Human DNA-dependent protein kinase catalytic subunit deficiency: A comprehensive review and update.

BACKGROUND: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non-homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in Prkdc define the Scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far. OBJECTIVES: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human. METHODS: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material. RESULTS: We report on 7 patients; 6 patients displayed the autosomal recessive p.L3062R mutation in PRKDC-encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n = 5 of 7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naive CD4+CD45RA+ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values, naive CD4+CD45RA+ T cells decreased over time (n = 5 of 6). Hematopoietic stem cell transplantation was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was observed, respectively, for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 years). CONCLUSIONS: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.

Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome.

BACKGROUND: The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated. OBJECTIVE: We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent. METHODS: We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4+ or DN T cells. RESULTS: We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations. CONCLUSIONS: The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.

Real-world experience with CLAIRYG® 50 mg/mL (intravenous immunoglobulin) in children under 12 years with primary immunodeficiency or immmune thrombocytopenia: a post-approval safety study.

Introduction: This study presents the results of a real-life, multicenter, prospective, post-approval safety evaluation of Clairyg® 50 mg/mL, a 5% intravenous immunoglobulin (IVIg) liquid, in 59 children (aged < 12 years) with primary immunodeficiency diseases (PID) (n = 32) or immune thrombocytopenia (ITP) (n = 27) in France. Methods: The primary objective of the study was to assess the safety and tolerability of Clairyg®, recording all serious and non-serious adverse events (AEs), whether related (rAEs) or not related to the product. Secondary objectives aimed at evaluating the administration of Clairyg® under routine conditions and the available efficacy data to better document the benefit/risk ratio in this pediatric population. An exploratory objective was added to evaluate the potential factors associated with the occurrence of rAEs. Patients received Clairyg® according to the approved dosage under normal conditions of prescriptions over a median follow-up period of 11.8 months. Results: A total of 549 infusions (PID: n = 464 and ITP: n = 85), were administered, of which 58.8% were preceded by premedication. The most frequent rAEs were headache, vomiting, and pyrexia in both indications. Most of them were considered non-serious and mild or moderate in intensity. A severe single rAE was observed (aseptic meningitis) in a 4-year-old girl presenting with chronic ITP. The exploratory multivariate analysis of potential co-factors showed that the occurrence of rAEs is significantly linked to high IVIg doses and possibly to female gender. The annualized rate of serious bacterial infections was 0.11 for patients with PID. For patients with ITP, 74.1% experienced at least one bleeding episode during the follow-up, mostly a cutaneous one, and none had gastrointestinal, genitourinary, or central nervous system bleeding. Conclusion: Clairyg® was well tolerated and allowed for control of serious bacterial infection in PID and serious bleeding in ITP, which are the main complications in these respective pediatric disorders. No new safety signal was detected in children less than 12 years-old in real-life conditions of use.

[Triose phosphate isomerase deficiency: a rare erythrocyte enzymopathy with a poor prognosis]. / Le déficit en triose phosphate isomérase : une enzymopathie érythrocytaire rare et de pronostic sombre.

Triose phosphate isomerase (TPI) is a crucial enzyme for glycolysis. TPI deficiency is an autosomal recessive metabolic disease described in 1965, which remains exceptional by its rarity (less than 100 cases described worldwide), but by its extreme severity. Indeed, it is characterized by a chronic hemolytic anemia, an increased susceptibility to infections and especially, a progressive neurological degeneration which leads to death in early childhood for the majority of cases. We report in our observation the history of diagnosis and clinical course of monozygotic twins born at 32 WA with triose phosphate isomerase deficiency.

Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination.

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.

Allogeneic stem cell transplantation compared to conservative management in adults with inborn errors of immunity.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged ≥ 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de Référence Déficits Immunitaires Héréditaires registry was identified blindly for case-control analysis, with ≤3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.

The role of irinotecan-bevacizumab as rescue regimen in children with low-grade gliomas: a retrospective nationwide study in 72 patients.

