecii. Three patients (75%) had lymphopenia. Two patients had elevated IgE levels. Lymphocyte subgroup analysis showed an inverted CD4/CD8 ratio in all patients. In patients P1 and P2, the percentages of naive T cells and recent thymic emigrants were reduced, suggesting combined immune deficiency at the time of diagnosis. CD19+ B cells were also low in P1 and P2. Metabolic evaluations revealed low prolidase enzyme activity in P1 and P2. Conclusion: Beyond the well-known classical dermatological findings, the presence of recurrent opportunistic infections, gastrointestinal involvement, malignancy, and flow cytometry findings suggestive of combined immunodeficiency indicate that the diagnosis of prolidase deficiency may be underestimated. Knowing the atypical and rare presentations will facilitate diagnosis and treatment of affected patients.

Prolidase deficiency (PD) is a rare autosomal recessive disorder affecting collagen turnover, leading to diverse clinical manifestations including dermatologic lesions, hepatosplenomegaly, and vascular anomalies. Liver involvement in PD is poorly understood, with few reported cases. We present a child with early-onset non-cirrhotic portal hypertension and PD. The patient initially presented with neonatal hemolytic anemia and hepatosplenomegaly. At age 9, recurrent epistaxis and splenomegaly led to splenectomy. Liver biopsy revealed sinusoidal dilation and parenchymal nodularity, later progressing to esophageal varices. Genetic testing identified pathogenic variants in peptidase-D gene, suggestive of PD, and biochemical testing confirmed the diagnosis. Given suspected vasculopathy, tocilizumab was initiated with clinical improvement. This case suggests a potential link between PD and porto-sinusoidal vascular disorder (PSVD), particularly nodular regenerative hyperplasia. Further research is needed to explore prolidase's role in vascular remodeling and its contribution to PSVD-related liver pathology. Early recognition may improve management and outcomes.

Prolidase deficiency (PD) is an autosomal recessive inborn error of metabolism, with an estimated incidence of 1 per 1.25 million births. Prolidase is critical for the turnover of proline and hydroxyproline-rich proteins, such as collagen. Collagen metabolism is essential for matrix regeneration during cellular proliferation and complex bodily functions such as wound healing and immunological cell differentiation. PD clinical manifestations include persistent skin ulcerations and poor wound healing, hypertelorism, high arched palate, depressed nasal bridge, micrognathia, splenomegaly, intellectual disability, recurring infections, and hematological abnormalities. Biochemically, a diagnosis of PD is supported by increased urinary excretion of glycyl-proline and other proline-containing iminopeptides detected by amino acid analysis. There are no current targeted therapies, but suggested interventions have included topical proline-glycine ointment, manganese supplementation, topical and oral steroids, and immunomodulation with monoclonal antibodies. Here, we describe a 30-year-old patient with PD whose clinical course has been characterized by recurrent skin ulcerations/cysts with secondary scarring, recurrent infections, anemia, thrombocytopenia, lymphopenia, elevated liver enzymes, hirsutism, and seemingly unrelated papillary thyroid cancer. Skin manifestations were particularly severe due to the added complication of a diagnosis of hidradenitis suppurativa. Quantitative analysis of amino acids and related compounds revealed markedly elevated glycyl-proline in urine and plasma. To further characterize the biochemical phenotype, untargeted metabolomic analysis was sent on both plasma and urine. An increase was noted in several metabolites from the prolidase-dependent dipeptide recycling pathways. A better understanding of the pathophysiological mechanisms involved in prolidase deficiency may prove useful as different therapeutic approaches are being considered.