INTRODUCTION: At least half of children with low-grade glioma (LGG) treated with first line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to define the efficacy, toxicity and predictors for response to the combination on a larger cohort. METHODS: We reviewed the files from children < 19 years of age with progressive or refractory LGG treated between 2009 and 2016 in 7 French centers with this combination. RESULTS: 72 patients (median age 7.8 years [range 1-19]) received a median of 16 courses (range 3-30). The median duration of treatment was 9 months (range 1.4-16.2). 96% of patients experienced at least disease stabilization. The 6-month and 2-year progression-free survivals (PFS) were 91.7% [IC 95% 85.5-98.3] and 38.2% [IC 95% 28.2-51.8] respectively. No progression occurred after treatment in 18 patients with a median follow-up of 35.6 months (range 7.6-75.9 months). Younger patients had a worse PFS (p = 0.005). Prior chemoresistance, NF1 status, duration of treatment, histopathology or radiologic response did not predict response. The most frequent toxicities related to bevacizumab included grades 1-2 proteinuria in 21, epistaxis in 10, fatigue in 12 and hypertension in 8 while gastro-intestinal toxicity was the most frequent side effect related to irinotecan. CONCLUSIONS: Bevacizumab-irinotecan has the potential of disease control clinically and radiographically in children with recurrent LGG whatever their previous characteristics; in many cases however these responses are not sustained, especially in younger children.

Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.

Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IM). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 years (range, 6.8-50.0 years) and the median follow-up period was 11.3 years (range, 5.1-38.0 years). At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IM increased with age: at the age of 20 years, 74% had at least one clinical IM (cIM). A wide range of cIM occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IM. The number of cIM was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio 1.4, 95% Confidence Interval: 1.15-1.60, P=0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 years (range, 1.7-31.5 years), and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, long-term outcomes of pES showed remission of cytopenias but frequent IM linked to high second-line treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.

What does a non-response to induction chemotherapy imply in high-risk medulloblastomas?

PURPOSE: High-risk medulloblastomas (HR-MB) may not respond to induction chemotherapy, with either post-induction stable (SD) or progressive disease (PD). There is no consensus regarding their optimal management. METHODS: A retrospective, multicentre study investigated patients with non-responder HR-MB treated according to the PNET HR + 5 protocol (NCT00936156) between 01/01/2009 and 31/12/2018. After two courses of etoposide and carboplatin (induction), patients with SD or PD were analyzed. Upon clinician's decision, the PNET HR + 5 protocol was either pursued with tandem high-dose chemotherapy (HDCT) and craniospinal irradiation (CSI) (continuation group) or it was modified (switched group). RESULTS: Forty-nine patients were identified. After induction, 37 patients had SD and 12 had PD. The outcomes were better for the SD group: the 5-y PFS and OS were 52% (95% CI 35-67) and 70% (95% CI 51-83), respectively, in the SD group while the 2-y PFS and OS were 17% (95% CI 3-41) and 25% (95% CI 6-50), respectively, in the PD group (p < 0.0001). The PNET HR + 5 strategy was pursued for 3 patients in the PD group, of whom only one survived. In the SD group, it was pursued for 24/37 patients whereas 13 patients received miscellaneous treatments including a 36 Gy CSI in 12 cases. Despite that continuation and switched group were well-balanced for factors impacting the outcomes, the latter were better in the continuation group than in the switched group: the 5-y PFS were 78% (95% CI 54-90) versus 0% (p < 0.001), and the 5-y OS were 78% (95% CI 54-90) versus 56% (95% CI 23-79) (p = 0.0618) respectively. In the SD group, multivariate analysis revealed that MYC amplification, molecular group 3, and a switched strategy were independent prognostic factors for progression. CONCLUSION: Patients with post-induction SD may benefit from HDCT and CSI, whereas patients with early PD will require new therapeutic approaches.

Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma.

BACKGROUND: New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation. METHODS: This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922). RESULTS: Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m2 weekly for vinblastine with 230 mg/m2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7-29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9-23.7), and the disease control rate was 85.3% (95% CI, 68.9-95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2-53.67). CONCLUSIONS: Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.

Second-line treatment trends and long-term outcomes of 392 children with chronic immune thrombocytopenic purpura: the French experience over the past 25 years.

Childhood chronic immune thrombocytopenic purpura (cITP) is a rare disease. In severe cases, there is no evidence for the optimal therapeutic strategy. Our aim was to describe the real-life management of non-selected children with cITP at diagnosis. Since 2004, patients less than 18 years old with cITP have been enrolled in the national prospective cohort, OBS'CEREVANCE. From 1990 to 2014, in 29 centres, 392 children were diagnosed with cITP. With a median follow-up of six years (2·0-25), 45% did not need second-line therapy, and 55% (n = 217) received one or more second lines, mainly splenectomy (n = 108), hydroxychloroquine (n = 61), rituximab (n = 61) or azathioprine (n = 40). The overall five-year further second-line treatment-free survival was 56% [95% CI 49·5-64.1]. The use of splenectomy significantly decreased over time. Hydroxychloroquine was administered to children with positive antinuclear antibodies, more frequently older and girls, and reached 55% efficacy. None of the patients died. Ten years after the initial diagnosis, 55% of the 56 followed children had achieved complete remission. Children with cITP do not need second-line treatments in 45% of cases. Basing the treatment decision on the pathophysiological pathways is challenging, as illustrated by ITP patients with positive antinuclear antibodies treated with hydroxychloroquine.

Spinal cord atypical teratoid/rhabdoid tumors in children: Clinical, genetic, and outcome characteristics in a representative European cohort.

BACKGROUND: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT. METHODS: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3). RESULTS: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation. CONCLUSIONS: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.

Deletion of chr7p22 and chr15q11: Two Familial Cases of Immune Deficiency: Extending the Phenotype Toward Dysimmunity.

Background: We report here two new familial cases of associated del15q11 and del7p22, with the latter underlining the clinical variability of this deletion. Two siblings patients presented a similar familial imbalanced translocation, originating from a balanced maternal translocation, with deletions of 7p22 and of 15q11 [arr[GRCh37] 7p22.3-p22.2(42976-3736851)x1, 15q11.1-q11.2(20172544-24979427)x1]. Methods: We used aCGH array, FISH, and karyotype for studying the phenotype of the two patients. Results: The 7p22 deletion (3.5 Mb) contained 58 genes, including several OMIM genes. Patients 1 and 2 exhibited acquisition delays, morphological particularities, and hypogammaglobulinemia, which was more severe in patient 1. Patient 1 presented also with cerebral vasculitis. Conclusion: We discuss here how the PDGFa, CARD11, LFNG, GPER1, and MAFK genes, included in the deletion 7p22, could be involved in the clinical and biological features of the two patients.

Genotype/phenotype correlations of childhood-onset congenital sideroblastic anaemia in a European cohort.

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23·3%) and SLC25A38 (n = 8; 18·6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited B-cell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.

Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes.

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study.

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

Burden of Poor Health Conditions and Quality of Life in 656 Children with Primary Immunodeficiency.

OBJECTIVE: To gain insight into how primary immunodeficiencies (PIDs) affect children's health status and quality of life. STUDY DESIGN: The French Reference Center for PIDs conducted a prospective multicenter cohort that enrolled participants who met all criteria: patients included in the French Reference Center for PIDs registry, children younger than18 years, and living in France. Participants were asked to complete both a health questionnaire and a health-related quality of life (HR-QoL) questionnaire. A severity score was assigned to each health condition: grade 1 (mild) to grade 4 (life-threatening). HR-QoL in children was compared with age- and sex-matched French norms. RESULTS: Among 1047 eligible children, 656 were included in the study, and 117 had undergone hematopoietic stem cell transplantation; 40% experienced at least one grade 4 condition, and 83% experienced at least one grade 3 or 4 condition. Compared with the French norms, children with PID scored significantly lower for most HR-QoL domains. Low HR-QoL scores were associated strongly with burden of poor conditions. CONCLUSIONS: Our results quantify the magnitude of conditions in children with PID and demonstrate that the deleterious health effects borne by patients already are evident in childhood. These results emphasize the need to closely monitor this vulnerable population and establish multidisciplinary healthcare teams from childhood. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02868333 and EudraCT 2012-A0033-35.